A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs. Single Agent Nivolumab for the Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age Groups
Phase: PHASE2
Conditions: Metastatic Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, TFE3-Rearranged Renal Cell Carcinoma, Unresectable Renal Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Chief Operating Officer 
Elizabeth O’Connor, MPH 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, MS 
crabtreed@email.chop.edu 
 
Group Administration Office 
Children’s Hospital of 
Philadelphia Research Institute 
Roberts Center for Pediatric  
Research 
2716 South Street 
14th Floor, RC#14251 
Philadelphia, PA 19146-2305 
P 215 590 6354 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
800 Royal Oaks Drive 
Suite 210 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
SDC Gainesville Office 
6011 NW 1st Place 
Suite 10 
Gainesville, FL 32607 
P 352 273 0566 
F 352 392 8162 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
December 14, 2021 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #5A to protocol AREN1721, A Randomized Phase 2 
Trial of Axitinib/Nivolumab Combination Therapy vs. Single Agent Nivolumab for the 
Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age Groups.  
 
This amendment is being done to include proposed language from a stipulation in the 
PedCIRB’s Continuing Review of AREN1721. 
 
Minor administrative updates have been made; specific changes are detailed in the 
Summary of Changes table below.  
 
 
Please let me know if you have any questions or need additional information. 
 
Sincerely, 
 
 
Kathryn Franklin Protocol Coordinator (for) 
James Geller, MD, AREN1721 Study Chair,  
Jeff Dome, Interim Renal Committee Chair, and 
Douglas S. Hawkins, MD, COG Group Chair 
 

AREN1721 
Version Date: 12/14/2021 
 
 Page 1 
 
Activated: 
10/9/2018 
Version Date: 
12/14/2021 
Closed: 
      
Amendment #: 5A 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
AREN1721 
 
 
A Randomized Phase 2 Trial of Axitinib/Nivolumab Combination Therapy vs. Single Agent 
Nivolumab for the Treatment of TFE/Translocation Renal Cell Carcinoma (tRCC) Across All Age 
Groups 
 
An Intergroup NCTN Phase 2 Study 
 
Open to Institutions within the United States 
 
 
NCI Supplied Agents: Axitinib (NSC# 757441, IND# 
), Nivolumab (NSC# 748726, IND# 
) 
IND sponsor for Axitinib and Nivolumab: DCTD, NCI 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A 
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO 
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED 
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE 
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN 
THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, 
AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL 
CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST 
LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
James Geller, MD 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue 
MLC 7015 
Cincinnati, OH 45229 
Phone: (513) 636-6312 
Fax: 
(513) 636-3549 
E-mail: James.Geller@cchmc.org 
 
 
 

AREN1721 
Version Date: 12/14/2021 
 
 Page 2 
 
 
Participating Organizations 
 
COG / Children's Oncology Group 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
Study Champion: Ana Molina, MD 
amm9052@med.cornell.edu 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
Study Champion: Matthew Zibelman, MD 
Matthew.Zibelman@fccc.edu 
 
NRG / NRG Oncology  
 
SWOG / SWOG 
Study Champion: Mamta Parikh, MD, MS 
mbparikh@ucdavis.edu  
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
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 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 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_SYSTEM/ 
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 Schedule in the 
CRF packet for further 
instructions.  
 
 
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. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 

AREN1721 
Version Date: 12/14/2021 
 
 Page 3 
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. 
 
 

 
 
 
 
AREN1721 
 
Version Date: 12/14/2021 
 
 Page 4 
TABLE OF CONTENTS 
SECTION 
PAGE 
TABLE OF CONTENTS 
4 
STUDY COMMITTEE 
7 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aim 
11 
1.2 
Secondary Aim 
11 
1.3 
Exploratory Aims 
11 
2.0 
BACKGROUND 
11 
2.1 
Introduction/Rationale for Development 
11 
2.2 
Adult Studies 
13 
2.3 
Pediatric Studies 
15 
2.4 
Immune Biomarkers 
16 
2.5 
Dosing Rationale 
16 
2.6 
Pharmacokinetics Studies (Effective with Amendment 5A) 
17 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
17 
3.1 
Study Enrollment 
17 
3.2 
Patient Eligibility Criteria 
21 
4.0 
TREATMENT PROGRAM 
27 
4.1 
Overview of Treatment Plan 
27 
4.2 
Concomitant Therapy 
28 
4.3 
Arm A: Axitinib + Nivolumab 
30 
4.4 
Arm B: Axitinib (For patients enrolled and randomized to Arm B prior to Amendment 
2A) Closed to new accrual with Amendment 2A 
35 
4.5 
Arm C: Nivolumab 
40 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
44 
5.1 
Definitions of Dose-Limiting Toxicities (DLT) 
44 
5.2 
Dose Modifications for Axitinib 
46 
5.3 
Dose Modifications for Nivolumab 
53 
6.0 
DRUG INFORMATION 
57 
6.1 
AXITINIB 
57 
6.2 
NIVOLUMAB 
64 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
72 
7.1 
End of Therapy & Follow-up 
72 
7.2 
Follow-up Studies to be Obtained 
72 
7.3 
Research Studies for which Patient Participation is Optional 
73 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY     
CRITERIA 
73 
8.1 
Criteria for Removal from Protocol Therapy 
73 
8.2 
Off Study Criteria 
74 

 
 
 
 
AREN1721 
 
Version Date: 12/14/2021 
 
 Page 5 
9.0 
STATISTICAL CONSIDERATIONS 
74 
9.1 
Sample Size and Study Duration 
74 
9.2 
Study Design 
75 
9.3 
Methods of Analysis 
77 
9.4 
Endpoints and Evaluability 
79 
9.5 
Monitoring Boundary for Dose-Limiting Toxicities 
79 
9.6 
Gender and Minority Accrual Estimates 
80 
10.0 
EVALUATION CRITERIA 
80 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
80 
10.2 
Response Criteria for Patients with Solid Tumors 
80 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
88 
11.1 
Purpose 
88 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
88 
11.3 
Specific Examples for Expedited Reporting 
89 
11.4 
Reporting Requirements for Specialized AEs 
91 
11.5 
Exceptions to Expedited Reporting 
92 
11.6 
Reporting Requirements - Investigator Responsibility 
92 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
92 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
94 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
95 
11.10 
Routine Reporting of Adverse Events 
95 
12.0 
STUDY REPORTING AND MONITORING 
95 
12.1 
CDUS 
95 
12.2 
Data and Safety Monitoring Committee 
95 
12.3 
CRADA/CTA 
96 
13.0 
SURGICAL GUIDELINES 
97 
13.1 
Surgical Principles 
97 
13.2 
Staging of Renal Cell Carcinoma 
102 
13.3 
Surgical Specimens 
103 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
103 
14.1 
Institutional Pathology Requirements 
103 
14.2 
Tissue Specimens/Pathology Review at Time of Diagnosis 
103 
14.3 
Pathology Review Submission Checklist 
104 
14.4 
Shipping 
104 
14.5 
Consultation 
104 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
105 
15.1 
Required Pharmacokinetics 
105 
15.2 
Optional Studies 
107 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
114 
16.1 
Goals of Diagnostic Imaging 
114 
16.2 
Timing of Diagnostic Imaging 
114 
16.3 
Required Imaging Studies 
115 
17.0 
RADIATION THERAPY GUIDELINES 
115 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
116 

 
 
 
 
AREN1721 
 
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APPENDIX II: PERFORMANCE STATUS SCALES/SCORES 
120 
APPENDIX III: BLOOD PRESSURE FOR PATIENTS < 18 YEARS OLD BY AGE AND HEIGHT 121 
APPENDIX IV: AXITINIB DOSING NOMOGRAMS FOR PATIENTS < 18 YEARS OLD 
123 
APPENDIX V: BRISTOL MYERS SQUIBB NIVOLUMAB TREATMENT GUIDELINES 
ALGORITHM 
124 
APPENDIX VI: CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
131 
APPENDIX VII: GLOMERULAR FILTRATION RATE (GFR) CALCULATIONS 
134 
APPENDIX VIII: YOUTH INFORMATION SHEETS 
135 
REFERENCES 
137 
 
 

 
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STUDY COMMITTEE 
 
STUDY CHAIR 
James Geller, MD 
Hematology/Oncology 
3333 Burnet Ave. 
MLC 7015 
Cincinnati, OH 45229 
Phone: (513) 636-6312      
Fax: 
(513) 636-3549     
E-mail: James.Geller@cchmc.org  
 
STUDY VICE CHAIR 
Nicholas Cost, MD 
Surgery 
Children’s Hospital Colorado 
13123 E. 16th Avenue B463 
Aurora, CO 80045 
Phone: (720) 777-6167      
Fax: 
(720) 777-7370     
E-mail: nicholas.cost@childrenscolorado.org  
 
STUDY STATISTICIAN 
Lindsay Renfro, PhD 
Biostatistics 
Children’s Oncology Group 
222 E. Huntington Dr., Suite 100 
Monrovia, CA 91016 
Phone: (626) 241-1613      
Fax: 
(626) 445-4334     
E-mail: lrenfro@childrensoncologygroup.org  
 
STUDY COMMITTEE MEMBERS 
Conrad Fernandez, MD 
Hematology/Oncology 
IWK Health Centre 
Dalhousie University and the IWK Health Centre 
5850 University Ave. 
Halifax, NS B3K 6R8 
Phone: (902) 470-6839      
Fax: 
(902) 470-7216      
E-mail: conrad.fernandez@iwk.nshealth.ca  
 
John Kalapurakal, MD 
Radiation Oncology 
Ann and Robert H Lurie Children’s Hospital of Chicago 
25i East Huron Street 
Chicago, IL 60611 
Phone: (312) 926-2520      
Fax: 
(312) 926-6374     
E-mail: j-kalapurakal@northwestern.edu  
STUDY COMMITTEE MEMBERS 
Jeffrey Dome, MD PhD 
Hematology/Oncology 
Children’s National Medical Center 
Center for Cancer and Blood Disorders 
111 Michigan Ave NW 
Washington, DC 20010  
Phone: (202) 476-3656      
Fax: 
(202) 476-5685     
E-mail: jdome@childrensnational.org  
 
Elizabeth Mullen, MD 
Hematology/Oncology 
Dana-Farber/Harvard Medical Cancer Center 
450 Brookline Ave. Office # SW360A 
Boston, MA 02215 
Phone: (617) 632-1938      
Fax: 
(617) 632-5710 
E-mail: Elizabeth_Mullen@dfci.harvard.edu  
 
Elizabeth Perlman, MD 
Pathology 
Ann and Robert H Lurie Children’s Hospital of Chicago 
225 East Chicago Ave. 
Pathology – Mailbox #17 
Chicago, IL 60611  
Phone: (312) 227-3970  
Fax: 
(312) 227-9615 
E-mail: eperlman@luriechildrens.org  
 
Peter Ehrlich, MD MSc 
Surgery 
C.S. Mott Children’s Hospital 
4-945 C.S. Mott Children’s Hospital SPC 4211 
1500 E. Medical Center Dr. 
Ann Arbor, MI 48109 
Phone: (312) 227-3970  
Fax: 
(312) 227-9615 
E-mail: pehrlich@med.umich.edu  
 
Elisabeth Tracy, MD 
Surgery 
Duke University Medical Center 
DUMC Box 3815 
Durham, NC 27710 
Phone:  (919) 681-5077 
Email:  elisabeth.tracy@duke.edu  
 
 

 
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STUDY COMMITTEE 
 
STUDY COMMITTEE MEMBERS 
Geetika Khanna, MBBS MS 
Diagnostic Imaging 
Washington University School of Medicine 
510 S. Kingshighway, Box 8131 
St. Louis, MO 63110 
Phone: (314) 454-6229  
Fax: 
(314) 454-2868 
E-mail: khannahg@mir.wustl.edu  
  
Denise Mills, MN NP 
Nursing 
Hospital for Sick Children 
555 University Ave. 
Toronto, ON M4S 3G4 
Phone: (416) 813-6934      
E-mail: denise.mills@sickkids.ca  
 
Julie McDonald 
Clinical Research Associate 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Ave. 
Cincinnati, OH 45229 
Phone: (513) 636-8773      
Fax: 
(513) 803-0347 
E-mail: Julie.McDonald@cchmc.org  
  
Kathryn Bruce, PharmD 
Pharmacy 
The Children’s Hospital at TriStar Centennial 
2300 Patterson St. 
3rd Floor Tower Pharmacy 
Nashville, TN 37203 
Phone: (615) 342-4757 
Fax: 
(615) 340-4099 
Email: Kathryn.Bruce@hcahealthcare.com  
 
 
PROTOCOL COORDINATOR 
Kathryn Franklin 
Children’s Oncology Group 
800 Royal Oaks Dr., Suite 210 
Monrovia, CA 91016 
Phone: (626) 241-1622  
Fax: 
(626) 445-4334     
E-mail: kfranklin@childrensoncologygroup.org  
      
RESEARCH COORDINATOR 
Pierre Menard, MS 
Children’s Oncology Group 
800 Royal Oaks Dr., Suite 210 
Monrovia, CA 91016 
Phone: (626) 241-1548 
Fax: 
(626) 445-4334     
E-mail: pmenard@childrensoncologygroup.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agents Supplied by NCI: 
 
AGENT 
NSC# 
Axitinib (AG-013736) 
757441 
Nivolumab (MDX-1106) 
748726 
 
IND#: 
 
IND Sponsor: DCTD, NCI 
SEE SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES 
 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
ABSTRACT 
 
TFE/translocation Renal Cell Carcinoma (tRCC) was formally recognized by the WHO in 2004 as a 
distinct, typically translocation-associated, RCC with characteristic morphology and strong nuclear 
immunohistochemical expression of transcription factor E3 (TFE3) or transcription factor Eb (TFEb). 
Cytogenetic translocations may include TFE3-ASPS, TFE3-PRCC, TFEb-alpha, or other variants. TFE3 
and TFEb are members of the MiTF/TFE family of basic helix-loop–helix-leucine zipper transcription 
factors.1-3 Nearly 50% of pediatric RCCs are tRCC, with a slight female predominance.4-6 tRCC presents in 
all races, and accounts for 1-5% of RCC overall, typically in adolescent and young adult ages.4, 7-11 This 
will be the first prospective therapeutic study dedicated to tRCC. Efficacy data for VEGFR TKI (axitinib) 
and PD1/PD-L1 targeted therapy (nivolumab), two key RCC therapeutic targets, will be assessed 
prospectively as single agents and in combination through a three-way randomization. As of Amendment 
2A, Arm B is permanently closed to accrual and the study will proceed as a two-arm randomized trial 
assessing axitinib and nivolumab in combination or nivolumab alone. As of Amendment 5A, for those 
patients randomized to the nivolumab arm, cross-over to combination therapy will be permitted at disease 
progression. All patients treated with axitinib who, at the time, are < 18 years of age, will have 
pharmacokinetic assessments included. 
 
Important biomarkers of response will be investigated and the biobanking of tissue for this rare cancer will 
occur. In addition, the behavior of tRCC will be comprehensively described across all ages. Baseline 
historical data, in combination with efficacy data from anti-angiogenic and immune checkpoint inhibitor 
therapy, will pave the way for continued future clinical investigation in this patient population. 
 
 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
1.1.1 
To establish the clinical activity, assessed primarily by progression-free survival, 
of nivolumab therapy with or without axitinib for advanced transcription factor 
E3/translocation morphology renal cell carcinoma (TFE/tRCC). 
 
1.2 
Secondary Aim 
1.2.1 
To further define the toxicities of the study arms in the treatment of translocation 
morphology RCC across all ages. 
 
1.3 
Exploratory Aims 
1.3.1 
To characterize tRCC clinical behavior across all age groups. 
 
1.3.2 
To evaluate type of antitumor immune response and stability of T cell activation 
before and after treatment with immunotherapy or antiangiogenic therapy. 
 
1.3.3 
To develop a tumor bank of tRCC tumor samples treated on study for further 
biological investigations. 
 
1.3.4 
To characterize the pharmacokinetics of axitinib when given in combination with 
nivolumab in pediatric patients with tRCC. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Anti-vascular endothelial growth factor (anti-VEGF) receptor tyrosine kinase inhibitors 
and programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors (anti-PD1) are either 
established treatment (anti-VEGF) or are being investigated (anti-PD1) for first-line 
treatment of patients with metastatic or unresectable renal cell carcinoma (RCC). Neither 
has been systematically investigated in a variant of RCC called TFE/tRCC. 
 
TFE/tRCC was formally recognized by the WHO in 2004 as a distinct, typically 
translocation-associated, RCC with characteristic morphology and immunohistochemical 
expression of TFE3 or TFEb. Cytogenetic translocation partners to TFE3 may include 
TFE3-ASPS, TFE3-PRCC, TFEb-alpha, or other variants. Mechanisms for TFE 
upregulation are heterogeneous. TFE3 and TFEb are members of the MiTF/TFE family of 
basic helix-loop–helix-leucine zipper transcription factors.1-3 Half of pediatric RCCs are 
tRCC, with a slight female predominance.4-6 tRCC occurs in all races, and accounts for 
1-5% of RCC, typically in adolescents and young adults.4, 7-11 
 
The dominant presentation pattern for tRCC is one of advanced stage and rapid fatality, 
pointing to an aggressive cancer,12-15 though infrequent late recurrences13, 16 and prolonged 
stable disease4, 17, 18 point to an infrequently-occurring indolent pattern in a subset of 
patients. The import of positive lymph nodes, with rates of 41% in younger cohorts4, 5 and 
up to 50-80% in older tRCC cohorts,9, 10 is debated, with reports suggesting both favorable4, 
11, 13, 19 and unfavorable outcomes.10 Nodal disease is also common with small primary 
tumors, with rates ranging from 20-33% for T1/T2 disease.5, 6, 11 Rates of hematogenous 
metastatic disease range from 9%5, 11 to 35-75% in select older tRCC cohorts.10 A meta-

 
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analysis suggests that ASPS-TFE3 RCC is more likely to metastasize than PRCC-TFE3, 
but only older age or advanced stage, and not fusion subtype, was predictive of death.13 
More recent reports from Korea and China respectively suggest that age > 45 years is an 
adverse prognostic factor12, but neither Fuhrman grade nor WHO/ISUP grading is 
prognostic for tRCC.20 Overall, in pediatric series, approximately 65% of tRCC cases 
present with the TNM classification system Stage 3 or 4 disease.5 For tRCC adult patient 
cohorts published by medical oncologists, referral patterns may have an impact on stage 
distribution since low-stage cases are not often referred by urologic oncologists.9, 10 
 
Despite typical advance stage at presentation, often aggressive behavior, and apparent 
increasing awareness and diagnosis of tRCC, no formal treatment recommendations are 
available, as no dedicated adequately powered prospective therapeutic trials have been 
conducted. Biological targets of interest include c-Met,21-23 VEGFR, mTOR,8, 24, 25 and 
PD1/PD-L1 immune checkpoint inhibition strategies.26 Unfortunately, a phase 2 study of 
the c-MET inhibitor tivantinib did not produce responses in 6 tRCC patients treated, and 
more recent mTOR inhibitor trials (everolimus; ESPN trial) also failed to demonstrate any 
benefit in 7 tRCC patients treated.23, 27 
 
This will be the first prospective therapeutic study of tRCC to date, combining the 
resources of the Children’s Oncology Group (COG) and other adult cooperative groups 
through the National Clinical Trials Network (NCTN). Efficacy data for vascular 
endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) and 
programmed death-protein 1/programmed death-ligand 1 (PD1/PD-L1) targeted therapy, 
the two key RCC therapeutic targets, will be assessed prospectively for the first time 
specifically in tRCC, and the behavior of tRCC comprehensively described across all ages. 
Inter-group cooperation will be established for study of tRCC along with baseline historical 
data, and in combination with efficacy data from anti-angiogenic and immune checkpoint 
inhibitor therapy (as assessed by primary survival endpoints and secondary RECIST-based 
response metrics), pave the way for continued future clinical investigation in this patient 
population. Important biomarkers of response will be investigated and a disease-specific 
tissue bank of this rare cancer will be developed. In sum, this trial will provide the 
framework for establishing treatment guidelines for tRCC, based on biological and clinical 
interrogation. 
 
2.1.1 
VEGFR TKI in tRCC and Axitinib 
VEGFR TKIs are approved by the US FDA for the treatment of clear cell RCC. 
Evidence of response of tRCCs to VEGFR TKIs is growing, with objective 
responses and rare durable complete remissions observed in both pediatric and 
adult patients.9, 24, 28-33 Malouf et al. reported the results of first-line therapy with 
sunitinib for tRCC; a median PFS of 8.2 months (n=11) vs. 2 months for cytokines 
(n=9) was achieved (log-rank p=0.003).24 Unfortunately, the data from this report, 
which were extrapolated via retrospective reviews with varying selection criteria, 
have not been consistently reproduced. Choueiri et al. reported results from a 
retrospective review of 15 adult tRCC patients treated with anti-VEGF-based 
therapy (sunitinib [n=10], sorafenib [n=3], monoclonal anti-VEGF antibodies 
[n=2]) that demonstrated 3 objective responses (20%), 7 stable disease (47%), and 
5 progressive disease (33%).9 Most recently, additional data regarding anti-VEGF 
based therapy in pediatric patients with tRCC demonstrated a PFS in the 5-8 month 
range.34 Second generation more specific and potent VEGFR TKIs are 
demonstrating promising clinical benefit and diminished off-target effects. 

 
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Axitinib is a small molecule inhibitor of VEGFRs 1-3 that was FDA approved in 
January 2012 for advanced RCC after failure of one prior systemic therapy. 
Mechanistically, axitinib is a small molecule adenosine triphosphate (ATP)-
competitive inhibitor that binds to the unphosphorylated “DFG-out” conformation 
of the catalytic domain of RTKs. The unique binding mode in the kinase domain 
affords its selectivity and relative high potency for VEGFRs 1-3 compared with 
sunitinib, pazopanib, sorafenib, and cedirinib.35, 36 
 
2.1.2 
PD1/PD-L1 in tRCC and Nivolumab 
Recent reports of possibly improved durable response rates using immune 
checkpoint inhibitor therapy for RCC26, 37, 38 as compared with historical data using 
cytokine therapy, coupled with the FDA approval of several such inhibitors for 
other cancers,26, 39 have propelled PD1/PD-L1 immune checkpoint inhibitor 
therapy to the forefront of many RCC-based clinical investigations. The PD-L1 
ligand is not expressed in normal kidney but is expressed in many RCC specimens, 
including 25-30% of tRCC.26, 40, 41 Specifically, Chang et al reported 25% (9/36) 
tRCC express PD-L1 which was associated with advanced stage and poor 
prognosis. Interestingly, PD-L1 tumor expression is associated with a worse 
clinical outcome in general, and shorter overall survival (OS) in RCC patients 
treated with anti-VEGF RTKIs.42 
 
2.1.3 
Closure of Arm B: Axitinib monotherapy arm (Amendment 2A) 
As of Amendment 2A, Arm B (the axitinib monotherapy arm) is closed to accrual 
of new patients. Enrollment challenges related to prohibiting prior anti-VEGF 
therapy and shifting community practice in favor of emphasizing PD1-targeted 
therapy in various carcinomas including renal cell carcinoma were key factors that 
led to the changes in Amendment 2A. Additional information has been recently 
published regarding the use of combination therapy with axitinib and PD-1/PD-L1 
inhibitor compared to sunitinib in adults with advanced RCC.43, 44  
 
A key revision in Amendment 2A was to modify the eligibility criteria to permit 
patients who received one prior anti-VEGF agent to remain eligible for the study. 
As a result, Arm B (axitinib-only) becomes a less attractive treatment option, 
particularly for those patients who will have received prior anti-VEGF therapy, 
contributing to the closure of Arm B. Patients who were enrolled and assigned to 
Arm B prior to Amendment 2A will continue therapy on Arm B until off protocol 
therapy criteria is met. 
 
2.2 
Adult Studies 
2.2.1 
Axitinib 
Axitinib, an FDA-approved anti-angiogenic therapy for second-line treatment of 
adult RCC, is the first VEGFR TKI to show superior activity when randomized 
against another VEGFR TKI (sorafenib) in a pivotal phase 3 RCC trial (AXIS 
trial), although tRCC was not studied.35 Importantly, dose titration beyond 5 mg 
PO BID is feasible in some patients, and appeared to positively impact 
progression-free survival. Rini et al. recently reported a randomized phase 2 study 
of axitinib with or without dose titration in first-line metastatic RCC patients, 
demonstrating a survival advantage to dose titration (42.7 months vs. 30.4 months 
median survival).45 In a prior study, Rini et al. reported that optimal axitinib 
exposure may differ among adult RCC patients, and that PK and blood pressure 

 
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could not be used to guide dosing.46 Nonetheless, criteria for dose titration have 
included the following criteria for ≥ 2 consecutive weeks: BP ≤ 150/90 mm Hg, 
no Grade 3/4 axitinib-related toxicities, no prior axitinib dose reductions, and use 
of no more than 2 concurrent antihypertensive medications.45 
 
2.2.2 
Nivolumab in RCC 
Motzer et al. published results of a phase 2 trial of the PD1 inhibitor nivolumab in 
metastatic RCC, demonstrating an objective response rate of 20%, 22%, and 20% 
and median OS of 18.2, 25.5, and 24.7 months for doses of 0.3, 2, and 10 mg/kg 
given intravenously every 3 weeks, respectively. Responses occurred more 
commonly in PD-L1 expressing tumors (≥ 5% PD-L1 expression) with overall 
response rate (ORR) of 31%, but the ORR of 18% for tumors expressing < 5% PD-
L1 is still among the best ORRs in RCC. Median OS was not reached in the PD-
L1 ≥ 5% group and was 18.2 months in the PD-L1 < 5% group, the latter similar 
to that achieved with axitinib therapy in the second-line setting.37 Some responding 
patients continued to respond for nearly a year after cessation of therapy.38 
Subsequently, results of the CheckMate 025 trial, where patients with advanced 
RCC previously treated with 1 or 2 regimens of antiangiogenic therapy were 
randomized to receive either nivolumab 3 mg/kg given q 2 weekly vs. everolimus 
10 mg by mouth daily, were reported, demonstrating a median OS of 25 months 
with nivolumab and 19 months with everolimus. The ORR with nivolumab was 
25% (vs. 5% with everolimus). Grade 3 and 4 events were less common with 
nivolumab (19%) than with everolimus (37%).39 
 
2.2.3 
Anti-angiogenic plus PD1 Inhibitor Combination Trials 
Studies combining anti-angiogenic therapies and PD1 inhibitors in RCC have 
recently been performed. A trial of nivolumab plus sunitinib confirmed that 
combining each agent at full dose was tolerable (nivolumab up to 5 mg/kg IV 
q 3 weekly; sunitinib 50 mg PO daily 4 weeks on/2 weeks off) and demonstrated 
objective anti-tumor activity (41% ORR by 6 weeks); however, hepatotoxicity was 
noted. Similarly, combining nivolumab with pazopanib resulted in increased 
toxicity, notably hepatotoxicity. Specifically, in trial NCT01472081, patients with 
mRCC (≥ 1 prior systemic therapy) received nivolumab in combination with 
sunitinib (50 mg, 4 weeks on/2 weeks off; Arm S) or pazopanib (800 mg daily; 
Arm P), until progression/unacceptable toxicity. The starting dose of nivolumab 
was 2 mg/kg IV Q3W (N2), with planned escalation to 5 mg/kg IV Q3W (N5). 
Based on tolerability, the Arm S N5 cohort was expanded to treatment-naïve 
patients. Primary objectives were safety/tolerability and determination of 
maximum tolerated dose (MTD) for the combinations; the secondary objective was 
antitumor activity (ORR and duration of response [DOR]). Seven patients were 
assigned to each of Arms S N2 and N5. No dose-limiting toxicities (DLTs) were 
observed and a MTD was not reached, thus N5 was expanded with 19 additional 
patients (total n=33). Arm P enrolled 20 patients at N2; 4 DLTs (elevated 
ALT/AST [n=3], fatigue [n=1]) were observed, leading to closure of this arm. 
Grade 3–4 related AEs were observed in 24/33 patients (73%) in Arm S and 12/20 
patients (60%) in Arm P. The most common related Grade 3–4 AEs included 
elevated ALT (18%), hypertension and hyponatremia (15% each) in Arm S and 
elevated ALT/AST (20% each) and fatigue (15%) in Arm P. Hepatotoxicities were 
manageable using treatment algorithms. Grade 3 pneumonitis occurred in 1 patient 
(Arm S, N5). Grade 3–4 related AEs led to therapy discontinuation in 8/33 patients 

 
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(24%; 1 N2, 7 N5) in Arm S and 4/20 patients (20%) in Arm P. ORR was 52% 
(17/33) in Arm S and 45% (9/20) in Arm P. Responses occurred by first assessment 
(6 wks) in 41% (Arm S) and 56% (Arm P) of responding patients and were durable 
(range: Arm S: 12.1+ to 54 wks; Arm P: 12.1 to 69.1+ wks). Stable disease rate 
was 33% (n=11) in Arm S and 35% (n=7) in Arm P. PFS rate at 24 wks was 78% 
for Arm S and 55% for Arm P. The authors concluded that nivolumab plus 
sunitinib or pazopanib showed encouraging antitumor activity and a manageable 
safety profile in patients with mRCC.42 
 
Axitinib has been combined with a PD1 inhibitor (pembrolizumab) in RCC 
(NCT02133742) and proven tolerable when each agent is administered at its 
independent MTD/RP2D.47, 48 
 
2.3 
Pediatric Studies 
There have been no combination data for axitinib and nivolumab in children. The 
Children’s Oncology Group has completed accrual to study ADVL1315 (NCT02164838), 
a phase 1 study of axitinib in pediatric solid tumor patients with relapsed or refractory 
disease. Oral axitinib tablets were administered BID, continuously in 28-day cycles. Dose 
Levels 2.4 and 3.2 mg/m2/dose were evaluated using a rolling 6 design. Serial PK were 
obtained in Cycle 1. Eighteen patients were enrolled with 1 ineligible (inadequate time 
from prior therapy). The median age was 13.5 years (range: 5-17 years); 10 were male. 
Patients received a median 3 prior chemotherapy regimens (range: 1-8). Cancer diagnoses 
included soft tissue sarcomas (n=7), Ewing (n=3) and osteosarcoma (n=1), neuroblastoma 
(n=2), Wilms tumor (n=1), hepatoblastoma (n=1), hepatocellular carcinoma (n=1), 
medullary carcinoma (n=1), and epithelial-myoepithelial carcinoma (n=1). Toxicity data 
are available for 15 patients (6 patients at Dose Level 1; 5 patients at Dose Level 2, and 4 
patients on an expanded PK cohort). Two patients were inevaluable for toxicity due to 
inadequate drug exposure. DLTs occurred in 0/6 and 2/5 patients treated at Dose Levels 1 
and 2, respectively (palmar-plantar erythrodysesthesia syndrome [1]; intratumoral 
hemorrhage [1]). Cycle 1 hematologic toxicities included Grade 3 lymphopenia (1) and 
Grade 1 or 2 anemia (4), lymphopenia (3), elevated hemoglobin (3), leukopenia (2), 
neutropenia (1), thrombocytopenia (1), and lymphocytosis (1). Non-hematologic toxicities 
included Grade 1 or 2 nausea (5), hypertension (4), anorexia (3), creatinine elevation (2), 
diarrhea (2), fatigue (2), headache (2), lipase elevation (2), proteinuria (2), and acneiform 
rash (2). The most common subsequent cycle Grade 3 or 4 toxicities included neutropenia 
(Grade 3 [3], Grade 4 [1]) and lymphopenia (Grade 3 [1], Grade 4 [1]). Authors concluded 
that axitinib is tolerated in pediatric patients. The MTD of axitinib given to children with 
solid tumors is 2.4 mg/m2/dose, corresponding to 4 mg BID (or 80%) of the adult dose.49 
PK analysis demonstrated peak plasma concentrations 2 h after dose with an average half-
life of 0.9 to 5.2 h. There was substantial variability in exposure that appeared to be dose 
dependent and unexpected accumulation ranging from 0.27- to 4.74-fold. AUC exposures 
at the pediatric MTD were at levels predicted to be active in adult RCC trials.49 
 
In ADVL1315, sixteen patients were evaluable for response; 15 patients had sufficient 
evaluations to report a response (1 patient did not have all required evaluations obtained). 
One patient with alveolar soft part sarcoma (also known to be a TFE3 driven cancer) had 
a confirmed partial response that was durable for 6 months prior to clinical progression of 
disease and discontinuation of protocol therapy. Five patients had stable disease for up to 
6 cycles including 2 patients with osteosarcoma and 1 each with malignant peripheral nerve 
sheath tumor, Ewing sarcoma, and hepatocellular carcinoma.49 

 
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COG study ADVL1412 (NCT02304458), A Phase 1/2 Study of Nivolumab (IND# 
) 
in Children, Adolescents, and Young Adults with Recurrent or Refractory Solid Tumors as 
a Single Agent in Combination with Ipilimumab, is closed to accrual. Full dose therapy 
analogous to adult trials dosing was confirmed tolerable. (COG ADVL1412 study report) 
 
2.4 
Immune Biomarkers 
Immunologic evaluations will include PD-L1 expression, type of antitumor immune 
response and stability of T cell activation before and after treatment. Tissue slides will be 
used to assess PDL1 expression and TIL composition/distribution before treatment using 
multicolor imaging. The frequency of tumor infiltrating T cells as well as the expression 
level of inhibitor molecule PDL-1 on the tumors has been associated with efficacy of PD1 
blocking therapy. 50-52 
 
Peripheral blood mononuclear cells (PBMC) will be assessed for composition of CD4 and 
CD8 T cells; naïve and memory cells (CD45RO/RA, CCR7), recently activated T cells 
(HLADR, CD38, Nur77, Ki67), the frequency of T cells with an exhausted phenotype (PD-
1, Lag-3, Tim3, CD244), and regulatory phenotype (CD25, FoxP3). It is well established 
that tumors suppress the immune system and promote the development of immune cells 
with immune suppressive and tumor promoting capacities including myeloid-derived 
suppressor cells (MDSC) that directly inhibit cytolytic CD8 T cell proliferation/function 
and promote angiogenesis and metastases and Tregs that can directly suppress CD8 T cells. 
In addition, CD8 T cells associated with tumor environments often express a dysfunctional 
and exhausted phenotype that we aim to overcome with PD1 blocking therapy. 
Longitudinal assessment of the patients’ immune status could provide important clues on 
the immune mechanisms that may affect immunotherapy efficacy. 53-55 
 
2.5 
Dosing Rationale 
2.5.1 
Axitinib 
2.5.1.1 
Adult patients (≥ 18 years of age) 
Available data presented above have demonstrated the safety of 
administering antiangiogenic therapy and PD1 inhibitor therapy in 
combination to patients with adult RCC at each agent’s recommended 
phase 2 dose (RP2D). In addition, per the axitinib package insert, based 
on available published data, it has become an accepted standard to dose 
increase adults with RCC amenable to dose titration upwards beyond 
5 mg PO BID. This is an acceptable standard and will be permitted on 
trial (see Section 4.3.3 and Section 4.4.3). 
 
2.5.1.2 
Pediatric patients (< 18 years of age) 
Available data (study ADVL1315) noted above has established the 
RP2D for axitinib as 2.4 mg/m2/dose (maximum of 5 mg/dose) PO 
BID.49 Dose titration will be permitted in patients < 18 years of age on 
this trial (see Sections 4.3.3, 4.4.3, and Appendix IV). 
 
2.5.2 
Nivolumab 
2.5.2.1 
Adult patients (≥ 18 years of age) 
A fixed nivolumab FDA Approved dose of 240 mg IV every 2 weeks or 
480 mg IV every 4 weeks will be used for adult patients. 
 

 
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With Amendment #5, adults will have the option to receive nivolumab 
on one of the above mentioned schedules as both are FDA approved and 
felt equivalent with regards to efficacy in adult patients. 
 
2.5.2.2 
Pediatric patients (< 18 years of age) 
The recommended nivolumab dose of 3 mg/kg (up to a maximum dose 
of 240 mg) IV every 2 weeks will be used for pediatric patients. 
 
2.6 
Rationale for Cross-Over Design (Effective with Amendment 5A) 
For patients who progress on Arm C (nivolumab monotherapy), evolving clinical options 
include simple ‘continuing beyond progression’, change to anti-VEGF TKI-based therapy, 
or the addition of anti-VEGF TKI-based therapy. The concept of continuing on PD1 
inhibitor-based therapy beyond progressive disease, which at times occurs in the setting of 
mixed responses, has been formally investigated in multiple cancers including renal cell 
carcinoma.56-59 Available data suggest that continuing such therapy is both safe, and at 
times, efficacious,57, 58 with potential improvements noted in overall survival.59 That said, 
either switching to or adding an anti-VEGF TKI-based therapy can be effective in some 
RCC variants.60 Considering existing standards in management of RCC and the goals of 
this trial, cross-over from Arm C (nivolumab monotherapy) to Arm A (combination 
nivolumab/axitinib therapy) will be permitted for patients on Arm C at first disease 
progression. Data that results from such cross-over will not impact the primary aim of the 
study, but will contribute to our understanding of tRCC patient clinical tolerance and 
response to such therapies, survival outcomes, and pharmacokinetics of axitinib in pediatric 
patients treated with combination therapy. 
 
2.7 
Pharmacokinetics Studies (Effective with Amendment 5A) 
COG study ADVL1315 described the phase 1 experience of axitinib in children with 
relapse/refractory solid tumors, including pharmacokinetic parameters.49 While helpful, 
such data remains limited. The FDA has requested that additional PK be obtained in 
children randomized to Arm A (axitinib/nivolumab) where they are treated with axitinib 
on study AREN1721 to further characterize the PK specifically in children and adolescents 
with TFE RCC treated with concurrent nivolumab (a combination for which no PK for 
axitinib is currently available). AREN1721 also permits the option for axitinib dose 
escalation beyond doses used in ADVL1315. Such PK data will be used to help define 
future guidelines of use for axitinib in the pediatric population. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 

 
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For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
NOTE: In order for an institution to maintain COG membership requirements, every 
patient with a known or suspected neoplasm needs to be offered participation in 
APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
3.1.2 
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. For 
CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 

 
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In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria in order for the processing 
of the IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system. Patients must 
be enrolled within 5 calendar days of making a reservation.  
Note: As of Amendment 5A, each time a reservation is made for a pediatric 
patient, sites should order a sample collection kit for required 
pharmacokinetic studies. This is to ensure timely receipt of the kit in the event 
the pediatric patient is randomized to Arm A, and to ensure a kit is readily 
available in the event that a patient randomized to Arm C should cross-over 
to Arm A. See Section 15.1 for complete details. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the registration system in OPEN. Prior to discussing 
protocol entry with the patient, all site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available to the patient. 
Once a slot reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  

 
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If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient 
number. Click on the ‘Slot Reservation’ tab to create an OPEN patient 
number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient. 
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter 
the COG Patient ID, and choose the required stratum (if applicable) in 
order to obtain a reservation. 
 
Refer to the ‘Slot Reservation Site User Guide’ posted under the ‘Help’ tab in 
OPEN for detailed instructions: 
https://www.ctsu.org/open/Site_Resources/Training/Users_Manual/CTSU-
OPEN-SlotReservationSiteUserGuide.pdf 
 
3.1.4 
Study Enrollment 
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. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or the Theradex 
Interactive 
Web 
Response 
System 
(IWRS) 
for 
retrieval 
of 
patient 
registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an Associate 
Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars 
must hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. If a DTL is required 
for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 

 
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• 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. Patients who are started on protocol therapy on a phase 2 study 
prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT), and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy.  
 
Imaging studies, if applicable, must be obtained within 4 weeks prior to enrollment 
and start of protocol therapy (repeat the tumor imaging if necessary). 
 
Echocardiogram, must be obtained within 8 weeks prior to enrollment and start of 
protocol therapy (repeat echocardiogram if necessary). 
 

 
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3.2.1 
Age 
Patients must be ≥ 12 months at enrollment. 
 
3.2.2 
Body Surface Area (BSA) 
Patients must have a Body Surface Area (BSA) ≥ 0.53 m2. 
 
3.2.3 
Diagnosis  
Histologically confirmed unresectable or metastatic translocation morphology renal 
cell carcinoma diagnosed using WHO-defined criteria. Patients may be newly 
diagnosed or have received prior cancer therapy. 
 
3.2.3.1 
Patients must have had histologic verification of the malignancy. 
 
3.2.3.2 
Patients must have measurable disease, documented by clinical, 
radiographic, or histologic criteria as defined by RECIST v1.1. 
 
3.2.3.3 
Patients must have a tumor showing the appropriate morphologic 
appearance, and either confirmed TFE3 nuclear protein expression by 
immunohistochemistry with appropriate positive and negative controls 
performed at a CLIA-certified laboratory, or evidence of TFE3 or TFEb 
translocation by either FISH or RT-PCR performed at a CLIA-certified 
laboratory. For TFE3 immunohistochemistry, any nuclear positivity in 
the presence of appropriate positive and negative controls should be 
considered as evidence of TFE3 immunohistochemical expression. 
NOTE: If the institution is unable to perform these studies, unstained 
slides may be submitted to Dr. Elizabeth Perlman, who will perform 
TFE3 analysis at no charge. The slide will be returned to the referring 
institution for local evaluation, to be included in their institutional report. 
See Section 14.1.2 for complete details. 
 
3.2.4 
Performance Level  
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 
2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years 
of age. See Appendix II. 
 
3.2.5 
Life Expectancy 
Patients must have a life expectancy of  8 weeks. 
 
3.2.6 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
a. Myelosuppressive chemotherapy: Must not have received within 2 weeks 
of entry onto this study (6 weeks if prior nitrosourea). 
b. Immunotherapy: Must not have received within 4 weeks of entry onto this 
study. 
c. Biologic (anti-neoplastic agent): At least 7 days since the completion of 
therapy with a biologic agent.  
d. Radiation therapy (RT):  2 weeks for local palliative RT (small port); 
 6 months must have elapsed if prior craniospinal RT or if  50% 

 
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correctable causes of prolonged QTc addressed if possible (i.e., 
electrolytes, medications). 
 
3.2.7.5 
Adequate Coagulation Function Defined As: 
- 
International Normalized Ratio (INR) or Prothrombin Time (PT) 
≤ 1.5 X ULN. However, if patient is receiving anticoagulant therapy, 
PT or PTT should be within therapeutic range of intended use of 
anticoagulants. 
- 
Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless 
patient is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants. 
 
3.2.7.6 
Adequate Blood Pressure Control Defined As: 
- 
A baseline blood pressure (BP) ≤ the 95th percentile for age, height, 
and gender for patients < 18 years old (see Appendix III), or 
≤ 150 mmHg (systolic) and ≤ 90 mmHg (diastolic) for patients 
≥ 18 years old. 
Note: 2 serial blood pressures should be taken at least 1 hour apart 
and averaged to determine baseline BP (see Section 5.2.5.1). 
- 
Patients are eligible if on stable doses (≥ 7 days) of anti-hypertensive 
medications with a baseline BP meeting the criteria above. 
 
3.2.8 
Exclusion Criteria 
3.2.8.1 
Patients unable to swallow whole tablets. 
 
3.2.8.2 
Patients who in the opinion of the investigator are not able to comply 
with the study procedures are not eligible. 
 
3.2.8.3 
Prior Therapy 
- 
Patients who have received prior therapy with axitinib, nivolumab, 
or other PD1/PD-L1 targeted therapies. 
- 
Patients who have received prior therapy with more than one 
anti-VEGF based agent (antibody or tyrosine kinase inhibitor).  
- 
Patients with hypersensitivity to axitinib, nivolumab, or any of its 
excipients. 
- 
Patients who previously received an allogeneic stem cell transplant 
(SCT) or solid organ transplant are not eligible. 
- 
Patients may not be receiving any other investigational agents 
(within 4 weeks prior to study enrollment). 
- 
Patients who have received prior anti-cancer monoclonal antibody 
(mAb) within 4 weeks prior to study enrollment or who have not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks prior to enrollment. 
- 
Surgery: Patients who have had or who are planning to have the 
following invasive procedures are not eligible: 
o Major surgical procedure, laparoscopic procedure, open 
biopsy, core biopsy, fine needle aspirate, or significant 
traumatic injury within 7 days prior to enrollment. NOTE: 
External central lines must be placed at least 3 days prior to 

 
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planned treatment initiation and subcutaneous ports must be 
placed at least 7 days prior to planned treatment initiation. 
o Patients who are planning cytoreductive surgery within the 
first 12 weeks following therapy initiation. 
o Patients who have a serious or non-healing wound or ulcer 
at the time of study enrollment are not eligible. 
- 
Patients who have a history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 28 days of study 
enrollment are not eligible. 
- 
Patients who have received prior targeted small molecule therapy 
within 2 weeks of enrollment or have not recovered (i.e., ≤ Grade 1 
or at baseline) from adverse events due to agents administered more 
than 4 weeks prior to enrollment. NOTE: Subjects with ≤ Grade 2 
neuropathy are an exception to this criterion and may qualify for the 
study. 
 
3.2.8.4 
Pre-existing conditions, which may include: 
- 
Additional known malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, or 
squamous cell carcinoma of the skin that has undergone potentially 
curative therapy, or in situ cervical cancer. 
- 
Patients with underlying immune deficiency, chronic infections 
including hepatitis, tuberculosis (TB), or autoimmune disease. 
- 
HIV-infected patients with the exception of patients on an effective 
anti-retroviral therapy with an undetectable viral load within 6 
months prior to enrollment. 
- 
Patients with underlying hematologic issues including congenital 
bleeding diathesis, known previous GI bleeding requiring 
intervention within the past 6 months, history of hemoptysis within 
42 days prior to study enrollment, active pulmonary emboli, or deep 
vein thromboses (DVT) that are not stable on anticoagulation 
regimen. 
- 
Patients must not have had significant vascular disease (i.e. Moya-
Moya, aortic aneurysm requiring surgical repair). 
- 
A known history of, or any evidence of active, non-infectious 
pneumonitis. 
- 
Patients with known active central nervous system (CNS) metastases 
and/or carcinomatous meningitis or leptomeningeal disease. Patients 
with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at 
least 4 weeks prior to study enrollment and any neurologic 
symptoms have returned to baseline), have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 
7 days prior to study enrollment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical 
stability. 
- 
Any uncontrolled, intercurrent illness including but not limited to 
ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia. 

 
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- 
Any serious medical or psychiatric illness/condition including 
substance use disorders likely in the judgment of the Investigator(s) 
to interfere or limit compliance with study requirements/treatment. 
- 
Patients with active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
 
3.2.8.5 
Treatments and/or medications the patient is receiving or has received 
that would make her/him ineligible, including: 
- 
Concomitant (or receipt of) treatment with medications that may 
affect the metabolism of nivolumab and/or axitinib within 7 days 
prior to planned first dose of protocol therapy. 
- 
A live vaccine within 30 days of planned first dose of protocol 
therapy. NOTE: Inactivated flu vaccines are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
3.2.8.6 
Pregnancy and Breast Feeding 
3.2.8.6.1 Due to risks of fetal and teratogenic adverse events as seen in 
animal studies, a negative pregnancy test must be obtained in 
females of childbearing potential, defined as females who are 
post-menarchal. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be 
required. 
 
3.2.8.6.2 Females of childbearing potential that are sexually active must 
agree to either practice 2 medically accepted highly-effective 
methods of contraception at the same time or abstain from 
heterosexual intercourse from the time of signing the informed 
consent through 5 months after the last dose of study drug. 
 
3.2.8.6.3 Lactating females are not eligible unless they have agreed not 
to breastfeed their infants starting with the first dose of study 
therapy through 5 months after the last dose of study therapy. 
 
3.2.8.7 
Male patients of reproductive potential must agree to use an adequate 
method of contraception starting with the first dose of study therapy 
through 7 months after the last dose of study therapy. Prior history of 
vasectomy does not replace requirement for contraceptive use. 
 
3.2.9 
Regulatory Requirements 
3.2.9.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.9.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 

 
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4.0 
TREATMENT PROGRAM 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Prior to Amendment 2A, the study was a randomized three-arm phase 2 study evaluating 
the clinical benefit of axitinib, nivolumab, and their use in combination for the treatment 
of tRCC.  
 
As of Amendment 2A, Arm B (axitinib alone) is permanently closed to accrual, and 
prospective patients will be randomly assigned to one of the following arms: 
Arm A: Axitinib + Nivolumab 
Arm C: Nivolumab 
 
As of Amendment 5A, patients who are initially randomized to Arm C (nivolumab 
alone) and experience progressive disease prior to Cycle 22 will be permitted to 
crossover to Arm A (axitinib + nivolumab). For patients who crossover to Arm A, 
they are to continue on their current nivolumab schedule and start axitinib as soon as 
it is made available. NOTE: Patients must use the NCI supplied drug. Commercially 
supplied axitinib is not allowed. 
 
Axitinib will be administered at a starting dose of 5 mg PO BID for patients ≥ 18 years of 
age, and at 2.4 mg/m2/dose (maximum of 5 mg/dose) PO BID for patients < 18 years of 
age. See Appendix IV for axitinib dosing nomogram. Individual patient dose titration of 
axitinib (escalation from starting dose) is permitted on protocol therapy, at the discretion 
of the treating physician. Refer to Section 4.3.3 or 4.4.3 for dose titration criteria. 
 
Nivolumab will be given at either 240 mg IV every 2 weeks or 480 mg IV every 4 weeks 
for patients ≥ 18 years of age, and at 3 mg/kg IV (maximum of 240 mg/dose) every 2 weeks 
for patients < 18 years of age. Pre-medication is not required as infusion reactions are rare, 
but anaphylactic precautions should be observed during each infusion of nivolumab. 
If ≥ Grade 2 infusion reaction occurs, the infusion should be stopped and supportive care 
given as per institutional guidelines. See Section 5.3 for management and dose 
modification guidelines for infusion reactions. Investigators are advised to monitor for 
fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing 
during and immediately after administration of nivolumab. 
 
Combination therapy will be given with agents at full single agent doses as above. 
 
Each cycle of therapy will be 4 weeks. Tumor disease evaluation will occur after Cycles 2, 
4, 6, 9, 12, and then every 4 cycles thereafter, or at any time clinical progression is 
suspected. If pseudoprogression is suspected (until any degree of response is observed), 
disease evaluation must occur after every cycle (Section 10.2.1). Absent disease 

 
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progression or unacceptable toxicity, patients may continue on protocol therapy for up to 
2 years duration or completion of 26 cycles, whichever comes first. Disease evaluations 
(including imaging) will continue during follow-up according to the schedule outlined in 
Section 7.2. 
 
For patients who progress on Arm C prior to Cycle 22, cross-over to Arm A is permitted. 
Patients should resume Arm A therapy as soon as PD is identified. Nivolumab should 
continue uninterrupted according to the previously established schedule for that patient 
(either every 2 or 4 weeks). Axitinib should be added as soon as it becomes available from 
NCI and the patient has recovered from any relevant toxicity. Subsequent disease 
evaluations should occur as above timed from the first cycle of combination therapy The 
first cycle of combination therapy after cross-over will be defined as the cycle for which > 
14 days of axitinib is given, with Day 1 of Cycle 1 after cross-over defined as the day of 
first nivolumab dose during that cycle after axitinib is started or on the day axitinib is 
started if given concurrently. NOTE: The total protocol therapy received on AREN1721 
(whether delivered on Arm A, Arm C, or Arm C+A) is not to exceed 26 cycles or 2 years, 
whichever comes first. 
 
NOTE:  
• 
Patients who have not had cytoreductive nephrectomy prior to trial enrollment but 
who elect to have cytoreductive nephrectomy during therapy may remain on 
protocol therapy.  
• 
Cytoreductive therapy is not permitted in the first 12 weeks after starting protocol 
therapy.  
• 
Axitinib must be held for 7 days before and after surgery. See Section 13.1.2 for 
more details. 
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
4.2 
Concomitant Therapy 
4.2.1 
Patients may not receive other anti-cancer medications while on protocol therapy. 
 
4.2.2 
Small port radiotherapy and/or surgery for management of persistent and/or 
symptomatic tumor is permitted while on protocol therapy.  
 
4.2.3 
Patients may not have surgical resection of the tumor during the first 12 weeks of 
protocol therapy per Section 13.1.8.1. 
 
4.2.4 
Patients who have surgical resection of lesions that are increasing in size while on 
therapy must be removed from protocol therapy per Section 13.1.8.2. 
 
4.2.5 
If not done prior to study enrollment, cytoreductive nephrectomy should be 
reconsidered after 12 weeks of protocol therapy, taking into account the need to 
hold axitinib before and after surgery per Section 13.1.8.3. 
 
4.2.6 
Supportive care per institutional guidelines is permitted. 
 
4.2.7 
Steroid therapy is permitted as clinically indicated, though it is recommended that 
use of steroids in patients on nivolumab be limited to use for management of 

 
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immune-related adverse events per standard guidelines (see Section 5.3 for Dose 
Modifications). 
 
4.2.8 
Anti-hypertensives  
Patients who develop hypertension while on protocol therapy may be treated with 
anti-hypertensive agents and may remain on protocol therapy as long as 
hypertension is well controlled on medication. The algorithms in Section 5.2.5 will 
be used to grade and manage axitinib-related hypertension.  
 
4.2.9 
CYP3A4 Inhibitors and Inducers 
Axitinib is a major substrate for cytochrome P-450 3A4 isozyme. Strong inducers 
or inhibitors of CYP3A4 may alter the pharmacokinetics of axitinib and should be 
avoided for 7 days prior to enrollment. They should also be avoided for the 
duration of protocol therapy for patients in Arms A and B. Moderate inducers or 
inhibitors of CYP3A4 should be avoided as well, if reasonable alternatives exist. 
Please see Appendix VI for list of CYP3A4 inducers and inhibitors. Because the 
lists of these agents are constantly changing, it is important to regularly consult 
frequently updated medical references. 

  
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Arm A: Axitinib + Nivolumab 
 
4.3.2 
Required Observations in Arm A: Axitinib + Nivolumab 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
a. Physical Exam: Prior to each cycle, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly  
For patients ≥ 18 years old, perform every other week 
b. Height/Weight: Prior to each cycle. 
c. CBC/diff/platelets: Prior to each dose of nivolumab, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly 
For patients ≥ 18 years old, perform every other week 
d. Creatinine, bilirubin: Prior to each dose of nivolumab, weekly during Cycle 1 only. 
e. Electrolytes, BUN, Ca2+, PO4, Mg2+: Prior to each dose of nivolumab, weekly during 
Cycle 1 only. 
f. 
AST/ALT/Albumin: Prior to each dose of nivolumab, weekly during Cycle 1 only. 
g. Blood Pressure: Prior to each dose of nivolumab, weekly during Cycle 1 only. For 
pediatric patients who are dose escalated, weekly monitoring for the first cycle at the 
higher dose will be required (See Section 5.2.5.4) 
h. PT/INR: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
i. 
TSH: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
j. 
Urinalysis/Urine Protein/Creatinine: Prior to Cycles 1, 2, 3 and then prior to every odd-
numbered cycle (e.g., Cycles 5, 7, 9, etc.). 
k. Lipase: Prior to each cycle.  
l. 
Pregnancy Test: Female patients of childbearing potential require a negative pregnancy test 
within 72 hours prior to starting treatment and then prior to every odd-numbered cycle 
(e.g., Cycles 3, 5, 7, etc.); sexually active patients must use an acceptable method of birth 
control. 
m. ECG: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
n. MUGA or ECHO: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
o. GFR or Creatinine Clearance: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 
9, etc.). See Appendix VII for GFR calculation.  
p. Required Pharmacokinetics (for pediatric patients only): At 2, 4, and 6 hours post-
axitinib AM dose during Cycle 1, Day 1. Additionally, pre-dose of axitinib on Day 1 of 
Cycles 2 and 3. For pediatric patients on Arm C that crossover to Arm A, required PK 
will be obtained at 2, 4 and 6 hours post-axitinib AM dose after the first dose of axitinib 
is given, and then pre-dose of axitinib on Days 1 of the second and third cycles of 
combination therapy received. NOTE: The first cycle of combination therapy after 
cross-over will be defined as the cycle for which > 14 days of axitinib is given, with Day 
1 of Cycle 1 after cross-over defined as the day of first nivolumab dose during that cycle 
after axitinib is started or on the day axitinib is started if given concurrently. See Section 
15.1 for complete details. 
q. Immune biomarkers (patient consent is required): Before treatment initiation and before 
Day 1 of Cycles 2, 3, and 9 (within 72 hours prior to Day 1 dosing), and within 3 weeks 
after the last dose of study treatment. See Section 15.2.1 for complete details. 
r. 
Tumor Tissue (patient consent is required): Before treatment initiation and at any time 
tumor tissue is obtained (i.e. surgery). See Section 15.2.2 for complete details. 
s. Specimens for Banking (patient consent is required): See Section 15.2.3 for complete 
details. 
t. 
Tumor Imaging: After Cycles 2, 4, 6, 9, 12, and then every 4 cycles; at relapse. For 
patients who cross-over from Arm C to Arm A at initial progression, then for the purpose 
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Arm A: Axitinib + Nivolumab 
of imaging timing, the cycle number should restart at progression to “Cycle 1”. See 
Section 16.2 for complete details. 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
 
 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
Page 3 of 3 

  
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Arm A: Axitinib + Nivolumab 
 
4.3.3 
Treatment Details – Arm A: Axitinib + Nivolumab 
Each cycle lasts 28 days (4 weeks). Absent disease progression or unacceptable 
toxicity, patients may continue on protocol therapy for up to 2 years duration or 
completion of 26 cycles, whichever comes first.  
 
For patients who cross-over at disease progression on Arm C prior to Cycle 22, 
prior cycles received are included in total therapy calculations permitted on study. 
 
Criteria to start each cycle: ANC ≥ 1000/L, platelet count ≥ 75,000/L without 
transfusion support. See Section 5.0 for other requirements related to any ongoing 
toxicities. 
 
Axitinib: PO 
Days: 1 – 28 
Dose: Age-based dosing as follows: 
If ≥ 18 years old: 5 mg/dose BID* 
If < 18 years old: 2.4 mg/m2/dose BID (maximum starting dose of 
5 mg/dose)*. See Appendix IV for axitinib dosing 
nomogram and titrations. 
 
NOTE: Dose is BID. For example, if age < 18 years old administer 
2.4 mg/m2/dose BID. The total daily dose is 4.8 mg/m2/day, divided BID 
(maximum starting dose is 5 mg/dose BID). 
 
Axitinib should be taken by mouth twice daily approximately 12 hours apart. 
Axitinib may be taken with or without food. Tablets should be administered whole 
and intact with a glass of water or other liquid; do not crush or cut tablets. If a dose 
is missed or vomited, the patient/subject should not try to repeat or “catch up” the 
dose. The next dose should be given at the next regularly scheduled time point. 
 
Axitinib will be distributed by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. Do not use commercial supply. 
 
*Axitinib dose titration: 
Individual patient dose titration of axitinib (escalation from starting dose) is 
permitted on protocol therapy, at the discretion of the treating physician, if the 
following criteria are met for an individual patient: 
1. Two consecutive cycles are completed at a given dose without any adverse 
reactions > Grade 2 (according to the Common Toxicity Criteria for 
Adverse Events [CTCAE]). 
2. The patient is normotensive, and not receiving anti-hypertension 
medication. 
 
For patients ≥ 18 years old, when a dose increase from 5 mg twice daily is 
recommended, the axitinib dose may be increased by 1 mg/dose twice daily (for 
example, from 5 mg twice daily to 6 mg twice daily, etc), up to a maximum of 
10 mg twice daily. No more than 1 dose titration can occur in each 2-cycle period 
per the criteria above. Refer to the table in Section 5.2.1.1 for additional detail.  
 

  
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Arm B: Axitinib  
 
4.4.2 
Required Observations in Arm B: Axitinib  
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
a. Physical Exam: Prior to each cycle, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly  
For patients ≥ 18 years old, perform every other week 
b. Height/Weight: Prior to each cycle. 
c. CBC/diff/platelets: Prior to each cycle, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly 
For patients ≥ 18 years old, perform every other week 
d. Creatinine, bilirubin: Prior to each cycle, weekly during Cycle 1 only. 
e. Electrolytes, BUN, Ca2+, PO4, Mg2+: Prior to each cycle, weekly during Cycle 1 
only. 
f. 
AST/ALT/Albumin: Prior to each cycle, weekly during Cycle 1 only. 
g. Blood Pressure: Every other week, weekly during Cycle 1 only. For pediatric 
patients who are dose escalated, weekly monitoring for the first cycle at the higher 
dose will be required (See Section 5.2.5.4) 
h. PT/INR: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
i. 
TSH: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
j. 
Urinalysis/Urine Protein/Creatinine: Prior to Cycles 1, 2, 3, and then prior to every 
odd-numbered cycle (e.g., Cycles 5, 7, 9 etc.). 
k. Lipase: Prior to each cycle. 
l. 
Pregnancy Test: Female patients of childbearing potential require a negative pregnancy 
test within 72 hours prior to starting treatment and then prior to every odd-numbered 
cycle (e.g., Cycles 3, 5, 7, etc.); sexually active patients must use an acceptable 
method of birth control. 
m. ECG: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
n. MUGA or ECHO: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
o. GFR or Creatinine Clearance: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 
1, 5, 9, etc.). See Appendix VII for GFR calculation. 
p. Immune biomarkers (patient consent is required): Before treatment initiation and 
before Day 1 of Cycles 2, 3, and 9 (within 72 hours prior to Day 1 dosing), and 
within 3 weeks after the last dose of study treatment. See Section 15.2.1 for 
complete details. 
q. Tumor Tissue (patient consent is required): Before treatment initiation and at any 
time tumor tissue is obtained (i.e. surgery). See Section 15.2.2 for complete details. 
r. 
Specimens for Banking (patient consent is required): See Section 15.2.3 for 
complete details. 
s. Tumor Imaging: After Cycles 2, 4, 6, 9, 12, and then every 4 cycles; at relapse. See 
Section 16.2 for complete details. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
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Arm B: Axitinib  
Comments 
(Include any held doses, or dose modifications) 
 
 
 
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Arm B: Axitinib  
 
4.4.3 
Treatment Details – Arm B: Axitinib 
 
IMPORTANT: Arm B is closed to new patients as of Amendment 2A. For 
patients who were enrolled and randomized to Arm B prior to Amendment 
2A, please refer to the treatment details below. 
 
Each cycle lasts 28 days (4 weeks). Absent disease progression or unacceptable 
toxicity, patients may continue on protocol therapy for up to 2 years duration or 
completion of 26 cycles, whichever comes first. 
 
Criteria to start each cycle: ANC ≥ 1000/L, platelet count ≥ 75,000/L without 
transfusion support. See Section 5.0 for other requirements related to any 
toxicities. 
 
Axitinib: PO 
Days: 1 – 28 
Dose: Age-based dosing as follows: 
If ≥ 18 years old: 5 mg/dose BID* 
If < 18 years old: 2.4 mg/m2/dose BID (maximum starting dose of 
5 mg/dose)*. See Appendix IV for axitinib dosing 
nomogram and titrations. 
 
NOTE: Dose is BID. For example, if < 18 years old administer 
2.4 mg/m2/dose BID. The total daily dose is 4.8 mg/m2/day, divided BID 
(maximum starting dose is 5 mg BID). 
 
Axitinib should be taken by mouth twice daily approximately 12 hours apart. 
Axitinib may be taken with or without food. Tablets should be administered whole 
and intact with a glass of water or other liquid; do not crush or cut tablets. If a dose 
is missed or vomited, the patient/subject should not try to repeat or “catch up” the 
dose. The next dose should be given at the next regularly scheduled time point. 
 
Axitinib will be distributed by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. Do not use commercial supply. 
 
*Axitinib dose titration: 
Individual patient dose titration of axitinib (escalation from starting dose) is 
permitted on protocol therapy, at the discretion of the treating physician, if the 
following criteria are met for an individual patient: 
1. Two consecutive cycles are completed at a given dose without any adverse 
reactions > Grade 2 (according to the Common Toxicity Criteria for 
Adverse Events [CTCAE]). 
2. The patient is normotensive, and not receiving anti-hypertension 
medication. 
 
For patients ≥ 18 years old, when a dose increase from 5 mg twice daily is 
recommended, the axitinib dose may be increased by 1 mg/dose twice daily (for 
example, from 5 mg twice daily to 6 mg twice daily, etc), up to a maximum of 
10 mg twice daily. No more than 1 dose titration can occur in each 2-cycle period 
per the criteria above. Refer to the table in Section 5.2.1.1 for additional detail. 

  
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Arm B: Axitinib  
 
For patients < 18 years old, see Appendix IV for dose titration nomograms. No 
more than 1 dose titration can occur in each 2-cycle period per the criteria above. 
The maximum titration dose is as per the Dose Level 3 table in Appendix IV. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of a cycle, begin next cycle on Day 29 or when criteria to 
begin cycle are met, whichever occurs later. 

  
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Arm C: Nivolumab  
 
4.5.2 
Required Observations in Arm C: Nivolumab 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
a. Physical Exam: Prior to each cycle, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly  
For patients ≥ 18 years old, perform every other week  
b. Height/Weight: Prior to each cycle. 
c. CBC/diff/platelets: Prior to each dose of nivolumab, and additionally during Cycle 1: 
For patients < 18 years old, perform weekly  
For patients ≥ 18 years old, perform every other week  
d. Creatinine, bilirubin: Prior to each dose of nivolumab, weekly during Cycle 1 only. 
e. Electrolytes, BUN, Ca2+, PO4, Mg2+: Prior to each dose of nivolumab, weekly during 
Cycle 1 only. 
f. 
AST/ALT/Albumin: Prior to each dose of nivolumab, weekly during Cycle 1 only. 
g. PT/INR: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
h. TSH: Prior to every odd-numbered cycle (e.g., Cycles 1, 3, 5, etc.). 
i. 
Urinalysis/Urine Protein/Creatinine: Prior to Cycles 1, 2, 3 and then prior to every 
odd-numbered cycle (e.g., Cycles 5, 7, 9, etc.). 
j. 
Lipase: Prior to each cycle. 
k. Pregnancy Test: Female patients of childbearing potential require a negative pregnancy 
test within 72 hours prior to starting treatment and then prior to every odd-numbered 
cycle (e.g., Cycles 3, 5, 7, etc.); sexually active patients must use an acceptable 
method of birth control. 
l. 
ECG: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
m. MUGA or ECHO: Prior to every 4th cycle starting Cycle 1 (e.g., Cycles 1, 5, 9, etc.). 
n. GFR or Creatinine Clearance: As clinically indicated. See Appendix VII for GFR 
calculation. 
o. Immune biomarkers (patient consent is required): Before treatment initiation and 
before Day 1 of Cycles 2, 3, and 9 (within 72 hours prior to Day 1 dosing), and 
within 3 weeks after the last dose of study treatment. See Section 15.2.1 for 
complete details. 
p. Tumor Tissue (patient consent is required): Before treatment initiation and at any 
time tumor tissue is obtained (i.e. surgery). See Section 15.2.2 for complete details. 
q. Specimens for Banking (patient consent is required): See Section 15.2.3 for 
complete details. 
r. 
Tumor Imaging: After Cycles 2, 4, 6, 9, 12, and then every 4 cycles; at relapse. See 
Section 16.2 for complete details. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
 
Page 2 of 3 

  
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Arm C: Nivolumab  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
Page 3 of 3 

  
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Definitions of Dose-Limiting Toxicities (DLT) 
DLT will be defined as any of the following events that are possibly, probably, or definitely 
attributable to protocol therapy. 
 
NOTE: Dose-limiting hematological and non-hematological toxicities are defined 
differently. The Study Chair should be notified of any suspected or confirmed DLT. 
 
5.1.1 
Hematological DLT 
5.1.1.1 
Hematological dose-limiting toxicity is defined as: 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/L) or Grade 4 
neutropenia for > 7 days (see Section 5.2), not due to malignant 
infiltration. 
 
5.1.1.2 
Other hematological dose-limiting toxicities: 
• 
Any 
Grade 
2 
arterial 
thromboembolic 
events 
(including 
cerebrovascular ischemia, peripheral or visceral arterial ischemia). 
• 
Any ≥ Grade 3 venous thromboembolic event. 
• 
Any thrombotic event requiring systemic anti-coagulation. 
• 
Any ≥ Grade 2 hemorrhage. 
 
5.1.2 
Non-hematological DLT 
5.1.2.1 
Any Grade 3 or Grade 4 non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
• 
Grade 3 proteinuria (urine protein/ creatinine (P/C) ratio > 1.9 for 
age < 18; urine protein ≥ 3.5 g/24 hours for age 18 and greater) unless 
it is confirmed with a second measurement within 72 hours. 
• 
Grade 3 liver enzyme elevation, including AST/ALT that returns to 
levels that meet eligibility criteria within 7 days of study drug 
interruption and that does not recur upon study drug rechallenge. 
• 
Grade 3 GGT, if checked. (Note: monitoring GGT is not required for 
this study)  
• 
Grade 3 serum electrolyte elevation that returns to baseline within 7 
days and does not require systemic immunosuppression. 
• 
Grade 3 asymptomatic lipase elevation that resolves to meet the 
eligibility criterion within 7 days of study drug interruption and that 
does not recur upon study drug re-challenge. 
• 
Grade 3 or 4 amylase or lipase abnormalities that are not associated 
with diabetes mellitus (DM), associated liver or gall bladder 
inflammation clinical manifestations of pancreatitis and which 
decrease to ≤ Grade 2 within 7 days. 
• 
Grade 3 diarrhea ≤ 3 days duration. 
• 
Grade 3 nausea and vomiting of less < 3 days duration. 
• 
Grade 3 or 4 fever < 5 days duration. 
• 
Grade 3 infection < 5 days duration. 
• 
Grade 3 rash/oral lesion that resolves to Grade ≤ 1 within 7 days. 
• 
Fever greater than 40°C of ≤ 24 hr duration. 
• 
Grade 3 fatigue that resolves to Grade ≤ 2 within 7 days. 

  
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• 
Grade 3 creatinine increased that resolves to Grade ≤ 1 or baseline 
within 7 days. 
• 
Grade 3 pleural effusion that resolves per Section 5.2.6. 
• 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation. 
 
5.1.2.2 
Grade 2 uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 prior to the next 
scheduled dose. 
 
5.1.2.3 
Grade 
2 
non-hematological 
toxicity 
requiring 
systemic 
immunosuppressive therapy, including but not limited to, autoimmunity 
of the lung, heart, kidney, bowel, CNS, pituitary or eye, with the specific 
exclusion of: 
a. Grade 2 pleural effusion that resolves per Section 5.2.6. 
b. Drugs will be held for Grade 2 cardiac dysfunction pending 
evaluation. 
 
5.1.2.4 
Grade 2 endocrine toxicity requiring hormone replacement, with the 
exception of Grade 2 hypothyroidism, thyroiditis, and thyroid 
dysfunction adequately managed with thyroid hormone replacement (see 
Section 5.3). 
 
5.1.2.5 
Grade 2 adrenal insufficiency. 
 
5.1.2.6 
Grade 2 colitis or Grade 2 diarrhea attributable to protocol therapy that 
persists for > 7 days. 
 
5.1.2.7 
Any non-hematological toxicity requiring > 7 days delay in therapy. 
NOTE: Allergic reactions that necessitate discontinuation of study drug 
will not be considered a DLT. 
 
5.1.2.8 
Dose-limiting hypertension 
• 
Any Grade 4 hypertension. 
• 
Any Grade 3 hypertension that persists for > 14 days despite 
adequate antihypertensive treatment. 
 
5.1.2.9 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable 
by patients that it requires treatment interruption. 
 
 

  
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5.2.4 
If a patient experiences Grade 3 or 4 non-hematologic toxicity, axitinib should be 
held until toxicity resolves to ≤ Grade 2. If the toxicity resolves to ≤ Grade 2 within 
7 days, axitinib may be restarted either at the same dose level or at one dose level 
lower (see Section 5.2.1) at the discretion of the treating physician. For delays of 
more than 7 and up to 21 days, dose reduction is required. For delays of more than 
21 days, the patient must be removed from protocol therapy. 
 
5.2.5 
Dose Modifications for Hypertension: 
5.2.5.1 
Baseline blood pressure (BP) is defined as the blood pressure obtained 
at the examination used for study enrollment. This baseline BP should 
be obtained as follows: (1) Obtain 2 serial blood pressures from the same 
extremity with the patient in the same position that are separated by at 
least 1 hour. Avoid using the lower extremity if possible. (2) The baseline 
BP is the average of the systolic measurements over the average of the 
diastolic measurements. 
 
5.2.5.2 
The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender (see Appendix III) for patients 
< 18 years old, and 150/90 mmHg for patients ≥ 18 years old. 
• 
The NCI CTCAE will be utilized to determine the grade of 
hypertension for reporting purposes. 
• 
Elevated BP measurements should be repeated on the same day to 
confirm the elevation. Patients with elevated BP should have BP 
measurements performed at least twice weekly until BP is ≤ ULN. 
• 
Elevation in either systolic or diastolic blood pressure should be 
considered when following the algorithms below. 
• 
Hypertension should be managed with appropriate anti-hypertensive 
agent(s) as clinically indicated. It is strongly recommended that 
nephrology or cardiology be consulted in the evaluation and 
management of hypertension. 
 
5.2.5.3 
Adults (≥ 18 years of age): 
Patients/families will self-monitor BP at home twice weekly and will 
inform their physicians in the event of systolic BP ≥ 140 mmHg or 
diastolic BP ≥ 90 mmHg. In such instances, antihypertensive treatment 
will start or the dose of antihypertensives will be increased per physician 
discretion. Table 1 below provides guidelines for monitoring and 
managing axitinib-related hypertension in adult patients. If the patient 
was already on maximal antihypertensive treatment, the axitinib dose 
will be reduced by one dose level (see Section 5.2.1). 
 
 

  
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Table 1. Recommended Hypertension Monitoring and Management for Adult Patients 
CTCAE Grade 
Antihypertensive Therapy 
Blood Pressure 
Monitoring 
Dose Modification 
Grade 1 –  
Pre-hypertension 
Systolic 120-139 mmHg 
Diastolic 80-89 mmHg 
 
Standard 
No change 
Grade 2 – Moderate 
Systolic 140-159 mmHg 
Diastolic 90-99 mmHg 
1) Initiate LA DHP CCB# 
treatment and if needed, 
after 24-48 hr Rx, 
increase dose in stepwise 
fashion every 24-48 hrs 
until BP is controlled or 
at max dose of Rx. 
2) If BP still not controlled, 
add another 
antihypertensive Rx, a 
BB!, ACEI^, or ARB*; 
increase dose of this drug 
as described in Step 1. 
3) If BP still not controlled, 
add 3rd drug from the list 
of hypertensives in Step 
2; increase dose of this 
drug as described in Step 
1. 
4) If BP still not controlled, 
consider either 1 dose 
reduction of axitinib (see 
Section 5.2.1) or stopping 
axitinib.* 
BP should be monitored 
as recommended by the 
treating physician 
No change except as 
described in Step 4 
Grade 3 – Severe 
Systolic ≥ 160 mmHg 
Diastolic ≥ 100 mmHg 
HOLD axitinib* until 
systolic ≤ 159 mmHg and 
diastolic ≤ 99 mmHg. 
 
BP management is identical 
to that for Grade 2 above 
with 2 major exceptions: 
1) If systolic > 180 mmHg 
or diastolic > 110 mmHg 
and the patient is 
symptomatic: optimal 
management with 
intensive IV support in 
ICU; STOP axitinib.* 
2) If systolic > 180 mmHg 
or diastolic > 110 mmHg 
and the patient is 
asymptomatic: 2 new 
BP should be monitored 
as recommended by the 
treating physician unless 
the patient is 
symptomatic with 
systolic > 180 mmHg 
or 
diastolic > 110 mmHg, 
in which case 
monitoring should be 
intensive. 
HOLD axitinib* until 
systolic ≤ 159 mmHg 
and 
diastolic ≤ 99 mmHg. 
 
In most circumstances, 
if BP cannot be 
controlled after an 
optimal trial of 
antihypertensive 
medications, consider 
either 1 dose reduction 
of axitinib (see Section 
5.2.1) or stopping 
axitinib.* 
 
If the patient requires 
hospitalization for 

  
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antihypertensives must be 
given together in Step 1 
(and dose escalated 
appropriately as in 
Step 1). 
management of 
symptomatic 
systolic > 180 mmHg 
or 
diastolic > 110 mmHg, 
permanently 
discontinue axitinib, or 
if BP is controlled, 
restart axitinib at 1 dose 
level lower.* 
LA DHP CCB #: long-acting dihydropyridine calcium channel blocker 
BB!: beta-blocker 
ACEI^: angiotensin converting enzyme inhibitor 
ARB*: angiotensin II receptor blockers 
*NOTE: Stopping or reducing the dose of axitinib 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. 
 
5.2.5.4 
Pediatrics (< 18 years of age): 
Monitoring for children on axitinib will occur weekly during Cycle 1 
(the period during which development of hypertension is most evident), 
and every other week thereafter. For patients who are dose escalated, 
weekly monitoring for the first cycle at the higher dose will also be 
required. Blood pressure will be measured with an appropriate sized cuff 
at rest. This can be monitored in the clinic or by alternative monitoring 
(home, pediatrician, alternative). 
 
The algorithm in Figure 1 below provides guidelines for managing 
axitinib-related hypertension in pediatric patients. 
 
 

 
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Arm A of algorithm: 
• 
If blood pressure (BP) ≤ 95% for age, height, and gender, continue axitinib 
at the same dose. 
 
Arm B of algorithm: 
• 
If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue 
axitinib at the same dose and recheck the BP within 72 hours. 
o If the BP is ≤ ULN on recheck, continue axitinib at the same dose. 
• 
If the BP remains above the ULN on recheck, then start antihypertensive 
therapy (see Figure 1) and follow Arm C of the algorithm from the point 
that anti-hypertensive therapy is started. 
 
Arm C of algorithm: 
• 
If BP is 11 to 25 mm Hg above the 95% for age, height, and gender or 
> 35 mmHg above baseline, start anti-hypertensive therapy (see Figure 1), 
continue axitinib at the same dose, and monitor BP at least twice weekly. 
o If the BP returns to ≤ ULN within 14 days, continue axitinib at the 
same dose and continue anti-hypertensive therapy. 
o If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm 
Hg above baseline for more than 14 days after the initiation of 
antihypertensive therapy, hold axitinib, monitor BP at least every 
3 days, and follow Arm D of the algorithm from the point that axitinib 
is held. NOTE: When axitinib is held and the patient is on 
antihypertensive treatment, the patient should be closely monitored for 
hypotension. The antihypertensive therapy should be continued until 
the BP is less than the ULN. 
o If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold axitinib, but continue the anti-hypertensive 
agent(s). NOTE: When axitinib is held and the patient is on 
antihypertensive treatment, the patient should be closely monitored for 
hypotension. Monitor the BP as clinically indicated and follow Arm 
D of the algorithm from the point that axitinib is held. 
 
Arm D of algorithm: 
• 
If BP is > 25 mm Hg above the 95% for age, height, and gender hold 
axitinib, monitor BP and administer anti-hypertensive therapy as clinically 
indicated. Note: When axitinib is held and the patient is on 
antihypertensive treatment, the patient should be closely monitored for 
hypotension. 
o If the BP returns to ≤ ULN within 21 days, axitinib may be restarted 
as described in Section 5.2.4. 
o If the BP is > ULN for > 21 days, the patient must be removed from 
protocol therapy. 
 
Arm E of algorithm: 
• 
If the participant develops Grade 4 hypertension, discontinue axitinib, 
monitor BP and administer anti-hypertensive therapy as clinically 
indicated. The patient must be removed from protocol therapy. NOTE: 
When axitinib is held and the patient is on antihypertensive treatment, the 
patient should be closely monitored for hypotension. 

 
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ensue after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor patient closely. 
 
The following prophylactic premedications are recommended for future 
infusions: 
diphenhydramine 
(or 
equivalent) 
and/or 
paracetamol 
(acetaminophen) at least 30 minutes before additional nivolumab 
administrations, slowing infusion rate as above. 
 
5.3.2.2 For Grade 2 symptoms: (Moderate reaction requires therapy or infusion 
interruption but responds promptly to symptomatic treatment [e.g., 
antihistamines, 
non-steroidal 
anti-inflammatory 
drugs, 
narcotics, 
corticosteroids, bronchodilators, IV fluids]; close observation for 
recurrence and treatment medications may need to be continued for 24-
48 hours, and no further nivolumab will be administered at that visit.) 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and 
treat 
the 
subject 
with 
diphenhydramine 
and/or 
paracetamol 
(acetaminophen); remain at bedside and monitor patient until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate. Monitor patient closely. If symptoms 
recur, re-administer diphenhydramine IV, remain at bedside, and monitor 
the patient until resolution of symptoms. The amount of study drug infused 
must be recorded on the electronic case report form (eCRF). 
 
The following prophylactic premedications are recommended for future 
infusions: diphenhydramine (or equivalent) and acetaminophen (or 
paracetamol) should be administered at least 30 minutes before additional 
nivolumab administrations. If necessary, corticosteroids (recommended 
dose of up to 25 mg of IV hydrocortisone or equivalent) may be used. 
 
5.3.2.3 For Grade 3 or Grade 4 symptoms: (Severe reaction) 
Grade 3 symptoms: prolonged (i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, pulmonary infiltrates). 
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support 
indicated). 
 
Nivolumab will be permanently discontinued 
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of 
normal saline, and bronchodilators, epinephrine 1:1,000 solution for 
subcutaneous administration or 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine IV with methylprednisolone IV 
(or equivalent), as needed. Patient should be monitored until the 
investigator is comfortable that the symptoms will not recur. 

 
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Investigators should follow their institutional guidelines for the treatment 
of anaphylaxis. Remain at bedside and monitor patient until recovery from 
symptoms.  
 
5.3.3 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). Additional 
treatment may be administered prior to next dose as per guidelines in Section 5.3.2.  
 
Please note that late occurring events, including isolated fever and fatigue, may 
represent the presentation of systemic inflammation. Please evaluate accordingly. 
 
5.3.4 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject with 
continued study drug dosing should go off protocol treatment.  
 
5.3.5 
Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects must resume protocol 
therapy within 6 weeks of the scheduled interruption. Nivolumab dosing 
interruption lasting > 6 weeks will require treatment discontinuation, with the 
following exception: Dosing interruptions > 6 weeks that occur for non-drug-
related reasons may be allowed. The study chair should be notified when treatment 
is re-initiated in a subject with a dosing interruption lasting > 6 weeks. The reason 
for interruption should be documented in the patient's study record. If toxicity does 
not resolve to Grade 0-1 within 6 weeks after last infusion, protocol therapy should 
be discontinued. Subjects with a laboratory adverse event still at Grade 2 after 6 
weeks may continue protocol therapy only if asymptomatic and controlled. 
 
6.0 
DRUG INFORMATION 
 
6.1 
AXITINIB 
(Inlyta, AG-013736) NSC# 757441, IND# 
  
 
 
(05/21/20) 
 
Source and Pharmacology: 
Axitinib is an oral selective second generation tyrosine kinase inhibitor which blocks 
angiogenesis and tumor growth by inhibiting vascular endothelial growth factor receptors 
(VEGFR-1, VEGFR-2, and VEGFR-3). VEGF receptors are critical components of the 
processes leading to the branching, extension, and survival of endothelial cells which form 
new blood vessels during angiogenesis, an absolute necessity for tumor growth beyond 
microscopic size. Dynamic contrast enhanced-magnetic resonance imaging (Dce-MRI) 
studies showed that axitinib treatment decreased the overall tumor blood flow/permeability 
at as early as 2 days after initiation of treatment, with a maximum reduction in permeability 
surface area product (Ktrans) observed on Day 7 after dosing. The change in vascular 
Ktrans correlated with decreased microvessel density, cellular viability, and tumor growth. 
Axitinib is FDA approved for the treatment of advanced renal cell carcinoma after failure 
of one prior systemic therapy. 
 

 
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Studies showed that the anti-tumor efficacy of axitinib is not driven by Cmax, rather by 
adequate plasma exposure above the concentration for VEGFR target inhibition (Ctarget) 
over a prolonged period of time. Based on a series of studies using various xenograft tumor 
models, the pharmacologically active axitinib concentration for Ctarget was estimated as 
0.1-0.49 nM (or 0.04-0.19 ng/mL, unbound). This translates to a human Ctarget of 
24-98 nM (or 9.3-38 ng/mL, total plasma concentration), assuming a 99.5% human plasma 
protein binding.  
 
Axitinib is rapidly absorbed with bioavailability of 58% and maximal plasma 
concentrations (Cmax) generally occurring within the first 4 hours following oral 
administration. The plasma pharmacokinetics of axitinib at steady state are generally linear, 
with Cmax of 28.7-39.5 ng/mL, AUC0-24 of 261-382 ng•h /mL, mean volume of 
distribution (Vz/F) of 93.7-122 L, and half-life of 2.2-5.2 hours at the initial 5 mg BID 
dose. Axitinib is highly bound to plasma proteins (99.5%). Renal excretion does not 
contribute to the elimination of axitinib, which occurs primarily via hepatobiliary 
excretion. The estimated systemic clearance of 21 L/hr in plasma for axitinib (following 
administration of a 1-mg intravenous dose) is lower than hepatic blood flow (87 L/hr) in 
humans indicating a modest first-pass effect for axitinib. Mild hepatic impairment does not 
alter axitinib plasma exposures (AUC0-∞ and Cmax) compared to normal hepatic function. 
However, there was a ~2-fold increase in axitinib AUC0-∞ and a 1.3-fold increase in 
axitinib Cmax in subjects with moderate hepatic impairment. 
 
Drug Interactions: 
Metabolism of axitinib is primarily mediated by the CYP3A4 drug-metabolizing enzyme, 
and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1 as determined from in vitro 
studies with human liver microsomes. Ketoconazole (a potent CYP3A4 inhibitor) 
increased plasma exposure of axitinib 2-fold and peak plasma concentration 1.5-fold. 
Rifampin (a potent CYP3A4 inducer) caused a 79% decrease in axitinib plasma exposures 
and a 71% decrease in axitinib peak plasma concentrations.  
 
Axitinib is an inhibitor of CYP2C8 in vitro, however, drug interactions studies with 
paclitaxel (CYP2C8 substrate) demonstrated lack of in vivo inhibition of CYP2C8 by 
axitinib at a dose of 5 mg BID. Data from phase I/II studies indicated that plasma profiles 
and pharmacokinetic parameters of paclitaxel, carboplatin, capecitabine, gemcitabine, 
cisplatin, pemetrexed, oxaliplatin, 5-FU, bevacizumab, and irinotecan (including SN-38) 
were similar in the absence and presence of axitinib.  
 
Patients should be counseled to avoid strong inhibitors and inducers of CYP3A4. Please 
see Appendix VI for potential drug interactions with axitinib. 
 
Patient Considerations: 
Axitinib can cause fetal harm when administered to a pregnant woman based on its 
mechanism of action. There are no adequate and well-controlled studies in pregnant women 
using this agent. In developmental toxicity studies in mice, axitinib was teratogenic, 
embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at 
the recommended clinical dose. Women of childbearing potential should be advised to 
avoid becoming pregnant while receiving axitinib.  
 
Mothers taking this drug should not breastfeed. 
 

 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis; Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; 
Hepatic failure; Hepatobiliary disorders - Other (bile duct stone); Hepatobiliary disorders - Other (cholestasis); 
Hepatobiliary disorders - Other (colelithiasis); Hepatobiliary disorders - Other (hepatorenal syndrome); Hepatobiliary 
disorders - Other (jaundice) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture; Spinal fracture 
INVESTIGATIONS - GGT increased 
METABOLISM AND NUTRITION DISORDERS - Hypermagnesemia; Hypomagnesemia; Metabolism and 
nutrition disorders - Other (cachexia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Flank pain; Generalized muscle 
weakness; Myalgia; Neck pain; Trismus 
NERVOUS SYSTEM DISORDERS - Dysphasia; Encephalopathy; Ischemia cerebrovascular; Lethargy; 
Paresthesia; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - Other (mental 
status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Dysuria; Renal and urinary disorders - Other (acute 
prerenal failure); Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Hoarseness; Hypoxia; 
Oropharyngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (chronic obstructive pulmonary disease); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; Pruritus; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (scrotal skin rash); Skin ulceration 
VASCULAR DISORDERS - Hypotension; Vascular disorders - Other (circulatory collapse) 
 
 
Note: Axitinib (AG-013736) 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. 
 
 
Formulation and Stability: 
Formulation 
The agent is supplied as 1 mg and 5 mg tablets for oral administration. The 1 mg tablets 
are red film-coated, oval tablets debossed with “Pfizer” on one side and “1 XNB” on the 
other; available in bottles of 180 tablets each. The 5 mg tablets are red film-coated, 
triangular tablets debossed with “Pfizer” on one side and “5 XNB” on the other; available 
in bottles of 60 tablets each. Tablet excipients include microcrystalline cellulose, lactose 
monohydrate, croscarmellose sodium, and magnesium stearate.  The Opadry II red 
32K15441 film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, 
titanium dioxide, triacetin (glycerol triacetate), and red iron oxide. 
 
Stability and Storage 
Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 
86 °F) [USP Controlled Room Temperature]. Refer to the package label for expiration. If 
a storage temperature excursion is identified, promptly return axitinib 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. 
 

 
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Tablets may be removed from the original container and repackaged in a vial suitable for 
oral tablets by the dispensing pharmacy. 
 
Guidelines for Administration: 
See Treatment Details (Section 4.0) and Dose Modifications (Section 5.0) of the protocol. 
 
Axitinib should be taken by mouth twice daily approximately 12 hours apart. Axitinib may 
be taken with or without food. Tablets should be administered whole and intact with a glass 
of water or other liquid; do not crush or cut tablets. If a dose is missed or vomited, the 
patient/subject should not try to repeat or “catch up” the dose. The next dose should be 
given at the next regularly scheduled time point. 
 
Supplier: 
Axitinib is supplied by Pfizer Inc. and distributed by the CTEP, Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. Do not use commercial supply. 
 
Obtaining the Agent 
Agent Ordering 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), 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. 
 
Sites may order initial agent supplies when a subject has been randomized.  
 
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, and 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. 
 
Agent Accountability 
Agent Inventory Records 
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 
(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. 
 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent 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 IAM account and the maintenance 

 
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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. 
 
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 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator:  IBCoordinator@mail.nih.gov  
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
 
6.2 
NIVOLUMAB 
(BMS-936558, MDX1106, ONO-4538, anti-PD-1, Opdivo) NSC# 748726, 
IND# 
   
 
 
 
 
 
 
(03/09/2021) 
 
Source and Pharmacology:  
Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that 
selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 
receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor 
signaling that regulates T-cell activation and proliferation is therefore disrupted. This 
releases PD-1 pathway-mediated inhibition of the immune response, including the 
antitumor immune response. The clinical activity of nivolumab was initially evaluated in 
malignant melanoma and squamous non-small cell lung cancer (NSCLC), and the 
remarkable response rates, prolonged survival, and better safety profile were the basis of 
regulatory approval. Nivolumab is FDA-approved for a variety of solid tumors including 
advanced renal cell carcinoma (RCC). 
 
The pharmacokinetics of single-agent nivolumab was studied in patients over a dose range 
of 0.1 to 20 mg/kg administered as a single dose or as multiple doses every 2 or 3 weeks. 
Nivolumab clearance decreases over time, resulting in a geometric mean steady state 
clearance (CLss) of 8.2 mL/h; the decrease in CLss is not considered clinically relevant. 
The geometric mean volume of distribution at steady state (Vss) is 6.8 L, and geometric 
mean elimination half-life is 25 days. Steady-state concentrations of nivolumab were 
reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and 
systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased 
dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks.  
 
No formal pharmacokinetic drug-drug interaction studies have been conducted with 
nivolumab. The indirect drug-drug interaction potential of nivolumab was assessed using 
systemic cytokine modulation data for cytokines known to modulate CYP enzymes. There 
were no meaningful changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab. This lack of cytokine modulation suggests that 

 
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Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders - 
Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune thrombotic 
microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other (protein total 
decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab 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. 
 
Formulation and Stability: 
The agent is a clear to opalescent, colorless to pale yellow liquid; light (few) particulates 
may be present. It is available in a 100 mg/10 mL vial containing a sterile, non-pyrogenic, 
single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate dihydrate, 
sodium chloride, mannitol, diethylenetriamine pentacetic acid (pentetic acid), polysorbate 
80 (Tween® 80), and water for injection. Dilute solution of hydrochloric acid and/or 
sodium hydroxide may be used for pH adjustment (pH 5.5-6.5). A small amount of overfill 
(0.7 mL) is included with each vial to account for VNS (vial, needle, syringe) loss.  The 10 
mL type I flint glass vials are stoppered with fluoropolymer film-laminated rubber stoppers 
and sealed with aluminum seals. 
 
Preparation: Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose. When the dose is based on patient 
weight (i.e., mg/kg), nivolumab injection can be infused undiluted or diluted to protein 
concentrations as low as 0.35 mg/mL. When the dose is fixed (e.g., 240 mg or 480 mg flat 
dose), nivolumab injection can be infused undiluted or diluted so as not to exceed a total 

 
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infusion volume of 160 mL. For patients weighing less than 40 kilograms (kg), the total 
volume of infusion must not exceed 4 mL per kg of patient weight. During drug product 
preparation and handling, vigorous mixing or shaking is to be avoided. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles. 
 
Storage: Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected 
from light and freezing. Unopened vials can be stored at room temperature (up to 25°C, 
77°F) and room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°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. 
 
Stability: Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed 
within 24 hours of preparation. If not used immediately, the infusion solution may be stored 
up to 24 hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 
24 hours can be at room temperature (up to 25°C, 77°F) and room light. The maximum 8-
hour period under room temperature and room light conditions for nivolumab injection in 
IV bag includes the product administration period.  
 
CAUTION: The single-use vials of nivolumab for injection do not contain antibacterial 
preservatives or bacteriostatic agents and should be prepared as soon as possible prior 
to administration using aseptic technique. It is advised that the product be discarded 8 
hours after initial entry. 
 
Guidelines for Administration: 
See Treatment and Dose Modification sections of the protocol. 
Nivolumab is administered as an intravenous infusion over 30 minutes or per institutional 
guidelines through a line with a sterile 0.2 to 1.2 micron pore size, low-protein binding 
(polyethersulfone membrane) in-line filter. Nivolumab is not to be administered as an IV 
push or bolus injection. Do not administer other medications through the same IV line. 
Flush IV line at the end of the infusion. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles.  
 
Supplier: 
Nivolumab is supplied by Bristol-Myers-Squibb (BMS) and distributed by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. Do not use commercial supply. 
 
Obtaining the Agent 
Agent Ordering 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 

 
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investigator 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. 
 
Sites may order initial agent supplies when a subject has been randomized.  
 
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, and 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. 
 
Agent Accountability 
Agent Inventory Records 
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 
(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. 
 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent 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 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. 
 
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 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator:  IBCoordinator@mail.nih.gov  
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 
 
 

 
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• 
Year 2 (Months 16, 20 and 24) 
• 
Year 3 (Months 30 and 36) 
• 
Year 4 (Months 42 and 48) 
 
7.3 
Research Studies for which Patient Participation is Optional 
 
1. Immune biomarkers in blood (see Section 15.2.1) will be collected at: 
o Baseline, Day 1 of Cycles 2, 3, and 9 (within 72 hours prior to Day 1 dosing), and 
within 3 weeks after the last dose of study treatment. 
2. Immune biomarkers in tumor tissue (see Section 15.2.2) will be collected at: 
o Baseline (if available), and at any time tumor tissue is obtained (i.e., surgery, 
relapse). 
3. Specimens for Banking (see Section 15.2.3) will be collected at: 
o Baseline (if available), and at any time tumor tissue is obtained (i.e., surgery, 
relapse) for tumor tissue. Prior to any chemotherapy for whole blood, serum and 
urine specimens. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) For Arms A and C, progressive disease of ≥ 40% increase in total tumor burden from 
baseline or nadir at any time during protocol therapy (see Section 10.2) (see exception 
below).  
b) For Arms A and C, progressive disease of ≥ 20% increase in total tumor burden from 
baseline or nadir that occurs > 12 weeks after start of protocol therapy, except if a patient 
met the criteria for pseudoprogression in the first 12 weeks and the total tumor burden has 
subsequently stabilized or decreased with no additional growth (see Section 10.2) (see 
exception below). 
c) For Arm B, progressive disease of ≥ 20% increase from baseline or nadir in total tumor 
burden at any time during protocol therapy (see Section 10.2). 
d) Response followed by ≥ 20% increase in total tumor burden from the nadir at any time 
during protocol therapy (see Section 10.2.5.1) (see exception below). 
e) Appearance of one or more new lesions or unequivocal progression of non-target lesions 
(see Section 10.2.5.2) and refer to Section 10.2.1 for exceptions within the first 12 weeks 
of therapy (see exception below). 
f) Resection of any malignant lesion within the first 12 weeks of protocol therapy (see 
Section 13.1.8.1). 
g) Resection of any lesion that is increasing in size at any time while on protocol therapy 
(see Section 13.1.8.2).  
h) Completion of planned therapy. 
i) Unacceptable toxicity due to protocol therapy (see Section 5.0). 
j) Refusal of further protocol therapy by patient/parent/guardian. 
k) Physician determines it is in patient’s best interest. 
l) Development of a second malignancy. 
m) Pregnancy. 
n) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2). 
 

 
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Exception: Patients on Arm C who meet the protocol defined criteria of disease progression 
prior to Cycle 22 of therapy, may cross-over and receive the remainder of their protocol 
therapy per Arm A. For those patients who cross-over, the total protocol therapy received on 
AREN1721 is not to exceed 26 cycles or 2 years, whichever comes first. 
 
Important Note: For criteria (a)-(c) above, calculations of percentage change in total 
tumor burden should fully exclude from consideration any malignant lesions that were 
surgically resected at any time prior to the most recent response assessment. See Section 
10.2 for details. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Study Duration 
As of Amendment 5A, which now allows crossover upon progression from the nivolimab 
arm to the nivolumab + axitinib arm, we expect enrollment of approximately 2 patients per 
month. This is derived from tRCC prevalence, access to treatment centers, and enrollment 
patterns to date, which should be aided by the crossover.  
 
To reduce the overall sample size from the prior design, we have maintained the same 
overall study design but changed two design parameters: 1-sided alpha will be increased 
from 0.05 to 0.15, and the targeted hazard ratio will be reduced from HR = 0.50 to HR = 
0.40. With these changes, 22 PFS events will be required to address the primary objective 
comparing Arms A and C at the time of final analysis (see Section 9.2). Allowing that 
approximately 25% of eligible and evaluable patients may not have experienced a PFS 
event by the time of the final analysis, the target accrual on this study is 28 patients. To 
account for an additional estimated 5% of patients who might be found to be ineligible for 
the study or inevaluable for the primary endpoint at the time of or following study 
enrollment (e.g., due to randomization to Arm B, no central path review performed, or 
having central path review confirming a diagnosis other than tRCC), the ceiling accrual 
will be set to 40 patients, including those patients already enrolled.  
 
If the study accrues to the target accrual without interim stopping for futility, the additional 
time required to enroll up to this maximum once re-opening under Amendment 5A is 
estimated to be 14 months. As before, all eligible patients will be followed for 5 years after 
randomization, and the final analysis will be conducted once the target number of PFS 
events needed for the final analysis has been reached, or after 2 years of follow-up is 
obtained for the last patient enrolled, whichever occurs first.  
 

 
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9.2 
Study Design 
With Amendment 5A, as before, eligible tRCC patients will be randomized to receive 
either axitinib and nivolumab (Arm A) or nivolumab alone (Arm C) in a 1:1 ratio. The 
enrolling institutions will assess the initial patient eligibility, including the type of RCC. 
Randomization will incorporate stratification for age (< 18 years vs. ≥ 18 years), and prior 
systemic therapy for RCC (none, anti-VEGF based therapy, or systemic therapy other than 
anti-VEGF). Patients may receive their assigned therapy for up to 2 years or 26 cycles of 
therapy, whichever occurs first, as long as they do not experience either progressive disease 
as defined by the immune RECIST criteria (see Section 10.2.5) or unacceptable toxicities. 
The primary endpoint of this study is progression-free survival (PFS), defined as the time 
from randomization to the earliest of disease progression (according to RECIST adapted 
for immunotherapy) or death due to any cause (see Sections 9.4 and 10.2). 
 
In planning the amended 2-arm design of this study, patient-level data on tRCC patients 
with metastatic disease who would have been eligible for AREN1721 were extracted from 
three separate cohorts: 7 patients from the cohort described by Ambalavanan and Geller, 
15 patients from the cohort described by Malouf et al, and 3 patients from the COG study 
AREN03B2.34,24 PFS for the 3 cohorts was plotted together and found to be in agreement 
(log-rank test p = 0.72; Figure 1A). As such, these data were pooled into a single 
“historical” cohort used to select an appropriate parametric distribution for PFS in this 
disease setting from the proportional hazards family of models, from which determinations 
of power and sample size could be based. Upon superimposing the “best-fit” exponential, 
Weibull, and piecewise exponential models onto the Kaplan-Meier plot for PFS in the 
pooled historical cohort, it was determined that the piecewise exponential model offered a 
practically superior fit warranting the relative increase in model complexity (Figure 1B): 
 
Figure 1A 
 

 
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Figure 1B 
 
 
A comprehensive simulation study was then performed, varying the following: the target 
sample size and maximum number of events required at the final analysis time point, the 
number and timing of interim analyses for futility, futility stopping strategies (conditional 
power under the alternative and current HR), and the true underlying hazard ratio (from 
HR = 1.0, the null hypothesis type I error scenario, to HR = 0.40, the target alternative 
hypothesis scenario). For all settings and strategies evaluated in simulations, accrual was 
assumed to be uniformly distributed as 24 patients per year (as reasoned above, 
acknowledging that slower than expected accrual will yield greater statistical power than 
reported here). PFS in the control arm was assumed to follow the piecewise exponential 
distribution shown in Figure 1B. With 100,000 replicates (simulated trials) used to assess 
each scenario, we arrived at the following trial design and set of operating characteristics.  
 
The trial will enroll a target of 28 patients to observe 22 PFS events, which are required to 
achieve at least 80% power to detect a hazard ratio of HR=0.40 using a one-sided stratified 
log-rank test with alpha = 0.15. If stratum-specific sample sizes allow, stratification of the 
test will included those factors used for stratification at the time of randomization (age and 
prior systemic therapy).  
 
The trial will include one formal interim analyses for futility, conducted at 50% (11) of the 
required 22 PFS events. At this time, an observed hazard ratio greater than 1.00 (i.e., a 

 
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trend in the wrong direction) will result in early termination of the trial for futility. The 
simulated percentage change of early stopping for futility at the planned interim analysis 
(“early futility), continuing to the final analysis but failing to reach statistical significance 
(“lack of efficacy”), and continuing to the final analysis and reaching statistical 
significance (“efficacy”) are tabled below for a range of true underlying hazard ratios. Also 
presented are the average simulated sample size (“Average N”) and average simulated time 
from reopening with Amendment 5A to final trial outcome (“Average Remaining 
Duration”) corresponding to each possible trial outcome. These numbers take into account 
the patients already enrolled, eligible, and anticipated to be evaluable for the primary 
endpoint. 
 
 
 
True HR 
Interim Analysis (50% Events) 
Final Analysis (100% Events) 
 
Average N 
Average 
Remaining 
Duration 
Early 
Futility 
Lack of 
Efficacy 
 
Efficacy 
 
Average N 
Average 
Remaining 
Duration 
HR = 1.0 
24 
9 months 
50% 
36% 
14% 
28 
17 months 
HR = 0.5 
25 
10 months 
15% 
19% 
66% 
28 
21 months 
HR = 0.4 
26 
10 months 
8% 
12% 
80% 
28 
23 months 
 
 
9.3 
Methods of Analysis 
 
Primary Endpoint Analyses 
The primary endpoint, progression-free survival, is formally defined in Section 9.4 below. 
Due to the small size of this trial and the need to preserve alpha-spending for the final 
analysis, there will be no formal interim analyses of PFS for early efficacy, though this trial 
will be periodically reviewed by the COG DSMC.  
 
Prospective formal interim analyses for futility will be performed once 50% (11) of the 22 
targeted PFS events have been observed. The trial will stop early for futility if, given the 
data observed to date, the observed hazard ratio for PFS is greater than 1.00, suggesting a 
trend toward worse outcomes for Arm A (nivolumab + axitinib) compared to Arm C 
(nivolumab alone).  
 
The final PFS analysis will be performed based on the first quarterly data freeze where at 
least one of the following criteria are met: (1) a minimum of 2 years of follow-up has been 
obtained for each patient still “at risk” for a PFS event or (2) when at least 22 PFS events 
needed for a fully powered final analysis have been confirmed. At this time, a stratified, 
one-sided log-rank test (using the stratification factors at randomization, age and prior 
therapy, if stratum-specific sample sizes allow) will be performed to compare treatment 
arms with alpha = 0.15. A stratified Cox proportional hazards model will also be fit to 
evaluate the final hazard ratio between the treatment arms (stratification as numbers allow); 
this will be reported with a 70% confidence interval (to align with the overall alpha level 
of the primary log-rank test).  
 
While post-progression outcomes on combination therapy among patients who receive 
crossover upon first progression on the nivolumab-only arm (Arm C) will not be counted 
toward the primary endpoint analyses, their post-progression experience, including time 
from first progression to second progression or death (second PFS) will be summarized 
descriptively. 

 
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Secondary Endpoint Analyses 
 
Secondary endpoints OS and ORR (defined in Section 9.4 below) as well as all Grade 3 
non-hematologic adverse events and all Grade 4 and higher adverse events will be 
monitored for data cleanliness and routine reporting as well as formally compared at the 
time of the final analysis for the primary endpoint, as described below. For ORR and OS 
below, stratifications factors again may be collapsed and/or omitted depending on the final 
counts. 
 
ORR: A logistic regression model for overall response, stratified by the stratification 
factors used at randomization (age and prior therapy) will be fit, including treatment arm 
as a key covariate. From this model, the odds ratio for treatment arm will be reported with 
a 70% confidence interval.  The ORR observed within each treatment arm will also be 
reported.   
 
OS: A stratified, one-sided log-rank test (using the stratification factors at randomization, 
age and prior therapy) will be performed to compare treatment arms with alpha = 0.15.  
Cox proportional hazards models will also be fit to evaluate the final hazard ratio between 
the treatment arms, with exploratory modeling taking into account the potential influence 
of other factors (e.g., baseline disease burden, upfront vs. delayed nephrectomy). From 
these models, the hazard ratio for treatment assignment will be reported with a 70% 
confidence interval (to align with the overall alpha level of the primary log-rank test). 
 
AEs: All Grade 3 or higher non-hematologic toxicities and all Grade 4-5 adverse events 
occurring during protocol therapy or within 100 days of treatment discontinuation, 
including crossover for patients who receive crossover combination therapy, will be 
analyzed. The rates of these events will be reported separately by treatment arm (including 
crossover as a “3rd” arm for this purpose), and both by individual AE and class of AE (e.g., 
hematologic). Given that some AEs may be rare, Fisher Exact tests will be used to test for 
statistical significance among any apparent differences by treatment arm. 
 
Exploratory Analyses 
 
Exploratory Aim 1.3.1: To characterize tRCC clinical behavior across all age groups. 
We will list and summarize the frequency of site(s) of disease at presentation (including 
extent of lymph node involvement), site(s) of relapse, surgical practices on protocol 
therapy, and radiotherapy practices on protocol therapy. We will also summarize the 
overall response rate (ORR) submitted by the enrolling institution. 
 
Exploratory Aim 1.3.2: To evaluate type of antitumor immune response and stability of T 
cell activation before and after treatment with immunotherapy or antiangiogenic therapy. 
We will summarize the levels of analytes and tumor expression before and after treatment 
and evaluate the changes due to treatment after logarithmic transformation using the paired 
t-test. Analytes include myeloid derived stem cells (MDSC): CD45, CD11b, CD33, CD14, 
CD15, HLA-DR, viability, stain 1; Tregs: viability, CD45, CE4, CD3, CD24, FoxP3; CD8 
T cells (CD45, CD8, CD3); CD8 phenotype and activation and exhaustion (CD69, CD38, 
PD1, CD244, TIM3). Tumor expression of PDL-1, PD1, CD3, CD4 and CD8 will be 
assessed using TFE RCC samples from the study and scored for intensity (0 – 3). 
 

 
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Exploratory Aim 1.3.4: To characterize the pharmacokinetics of axitinib when given in 
combination with nivolumab in pediatric patients with tRCC. 
The population PK analysis will include all treated patients enrolled beyond Amendment 
5A who have at least 1 concentration above the below limit of quantitation (BLQ) in 
patients treated with axitinib. Pooled PK analysis with another study is to explore the effect 
of age and body size on axitinib CL/F and Vd/F and make predictions on the dosing of 
axitinib in pediatric patients in different age groups. Exposure-response relationships will 
also be explored. The results will be reported separately in a population modeling analysis 
report. For the purposes of PK analysis, patients who receive crossover therapy will be 
reported both as a separate cohort and pooled with patients receiving combination therapy 
up front. 
 
9.4 
Endpoints and Evaluability 
The primary endpoint is progression-free survival (PFS), which is defined as the time from 
randomization to the earliest occurrence of disease progression (as defined by modified 
RECIST criteria for immunotherapy, described in Section 10) or death due to any cause 
among patients who initiated protocol treatment. Patients not experiencing a PFS event by 
the time of a prospectively-planned interim or final analysis will be right-censored at the 
time of their most recent response/progression evaluation. Following the intent-to-treat 
principle, all patients who are randomized and confirmed to have tRCC by central 
pathology review will be evaluable for PFS. Patients randomized to Arm B prior to 
Amendment 2A, and patients who have a central path review confirming a diagnosis other 
than tRCC, or who never receive central path review per protocol, will be considered 
inevaluable for the primary endpoint comparison but included in study descriptive 
statistics. 
 
The overall response rate (ORR) will be defined as the rate of complete or partial responses 
(assessed by imaging) among patients who initiated protocol therapy and completed at least 
one subsequent imaging assessment. Patients who are randomized to Arms A or C and are 
confirmed to have tRCC by central pathology review will be evaluable for ORR. 
 
Overall survival (OS) will be calculated as the time from randomization to death due to 
any cause, with surviving patients being right-censored at their length of follow-up at the 
time of analysis. Patients who are randomized to Arms A or C and are confirmed to have 
tRCC by central pathology review will be evaluable for OS. 
 
Note: For calculations of both PFS and ORR, any lesions resected during protocol therapy 
for reasons other than progression (as noted by sites or documented upon central surgical 
review) 
will 
not 
contribute 
toward 
response/progression 
assessments. 
Response/progression assessments are scheduled to take place after Cycles 2, 4, 6, 9, 12, 
and then every 4 cycles thereafter, after every cycle following any suspected 
pseudoprogression until the total tumor burden subsequently diminishes, or at any time 
clinical progression is suspected.  Once in follow-up, patients without a documented PFS 
event will be evaluated according to the schedule in Section 7.2. ORR and OS will be 
analyzed as a part of exploratory aim 1.3.1. 
 
9.5 
Monitoring Boundary for Dose-Limiting Toxicities  
Definitions of DLTs provided in ADVL1315 (for axitinib related DLTs) and ADVL1412 
(for PD1-targeting immune checkpoint DLTs) will be used (Section 5.1). DLTs in each 
arm will be monitored at least weekly to ensure there is no excess toxicity, specifically. No 

 
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Following baseline evaluation and treatment initiation, patients should be re-evaluated for 
lesion response or progression after Cycles 2, 4, 6, 9, 12 and then every 4 cycles thereafter 
with additional imaging required (1) after every cycle following possible 
pseudoprogression until subsequent response is documented, and (2) at any time clinical 
progression is expected. During follow-up, repeat imaging evaluations should occur 
according to the schedule described in Section 7.2. Confirmatory scans should also be 
obtained 6-8 weeks (not less than 4 weeks) following initial documentation of objective 
response.  
 
At each imaging timepoint, the largest diameter (unidimensional measurement) of each 
target, non-target, or new lesion and the shortest diameter (axis) for each malignant lymph 
node should be recorded.  Any lesions that were surgically resected since the last imaging 
assessment should be explicitly noted, along with the date and rationale for removal, and an 
indication of whether the lesion had been increasing in size at the time of surgical removal. 
 
IMPORTANT NOTE: All calculations of percentage change in total tumor burden to 
assess response or progression should fully exclude from consideration any malignant 
lesions that were surgically resected at any time prior to the most recent response 
assessment. 
 
10.2.1 Exceptions for Possible Delayed Response (‘Pseudoprogression’) – only 
applicable for patients on Arms A and C  
Patients in whom the magnitude of increase in tumor size is ≥ 20% but < 40% from 
baseline may remain on protocol therapy for up to 12 weeks after start of 
protocol therapy if all of the following criteria are met, to allow for the possibility 
of pseudoprogression followed by a later tumor response (which may occur during 
treatment with immunotherapy): 
• 
In the judgment of the treating clinician, the patient does not show evidence 
for rapid disease progression or the patient has shown evidence for clinical 
benefit. 
• 
There is no decrease in performance status. 
• 
The patient is tolerating the study drug and there has been no DLT (see 
Section 5.1). 
• 
Continued treatment with nivolumab alone or in combination with axitinib 
will not delay an imminent intervention required to prevent a serious 
complications (e.g. CNS metastases which require radiation therapy or 
surgery). 
 
For response assessments occurring during the first 12 weeks on protocol therapy, 
new lesions with a longest diameter of < 10 mm (or newly noted lymph nodes with 
short axis < 15 mm) should not be counted toward the total tumor burden. Only 
new lesions with a longest diameter ≥ 10 mm (or lymph nodes with short 
axis  ≥ 15 mm) should be included in the total tumor burden and assessments of 
percentage change from baseline or nadir.  
 
For patients who remain on protocol therapy despite an increase in tumor 
burden ≥ 20% (possible pseudoprogression) during the first 12 weeks, imaging to 
include target lesions must occur every cycle, and the same radiographic and 
clinical criteria must be met in order to remain on protocol therapy. If tumor burden 
subsequently diminishes to < 20% increase from baseline or nadir, the patient may 

 
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be followed according to the standard protocol guidelines which will involve less 
frequent imaging. The decision to continue treatment beyond radiographic 
evidence for disease progression (≥ 20% increase in tumor burden) may be 
discussed with the study PI and should be documented in the study record. 
 
If at the Week 12 assessment the total tumor burden has not yet diminished 
to < 20% increase from baseline or nadir, a patient may stay on protocol therapy 
so long as tumor shrinkage/stabilization continues to occur. If at any point after 
Week 12 the total tumor burden increases and is ≥ 20% from baseline or nadir, this 
will be defined as progressive disease and the patient must be removed from 
protocol therapy. 
 
Patients whose best response in the first 12 weeks is pseudoprogression, but who 
subsequently come off protocol therapy prior to any further assessment, will be 
considered as having progressive disease. This will include patients who are 
removed from protocol therapy due to resection of tumor lesions that are increasing 
in size (see Section 13.1.8.2). 
 
Note: An increase in tumor size of ≥ 40% at any time will be considered true 
progression and will result in removal from protocol therapy. 
 
10.2.2 Definitions 
10.2.2.1 Evaluable for toxicity: All patients will be evaluable for toxicity from 
the time of their first treatment with axitinib, nivolumab, or the 
combination of axitinib and nivolumab. 
 
10.2.2.2 Evaluable for objective response: Only those patients who have 
measurable disease present at baseline, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of Cycle 1 will also be 
considered evaluable.) 
 
10.2.2.3 Evaluable non-target disease response: Patients who have lesions present 
at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
10.2.3 Disease Parameters 
10.2.3.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or 
≥ 10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable in the event that such 

 
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lesions have progressed subsequent to such radiation. 
 
10.2.3.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
10.2.3.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. Bone lesions, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
10.2.3.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included 
in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
10.2.3.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
10.2.4 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 

 
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calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
10.2.4.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (e.g., skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
10.2.4.2 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
 
10.2.4.3 Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (eg, for body 
scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for 
the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse 
sequence. It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
10.2.4.4 PET-CT: At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT 

 
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introduces additional data which may bias an investigator if it is not 
routinely or serially performed. 
 
10.2.4.5 Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound 
examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
10.2.4.6 Endoscopy, Laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised. However, such techniques 
may be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
10.2.4.7 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate 
between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
10.2.4.8 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site 
of disease confirmed by CT, this is PD. If the positive FDG-PET 
at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there 
is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid 
with an uptake greater than twice that of the surrounding tissue on the 

 
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attenuation corrected image. 
 
10.2.5 Response Criteria 
10.2.5.1 Evaluation of Target Lesions 
IMPORTANT: All calculations of percentage change in total tumor burden to 
assess response or progression should fully exclude from consideration any 
malignant lesions that were surgically resected at any time prior to the latest 
response assessment.   
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. See Section 10.2.1 for 
exceptions during the first 12 weeks. 
 
At least a 40% increase in the sum of diameters of 
target lesions at any time during the study, taking 
as reference the smallest sum measured on study (this 
includes the baseline sum if that is the smallest on 
study). 
 
Appearance of one or more new lesions is also 
considered progression. See Section 10.2.1 for 
exceptions during the first 12 weeks. 
 
For patients who achieve a CR, either due to protocol 
therapy or surgical resection of any remaining 
malignant lesions, occurrence of a new lesion 
≥ 10 mm or the short axis of a lymph node increasing 
to ≥ 15 mm at any time is considered PD. 
 
An initial response (any decrease in tumor size) 
followed by growth of at least 20% (relative to the 
nadir) at any time is considered PD. 
 
Patients who are removed from protocol therapy for 
resection of lesions that are increasing in size (per 
Section 13.1.8.2) will be considered to have PD at the 
time of tumor resection. 
 

 
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PD/not evaluated 
once ≥ 4 wks. from 
baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD# 
Any 
Any 
Yes 
PD# 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
#      See Section 10.2.1 for exceptions for pseudoprogression during the first 12 weeks of 
protocol therapy. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
10.2.6 Duration of Response 
10.2.6.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
10.2.6.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
10.2.7 Progression-Free Survival 
PFS is defined as the duration of time from randomization to the earlier of 
progression (as defined in this section) or death due to any cause. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Purpose 
Adverse event (AE) 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. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting table 

 
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assigned to the protocol (Section 11.8), using the CTEP Adverse Event Reporting System 
(CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
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 a serious adverse drug experience 
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. 
 
11.3 
Specific Examples for Expedited Reporting  
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting table in this protocol (Section 11.8).  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered serious AEs. 
 
11.3.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: Newborn death occurring during the first 28 days after 
birth.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 

 
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administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.3.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy. 
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.3.5 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 unless otherwise specified. 
 
11.3.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy 
loss”, or “Death Neonatal”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. 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. 
 
11.3.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to 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. 
 

 
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Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.3.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.3.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth” should be reported expeditiously, as Grade 
4 “Death neonatal” under the “General disorders and administration” 
SOC when the death is the result of a patient pregnancy or 
pregnancy in partners of men on study. Do NOT report a neonatal 
death resulting from a patient pregnancy or pregnancy in partners of men 
on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death.  
 
11.4 
Reporting Requirements for Specialized AEs  
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 

 
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EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
11.5.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.5.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed in Section 
11.9 of this protocol. 
 
11.6 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database. 
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to (301) 897-
7497.  

 
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In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site. 
 
• 
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 event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 897-7404.  
 
Also: Fax or email supporting documentation to COG for all IND studies 
(Fax# (310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: COG 
AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 

 
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Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
11.9.1 Grades 1-2 myelosuppression (anemia, neutropenia, and thrombocytopenia) do not 
require expedited reporting. 
11.9.2 Hospitalization for surgery to resect tumor, primary or metastatic, will not be 
considered an SAE. 
11.9.3 For patients who receive nivolumab as part of this study, reporting of immune 
related AEs (IMAEs) via CTEP-AERS must continue up to 100 days post last dose 
of nivolumab. 
 
11.10 Routine Reporting of Adverse Events 
NOTE: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events, all DLTs (see Section 5.1), and all Grade 3 and higher Adverse Events. 
 
NOTE: For patients who receive nivolumab as part of this study, routine reporting of 
immune related AEs (IMAEs) must continue up to 100 days post last dose of nivolumab. 
 
 
12.0 
STUDY REPORTING AND MONITORING  
 
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
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 quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 

 
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The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its own 
Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 

 
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Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13.0 
SURGICAL GUIDELINES 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
13.1 
Surgical Principles 
13.1.1 Study Inclusion Criteria 
This study is designed to study patients with histologically confirmed, unresectable 
or metastatic translocation morphology renal cell carcinoma diagnosed using 
WHO-defined criteria who also have measurable disease as defined by RECIST 

 
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v1.1 and an inability to undergo complete resection of the disease by surgery. 
Therefore, patients eligible for this study must have histological confirmation of 
disease either by biopsy, nephrectomy or metastectomy and after this diagnostic 
surgery still have remaining, measurable disease. The decision about the 
resectability of remaining disease is left to the treating institution. 
 
13.1.2 Cytoreductive Nephrectomy 
Cytoreductive nephrectomy is not required for patient enrollment; however, we 
encourage cytoreductive nephrectomy when feasible. Level I evidence from the 
prior immune-modulatory era (cytokine era) for treating metastatic renal cell 
carcinoma demonstrated the survival benefit of cytoreductive nephrectomy.64, 65 
While we await randomized-trial data about the impact of cytoreductive 
nephrectomy in the current era of targeted therapy for metastatic renal cell 
carcinoma, analyses of retrospective and administrative data suggest that it may be 
beneficial in select patients.66, 67 Therefore, when possible we would encourage 
cytoreductive nephrectomy prior to beginning protocol therapy. Per Section 
3.2.8.3, patients must be more than 7 days out from major surgery (which includes 
open or laparoscopic nephrectomy) for eligibility. For the purposes of this study 
cytoreductive nephrectomy may include radical or partial nephrectomy and may 
be achieved by either an open or laparoscopic approach. Additionally, delayed 
cytoreductive nephrectomy is permitted 12 weeks after starting protocol therapy, 
taking into account the need for holding axitinib before and after nephrectomy per 
Section 13.1.8.3. 
 
13.1.3 Primary Nephrectomy 
In many children and adolescents with translocation morphology renal cell 
carcinoma, their histologic diagnosis will be unknown at the time of primary 
nephrectomy since the vast majority of patients in this age group have a non-renal 
cell carcinoma histology such as Wilms tumor. The impact of this is that the 
surgical approach to these patients varies since in many cases the pre-operative 
assumption is that the tumor in question represents Wilms tumor compared to 
adults with renal tumors where the vast majority have renal cell carcinoma. 
Therefore, the surgical guidelines to renal tumors in children and adolescents are 
directed towards managing Wilms tumor and below we will outline these general 
guidelines which will also be sufficient for the surgical approach to managing 
those with renal cell carcinoma. 
 
A generous transabdominal, transperitoneal or thoracoabdominal incision is 
recommended for adequate exposure. Complete exploration of the abdomen 
should be performed. A radical nephrectomy is performed with the ureter divided 
as distally as possible. Routine exploration of the contralateral kidney is not 
necessary if imaging is satisfactory and does not suggest a bilateral process. 
 
The lateral peritoneal reflection is opened, and the colon is reflected medially. A 
plane is established outside of Gerota's fascia by sharp and blunt dissection. Before 
mobilizing the primary tumor, an attempt should be made to dissect, expose and 
ligate the renal vessels in order to lessen the chance of hematogenous spread of 
tumor cells while removing the tumor. Preliminary ligation should not be 
pursued if technically difficult or dangerous. The adrenal gland may be left in 
place if it is not abutting the tumor; but, if the mass arises in the upper pole of the 

 
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kidney, the adrenal gland should be removed with the neoplasm. The ureter is 
ligated and divided as low as conveniently possible, but it is not necessary to 
remove the ureter completely. The tumor and the uninvolved portion of the kidney 
are mobilized and removed intact.  
 
The use of titanium clips is strongly recommended to identify gross residual tumor. 
Clips should not be used for hemostasis and those placed for roentgenographic 
identification or radiation therapy portals should be limited to the minimum 
number necessary. Metallic clips can interfere with the CT scan. Clips are best 
applied by placing a non-absorbable suture in the structure to be marked, and 
attaching the clip to the suture. In general four small clips should be sufficient to 
delineate the margins of the tumor.  
 
Any suspicious areas that represent metastases should be biopsied, the site(s) 
identified with small titanium clips so that the locations can be determined later by 
roentgenograms. The specimen should be specifically identified as to the site from 
which it was removed. 
 
13.1.4 Partial Nephrectomy 
While partial nephrectomy in adult patients is commonly approached through a 
variety of incisions including open flank, open transperitoneal and minimally 
invasively, in children undergoing partial nephrectomy, we recommend a 
transperitoneal incision. Additionally, even though not planned as a radical 
nephrectomy, the surgeon should inspect the renal hilar and periaortic area and 
sample lymph nodes as recommended per radical nephrectomy to rule out 
lymphatic spread. Palpate the renal vein and IVC for evidence of tumor extension. 
Do not biopsy the tumor if a partial nephrectomy with margins can be performed 
since this is a criterion for local Stage III designation if the ultimate pathology is 
determined to be Wilms tumor. Avoid rupture or spillage by use of an adequate 
incision. Control of the renal vessels is recommended, but the surgery can 
generally be performed without hypothermia or vascular ischemia. In most 
children, manual compression of the kidney can be used to control bleeding during 
the dissection. Gerota’s fascia is opened and the perirenal fat is dissected off the 
renal surface excluding the fat attached to the mass. A circumferential incision of 
the renal capsule around the surface of the tumor should be performed and the 
capsule peeled back to expose the adjacent renal parenchyma. A wedge or 
guillotine resection of the tumor is performed. The tumor should be excised with 
a 0.5 to 1 cm rim of normal parenchyma. After removal of the tumor any bleeding 
vessels can be suture ligated with absorbable suture. If there is transection of the 
collecting system, a watertight closure with fine absorbable suture is 
recommended. If renorraphy is required this can be done by bringing the 
parenchyma back over the defect anchoring the sutures in the renal capsule. 
 
During the mobilization of the kidney and during dissection of the tumor, care must 
be taken not to place traction on the renal vessels. The small vessels in these young 
patients are prone to intimal injury which can lead to spasm and subsequent 
thrombosis. 
 

 
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13.1.5 Surgical Management of Lymph Nodes at the Time of Nephrectomy 
While there are no randomized clinical trial data to demonstrate that an extended 
lymph node dissection is mandated in patients with Wilms tumor or pediatric Renal 
Cell Carcinoma, there are data that insufficient surgical nodal staging may 
negatively impact outcomes in both diseases.68-71 Therefore, we encourage removal 
of nodal tissue in the anatomic drainage areas for the respective kidneys (see 
anatomic map below adapted from Crispen et al.72 and Capitano et al.73). The 
superior, inferior and lateral edges of these nodal templates should be controlled 
with suture ties and if needed, very selective use of titanium clips. The nodes 
should be carefully labeled by anatomic region for separate microscopic 
examination. The anatomic boundaries of these nodal drainage basins are as per 
Capitano et al.73: “Lymph node drainage for the right kidney includes the 
paracaval, retrocaval, precaval, and interaortocaval nodes from the adrenal vein to 
the level of the inferior mesenteric artery, and for the left kidney includes the para-
aortic and preaortic nodes from the crus of the diaphragm to the inferior mesenteric 
artery.” 
 
 
 
13.1.6 Surgical Management of Venous Tumor Thrombus 
Renal tumors extend as venous tumor thrombi into the renal vein and potentially 
the inferior vena cava and even atrium in 5-10% of cases. If preoperative imaging 
suggests a venous tumor thrombus but cannot adequately detail its extent for 
preoperative planning, preoperative sonography or magnetic resonance imaging 
may be helpful. Intraoperatively, the renal vein and inferior vena cava should be 
palpated carefully before ligation to rule out extension of the tumor into the wall 
or the lumen of the vein. If tumor extension is present, this should be removed en 
bloc with the kidney, if possible. Note should be made of whether tumor penetrates 
the vessel wall or is attached to the intima. 
 
The tumor that extends into the renal vein and cava may simply extend as a floating 
attachment and can then be ―fished out. Control of the renal vein and cava above 
and below the tumor with vessel loops or umbilical tape is necessary. The tumor 
and kidney should be completely mobilized prior to removing vascular thrombus. 

 
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A venotomy is then done and the tumor pulled out of the vein. A Foley balloon 
technique can also be used to pull out the tumor. The tumor should not be 
transected. In other instances the tumor may be fixed to the vascular lumen. 
Extraction is more difficult and a larger venotomy may be required. A similar 
technique used for removing plaque for a carotid endarterectomy is helpful to lift 
the tumor off the vein wall. If the tumor extends above the hepatic veins, 
cardiopulmonary bypass may be needed to remove the vascular extent of the 
tumor. The abdominal tumor is mobilized and removed first prior to administration 
of heparin. After placing the child on bypass the right atrium is opened and the 
tricuspid value inspected. The tumor is removed from the heart above and below 
at the same time to prevent tumor emboli. 
 
13.1.7 Biopsy 
For trial eligibility, biopsy of the primary tumor or sites of metastasis are 
acceptable for histologic confirmation of translocation morphology renal cell 
carcinoma. Biopsy may be done either via open or percutaneous needle 
approaches. Biopsy (whether needle biopsy or open biopsy) mandates waiting 
7 days prior to study enrollment. 
 
A word of caution for children undergoing biopsy of the primary mass, if this 
reveals a diagnosis of Wilms tumor then they will be mandatorily staged as a local 
Stage III which includes treatment intensification with doxorubicin and radiation 
therapy. Thus, biopsy in these cases should be undertaken only after considering 
such therapeutic implications. 
 
13.1.8 On Protocol Surgery 
13.1.8.1 Restrictions During the First 12 Weeks of Therapy 
Due to the need to assess tumor response to therapy, no surgical tumor 
resection is permitted during the first 12 weeks of protocol therapy. 
Patients who undergo surgery for tumor resection during this period 
must be removed from protocol therapy. 
 
13.1.8.2 Restrictions for Patients with Tumor Growth 
Any surgical tumor resection performed for lesions that are increasing 
in size (any increase in size based on radiology) will result in removal 
from protocol therapy. 
 
13.1.8.3 Cytoreductive Nephrectomy During Therapy 
Patients who have not had cytoreductive nephrectomy prior to trial 
enrollment but who elect to have cytoreductive nephrectomy during 
therapy must hold axitinib for 7 days before surgery and wait 7 days 
after surgery to restart axitinib. 
 
13.1.8.4 Elective Surgery 
Patients undergoing a major, elective surgical procedure must hold 
axitinib for 7 days before surgery and wait 7 days after surgery to restart 
axitinib. 
 
13.1.8.5 Emergency Surgery 
For an emergency, axitinib must be held for 7 days after surgery. 

 
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13.3 
Surgical Specimens 
Institutions are required to submit samples of diagnostic tumor tissue for retrospective 
central pathology review on this study (see Section 14.1.1). In addition, submission of 
tumor tissue from diagnosis and from subsequent surgical procedures for banking is 
strongly encouraged (see Section 15.2.3). All tumor specimens removed should be 
presented to the pathologist fresh or in saline, rather than fixed in formalin. Specimens 
should be transported to pathology immediately after removal to allow sampling of fresh 
tissue for molecular biology studies. Notification of the pathology laboratory in advance 
will facilitate proper specimen collections. 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
14.1 
Institutional Pathology Requirements 
14.1.1 Retrospective Central Review of Diagnostic Samples: 
All patients enrolling on this protocol will undergo a retrospective central 
pathology review to confirm histologic classification. The results of this review 
will not be returned to the referring institution.  
 
14.1.2 Required Special Studies: 
In order to be eligible for this study, the institution must confirm either TFE3 
nuclear protein expression by immunohistochemistry or evidence of TFE3 or 
TFEb translocation by either FISH or RT-PCR in a CLIA-certified laboratory. 
Institutions may choose to submit unstained slides directly to Dr. Elizabeth 
Perlman, who will perform TFE3 analysis at no charge. See Section 14.5 for Dr. 
Perlman’s contact information. The slide will be returned to the referring 
institution for local evaluation, to be included in their institutional report. Please 
note that this is separate from a consultation for a difficult case, for which a fee 
may be charged. The slide(s) for consultation should be sent directly to Dr. 
Perlman and not to the Biopathology Center. 
 
14.2 
Tissue Specimens/Pathology Review at Time of Diagnosis  
All patients enrolling on this protocol require institutional histological confirmation of 
translocation-renal cell carcinoma and institutional confirmation of either robust TFE3 
nuclear protein expression by immunohistochemistry or evidence of TFE3 or TFEb 
translocation by either FISH or RT-PCR in a CLIA-certified laboratory. Sites are required 
to submit tumor samples within 4 weeks of initiating protocol therapy, and are 
encouraged to submit tumor samples at second look surgery, relapse, or autopsy. All 
reviews are retrospective and results from the reviews will not be returned to the submitting 
institution. 
  
14.2.1 Suggested Minimal Histologic Sampling 
14.2.1.1 Incisional Biopsy Material 
If practical, all tissues should be processed. Needle biopsy specimens are 
the least desirable for classification of primary tumors. If needle biopsies 
are obtained, it is helpful to divide the tissue in multiple cassettes 
(1-2 cores per cassette) for optimum conservation of tissue. 
 

 
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14.2.1.2 Tumor Excision/Nephrectomy 
Representative tissue blocks are needed from various regions of the mass 
for tumor classification. Adequate sampling requires approximately 
1 section per cm diameter of tumor. The narrowest tissue margins should 
be sampled to adequately assess the surgical margins. Sections 
demonstrating the relationship between the tumor and the renal sinus, 
renal capsule, as well as the adjacent kidney are most useful. 
 
14.3 
Pathology Review Submission Checklist 
Please send the following items for the retrospective pathology review: 
• 
A complete set of recut H&E slides to be retained by the review pathologists. 
• 
A representative formalin-fixed paraffin block of tumor material (paraffin blocks 
will be returned after sectioning upon request only). NOTE: If blocks cannot be sent 
on a permanent basis, then send 10 plus-charged (polarized) unstained sections 
(4 micron section thickness) for immunoperoxidase and other special studies from 
1-2 representative blocks of tumor tissue. 
• 
Documentation including: 
- 
Institutional Final Pathology Report 
- 
Pathology Checklist 
- 
Institutional Cytogenetics/Molecular Pathology Report (if available) 
- 
Institutional Operative Report 
- 
AREN1721 Specimen Transmittal Form 
 
14.4 
Shipping 
Label all materials with the patient’s COG patient identification number. Blocks or slides 
for central review must also be labeled with the surgical pathology ID and block number 
from the corresponding pathology report.  
 
Send all pathology central review materials via regular mail or using the institution’s 
courier account to: 
 
Biopathology Center 
Nationwide Children's Hospital 
700 Children’s Drive WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
Email: BPCParaffinTeam@nationwidechildrens.org 
 
14.4.1 Study Pathologists 
The BPC will send pathology review materials for retrospective central review to 
the study pathologist, Elizabeth J. Perlman, MD, at Ann & Robert H. Lurie 
Children’s Hospital of Chicago. 
 
14.5 
Consultation 
If a consultation for a difficult case is desired, this would be on a consultation-only basis 
and a fee may be charged. If a consultation is desired, the institution should contact the 
pathologist directly to request a consultation. Consultation materials (all slides, a block or 
unstained slides, and surgical pathology report) should be shipped using your own courier 
account to the study review pathologist listed below. 

 
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Elizabeth J. Perlman, MD 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
225 E. Chicago Ave. 08-423 
Chicago, IL 60611 
Phone: (312) 227-3967 
Email: eperlman@luriechildrens.org  
 
Please note: materials sent to a reviewer for consultation are separate from study 
submission. 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
15.1 
Required Pharmacokinetics 
As of Amendment 5A, all pediatric patients enrolled and randomized to Arm A or those 
who cross-over from Arm C to Arm A are required to provide specimens for PK testing. 
Please refer to the PK lab manual posted on the protocol webpage for details on ordering a 
PK sample collection kit. PK kits are not provided by the BPC. 
NOTE: A kit should be ordered when a reservation is made for a potential pediatric 
enrollment on the study. 
 
15.1.1 Required population for PK studies  
For pediatric patients (age: ≥ 12 months to < 18 years) enrolled and randomized to 
Arm A (axitinib + nivolumab) or those who cross-over from Arm C to Arm A, 
sites will be required to collect and submit PK specimens. PK analysis will be 
conducted at a centralized laboratory.  
 
15.1.2 Sample Collection and Handling Instructions  
Patients should be instructed to hold the morning axitinib dose on Day 1 of Cycles 
2 and 3 until after the pre-dose PK has been drawn. 
 
Prior to collection of blood, wrap 2-mL K3-EDTA tubes completely in aluminum 
foil to protect the samples from light. 
 
NOTE: The samples for PK can be drawn from a central line, including a central 
line used to administer study drug. 
 
Blood samples (2 mL per sample) will be collected into aluminum foil covered 2-
mL tubes containing K3-EDTA anticoagulant at the time points listed below:  
 
For patients randomized to Arm A: 
• 
Cycle 1, Day 1: at 2, 4, and 6 hours after AM dose of axitinib 
• 
Cycle 2, Day 1: Pre-dose of axitinib 
• 
Cycle 3, Day 1: Pre-dose of axitinib 
 
For patients initially on Arm C who cross-over to Arm A at disease 
progression: 
• 
The day that the first dose of axitinib is given: at 2, 4, and 6 hours after 
AM dose  

 
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• 
Cycle 2, Day 1 of combination therapy: Pre-dose of axitinib 
• 
Cycle 3, Day 1 of combination therapy: Pre-dose of axitinib 
NOTE: The first cycle of combination therapy after cross-over will be 
defined as the cycle for which > 14 days of axitinib is given, with Day 1 of 
Cycle 1 after cross-over defined as the day of first nivolumab dose during that 
cycle after axitinib is started or on the day axitinib is started if given 
concurrently. 
 
Special precautions should be taken to minimize the exposure to light of the 
PK blood and plasma specimens to avoid rapid degradation of axitinib . 
 
Samples should be kept in an ice bath (do not submerge the tubes) until processing. 
Record the exact time the sample is collected along with the exact time the drug is 
administered in the Pharmacokinetic Sample Requisition Form. This requisition 
form will be provided in the PK sample collection kit. 
 
The samples must be processed immediately at 2 °C to 8 °C .  
 
15.1.3 Sample Processing  
1. 
Fill 2-mL K3-EDTA collection tube(s) completely.  
2. 
Mix immediately by gently inverting the tube(s) at least 8 to 10 times and 
place in an ice bath (do not submerge) until centrifugation.  
3. 
Centrifuge at 2°C to 8°C at approximately 1700 x g for at least 10 minutes 
until cells and plasma are well separated.  
4. 
Use a pipette to transfer all the plasma into the appropriately labeled amber 
tube. Use a different pipette to aliquot plasma for each PK sample collected 
to avoid cross-contamination between time points.  
5. 
All samples should be stored in an opaque box to protect from light exposure. 
Any sample inadvertently exposed to light for 5 minutes or more should 
be flagged (with an asterisk) for possibly spurious results. On the 
Pharmacokinetic Sample Requisition Form indicate whether the sample was 
exposed to light for ≥ 5 minutes.  
6. 
Freeze at -70 °C within 1 hour of collection and store frozen in a freezer with 
no defrost cycle until shipment.  
 
15.1.4 Sample Labeling and Shipping Instructions 
Please refer to the PK lab manual posted on the protocol webpage for complete 
sample labeling and shipping instructions. NOTE: PK samples are to be shipped 
to a central lab. Do NOT ship to the BPC. 
 
Any sample exposed to light for ≥ 5 minutes should be marked with an 
asterisk. Data should be recorded on the Pharmacokinetic Sample Requisition 
Form, which must accompany the sample(s).  
 
Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of each cycle.  
 
15.1.5 Methodology 
Plasma concentrations of axitinib will be determined at a centralized laboratory 
using validated assays. 

 
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Concentrations for axitinib will be plotted for each cohort using a box‑whisker plot 
by time, day, and cycle.  
 
15.2 
Optional Studies 
If limited specimens are available, specimens for correlative biology studies (Sections 
15.2.1 and 15.2.2) should be prioritized, followed by specimens for banking (Section 
15.2.3). 
 
15.2.1 Immunotherapy Biomarkers in Blood 
15.2.1.1 Specimens 
In consenting patients, peripheral blood will be acquired (15-20 mL per 
sample) in green top sodium tubes at the following timepoints: 
- 
Before treatment initiation 
- 
Before Day 1 of Cycles 2, 3, and 9 (within 72 hours prior to 
Day 1 dosing) 
- 
Within 3 weeks after the last dose of study treatment 
 
Lithium heparin tubes are also acceptable if a site is unable or unwilling 
to obtain green top sodium tubes due to cost or availability. 
 
15.2.1.2 Sample Processing 
Blood samples should be sent as whole blood at room temperature. 
 
15.2.1.3 Labeling 
Using a waterproof marker, label the tubes with the following: COG 
study number, patient ID, date and timepoint of specimen drawn. 
 
15.2.1.4 Shipping 
Samples must be received in the laboratory within 24 hours of being 
drawn. Plan the draw and shipping accordingly. Blood samples should 
be shipped Monday through Thursday by Priority Overnight for delivery 
Tuesday through Friday. Deliveries will not be accepted on Saturdays or 
holidays. Please contact the lab before specimens are shipped. 
 
Blood samples should be shipped to: 
 
Cincinnati Children’s Hospital Medical Center 
Davies Lab C/O Kelly Lake, Rm. R2543 
3333 Burnet Ave. 
Cincinnati, OH 45229-3039 
 
For the shipping account number and general questions, contact Kelly 
Lake at Kelly.Lake2@cchmc.org or (513) 636-3425. 
 
15.2.1.5 Methodology 
This study will assess biomarkers of clinical benefit when tRCC patients 
receive anti-VEGF and anti-PD1/PD-L1 based therapies. Immunologic 
evaluations will include PD-L1 expression, type of antitumor immune 
response and stability of T cell activation before and after treatment. 

 
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Peripheral blood mononuclear cell (PBMC) will be assessed for 
composition of CD4 and CD8 T cells, naïve and memory cells 
(CD54RO/RA, CCR7), recently activated T cells (HLADR, CD38, 
Nurr77, Ki67, the frequency of T cells with an exhausted phenotype 
(PD-1, Lag-3, Tim3, CD244), and regulatory phenotype (CD25, FoxP3). 
PBMC will also be assessed for Ca2+ influx capacity. 
 
PBMC Isolation:  
Immediately upon receipt of blood specimen, the laboratory will isolate 
the PBMCs via the Ficoll method. This isolation includes lysing the red 
blood cells (RBCs) and re-suspending the PBMCs in cryopreservation 
media with a minimum concentration of 1 million (1e6) cells/mL. These 
cells will be viably frozen and stored for future analysis. Additional 
samples including plasma may be stored from the blood specimen. 
 
PBMCs will be thawed, spun down, re-suspended in PBS, and 
immediately plated into a 96 well U bottom plate. Cells will be incubated 
at 4˚C for 10 minutes in 1 µg/mL PBS Keytruda. After 10 minutes, cells 
will be washed with PBS and then labeled with manufacturer suggested 
amounts of Live dead eFluor 780 (e-bioscience), anti-CD8 BV785, anti-
CD4 AF488, RA PerCP, RO BV510, anti-CD25 BV660, IgG FC PE, 
anti-CD244 Pacific Blue (BioLegend), and HLA-DR Dylight350 
(Novus Biologicals). Once labeled cells will be washed and re-
suspended in FoxP3 Fixation/Permeabilization solution (e-bioscience). 
After cells are fixed, they will be labeled with Foxp3 AF647 
(BioLegend) in Permeabilization buffer (e-bioscience). The cells are 
then washed with Permeabilization buffer and re-suspended in 
1% formaldehyde in PBS. Cells are stored in the dark at 4˚C until 
acquisition on BD LSRFortessa flow cytometer. 
 
15.2.2 Immunotherapy Biomarkers in Tissue 
Tissues will be used to assess PD-L1 expression and TIL composition/distribution 
before treatment using multicolor imaging. 
 
15.2.2.1 Specimens 
In consenting patients, tumor tissue samples should be acquired before 
treatment initiation and on protocol therapy only if tissue is obtained for 
any clinical reason (i.e., surgery, relapse/progression, etc.). Tissue 
samples will be acquired fresh in 100 mg pieces. Tumor tissue for 
Immunotherapy Biomarkers should be stored fresh in sterile tissue 
culture media and refrigerated (6-8°C) until fixation, if immediate 
fixation is not possible. The length of time that tissue is stored in media 
prior to fixation should be noted in the AREN1721 Optional Studies 
specimen transmittal form. 
 
15.2.2.2 Sample Processing 
Tumor tissue should be fixed in 10% buffered formalin only (no other 
fixatives acceptable) for not less than 6 hours and no more than 5 days 
before 
alcohol-xylene-paraffin 
dehydration, 
paraffinization 
and 
subsequent 
embedding 
using 
established/automated 
processing 

 
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protocols for the appropriate size of tissue fragments. Sections cut from 
the prepared formalin fixed paraffin embedded blocks may be 
submitted, cut 4-5 microns thick, and placed on unstained, charged, and 
unbaked slides (10 total). Alternatively, a paraffin block can be 
substituted for slides. 
 
15.2.2.3 Labeling 
Using a waterproof marker, label the slides with the following: COG 
patient ID, BPC number, date of collection, surgical pathology ID, and 
block number from the corresponding pathology report. 
 
15.2.2.4 Shipping 
Tumor tissue slides or blocks (preferred), and the corresponding 
institutional pathology report, should be shipped by regular mail in a 
padded envelop or box along with a printed copy of the completed 
AREN1721 Optional Studies Specimen Transmittal form. Slides must 
be placed in a hard-sided plastic slide holder and wrapped in bubble 
wrap prior to shipment. During warm months, ship paraffin block(s) 
with a cold pack. Ship to the BPC: 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AREN1721 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*The room number is required. Packages not listing the room number 
will be denied and returned to the sender. 
 
15.2.2.5 Specimen Handling by Biopathology Center 
Tissue specimens submitted as paraffin blocks will be sectioned by the 
BPC. The BPC will ship slides for immunotherapy biomarker testing to 
the Study Chair, James Geller, MD, at Cincinnati Children’s Hospital 
Medical Center. 
 
15.2.2.6 Methodology 
Immunohistochemical Stains: 
Preparation: 
Formalin-fixed, paraffin-embedded tissues are suitable for use with 
Ventana ultraView Universal DAB detection kit and BenchMark, 
BenchMark XT, and BenchMark ULTRA instruments. Tissue sections 
are baked/heated for at least 2 hours (but not longer than 24 hours) in a 
60° ± 5° C oven. 
 

 
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Immunostaining: 
Immunostain clones include: Ventana/Roche: PD-L1 (SP263) rabbit 
monoclonal; CD3 (2GV6) rabbit; CD4 (SP35) rabbit; and CD8 (SP57) 
rabbit; and Cell Marque PD-1 (NAT105) mouse monoclonal. 
Preprogrammed protocols on Ventana BenchMark, BenchMark XT, and 
BenchMark ULTRA are performed for each specific antibody 
(CD3 2GV6 rabbit; CD4 SP35 rabbit; CD8 SP57 rabbit; PD-1 NAT105; 
PD-L1 SP 142). Following completion of the automated stain protocols, 
the slides will be removed from the stainers for post-instrument 
procedures. 
 
Post-instrument procedures: 
Slides are then washed with mild dishwashing detergent to remove 
coverslip solutions. Slides are then rinsed in distilled water to remove 
detergent. Slides are then dehydrated, cleared, and coverslipped with 
routine permanent mounting media. Slides are then submitted for 
interpretation by the pathologist. 
 
15.2.3 Specimens for Banking 
15.2.3.1 Specimens 
In consenting patients, the following samples are requested. Blood and 
urine specimens are still requested if tissue is not available. 
 
SPECIMEN 
TIMEPOINT 
Snap Frozen Tumor Tissue from primary 
tumor 
• 
At least 1 gram and up to 10 grams if 
available, in 1 gram aliquots 
• 
At diagnosis prior to any chemotherapy 
• 
At any surgery while on study 
Snap Frozen Normal Kidney Tissue 
• 
At least 1 gram and up to 10 grams if 
available, in 1 gram aliquots 
• 
When available 
Snap Frozen Tumor Tissue from biopsied 
metastatic areas (if obtained in addition to 
primary diagnostic site) 
• 
At least 1 gram and up to 10 grams if 
available, in 1 gram aliquots 
• 
At diagnosis prior to any chemotherapy 
• 
At any surgery while on study 
Formalin Fixed Block 
• 
At diagnosis prior to any chemotherapy 
• 
At any surgery while on study 
Whole Blood 
• 
5-10 mL in EDTA tube 
• 
Prior to any chemotherapy* 
Serum 
• 
Spun from 6 mL of whole blood in red top 
tube 
• 
Prior to any chemotherapy* 
Urine 
• 
5-10 mL 
• 
Prior to any chemotherapy* 
*Although pre-treatment specimens are strongly preferred, specimens collected after starting 
chemotherapy are acceptable if a pre-treatment sample cannot be collected. 
 

 
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15.1.3.2 Specimen Procurement Kits 
Specimen procurement kits are provided to sites in North America by 
the BPC. To request a dual chamber specimen procurement kit, access 
the 
Kit 
Management 
system 
(https://ricapps.nationwidechildrens.org/KitManagement/) and select 
AREN1721 for the protocol. 
 
The kits include foil for frozen tissue, plastic zip-lock baggies, and vials 
for frozen sera and urine. Also included with each kit are instructions, a 
dry ice label, Exempt Human Specimen sticker and 2 sets of secondary 
shipping envelopes with absorbent material. 
 
15.1.3.3 Sample Processing and Labeling 
Operating Room personnel should not put the tissue into fixative. The 
specimen should be brought to the Pathology Department quickly (by 
special messenger if necessary). It may be appropriate to hold occasional 
meetings of surgical, laboratory, and clinical personnel to emphasize the 
urgency of processing these specimens rapidly, preferably within 
20 minutes. 
 
Tissues should be as sterile as possible. After the necessary tissues are 
obtained for local institutional diagnosis, the remaining tissue should be 
submitted. 
 
Specimens should be prepared promptly after collection as described 
below. 
 
Snap Frozen Tissue: 
Cut at least 1 specimen from the primary tumor or biopsy, and from 
metastatic areas (if resected or biopsied) into 1 gram (maximum) 
aliquots. Up to ten 1 gram aliquots may be submitted, if available. Wrap 
tissue in foil and snap freeze in vapor phase liquid nitrogen (do not 
submerge in liquid nitrogen) or cold isopentane. For biopsies which are 
less than 1 gram, please submit as much as possible. Foil and plastic 
baggies will be provided in the specimen procurement kit for the snap 
frozen tissue samples. Place a label inside each baggie stating the COG 
Patient ID Number, BPC number, specimen type (primary or 
metastatic), and collection date. If available, submit normal kidney 
tissue in addition to the tumor tissue. Each tissue type (primary, 
metastatic or normal) must be placed in separate baggies. 
 
Formalin Fixed Block: 
Submit formalin fixed tissue block(s) from representative primary, 
metastatic and normal tissue if available. The block must be labeled with 
the COG Patient ID number and the surgical pathology ID and block 
number from the corresponding pathology report. Primary, metastatic 
and normal tissue must be placed in separate bags and labeled 
appropriately.  
 

 
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Whole Blood: 
Prior to any chemotherapy, collect 5-10 mL of whole blood, 
anticoagulated with EDTA (purple top tubes which are not provided in 
the specimen procurement kit) and keep at room temperature. Using a 
waterproof marker, label the tubes with the COG Patient ID Number, 
BPC number, specimen type (blood), and the collection date. If a 
specimen cannot be shipped the same day it is collected, please store at 
4° C (refrigerator) and ship on the next working day. Although sampling 
prior to chemotherapy is strongly preferred, blood samples may be 
collected after the first dose of chemotherapy is administered. 
 
Serum: 
Prior to any chemotherapy, collect 6 mL of blood in a red top tube 
(which is not provided in the specimen procurement kit). Allow the 
blood to clot at 4°C (or in a bucket with ice) for at least 30 minutes. Spin 
at 1000g for 15 minutes at 4ºC (preferred) or room temperature to 
separate the serum. Transfer the serum into the cryovials provided in the 
specimen procurement kit and cap the tubes securely. Place a minimum 
of 0.25 mL into each cryovial. Due to protein degradation, the specimen 
should be processed and frozen within 2 hours of the blood collection. 
Using a waterproof marker, label the tubes with the COG Patient ID 
Number, BPC number, specimen type (serum), and the collection date. 
Place the tubes in a baggie labeled “serum”. Freeze serum in an upright 
position in a -80ºC freezer until shipment. 
 
Urine: 
Prior to any chemotherapy and nephrectomy (if applicable), 5-10 mL of 
urine (not required to be sterile) should be collected from the patient and 
then transferred into a 15 mL conical tube labeled with patient 
identifiers. If urine is not processed immediately, store at 4°C prior to 
processing. 
 
Spin urine at 1000g (2000rpm) for 10 minutes at 4°C (preferred). Urine 
may be spun at room temperature if a refrigerated centrifuge is not 
available. Aliquot urine into the 5 cryovials provided. Avoid any pellet 
that may have been formed at the bottom of the conical tube. Place a 
minimum of 0.25mL into each cryovial. The cryovials should be labeled 
with the COG Patient ID Number, BPC number, specimen type (urine), 
and date collected. Immediately freeze the urine in an upright position 
in a -80°C freezer until ready to ship. 
 
15.1.3.4 Shipping 
The dual chamber specimen procurement kit is constructed to allow 
shipment of frozen (on dry ice) and ambient temperature tissues in the 
same container. Dry ice may be placed in either compartment of the 
kit, but should not be put in both. Include an AREN1721 optional 
studies specimen transmittal form with each shipment and a 
pathology report (whenever tissue is submitted). 
 

 
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1. 
Before specimens are placed into the dual chamber specimen 
procurement kit, they first need to be placed in three separate 
layers of packaging. Package the frozen specimens and the 
ambient specimens separately since they will be placed in separate 
compartments of the kit. Two sets of the biohazard and Tyvek 
diagnostic envelopes are provided in the kit for this purpose. 
a. 
Place the specimens in zip lock bags (one bag per specimen 
type/time point).  
b. 
Place the zip lock bags in a biohazard envelope with the 
absorbent material. Expel as much air as possible and seal 
the envelope. 
c. 
Place the biohazard envelope inside a Tyvek envelope. 
Expel as much air as possible and seal the envelope. 
2. 
Frozen specimens should be placed in one of the kit compartments 
filled with dry ice. Layer the bottom of the compartment with dry 
ice until it is approximately one-third full. Place the frozen 
specimens on top of the dry ice. Cover the specimens with the dry 
ice until the compartment is almost completely full. Place the 
foam lid on top to insulate the specimens during shipment. 
3. 
Ambient temperature specimens should be shipped in the other kit 
compartment at room temperature. Insulate ambient specimens 
with bubble wrap or similar material. 
4. 
Place the transmittal form(s) and any other required paperwork 
inside the kit chamber with the ambient specimens. 
5. 
Place a foam cover on top of each kit chamber to insulate the 
specimens during shipment. 
6. 
Close the outer lid of the specimen procurement kit and secure 
with filament or other durable sealing tape. 
7. 
Sites in North America may print a shipping label via the BPC Kit 
Management application and attach to the top of the kit. Please 
note that a shipping label is not provided when blocks or slides are 
shipped separately. 
8. 
Complete the dry ice label (UN 1845). Place the dry ice and 
Exempt Human Specimen labels on the side of the kit. 
9. 
Arrange for Federal Express pickup per your usual institutional 
procedure or by calling 1-800-238-5355. 
 
Kits should be shipped to the BPC on Monday through Thursday for 
Tuesday through Friday delivery. Saturday delivery is only available for 
fresh blood. Please hold other specimens collected on a Friday and ship 
the following Monday. When shipping blood on a Friday, select “Yes” 
For Saturday Delivery when printing the shipping label.  
 
If a specimen is obtained on a week-end or holiday, please hold it under 
appropriate conditions until the next business day. 
 
Send the specimens to: 
 

 
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Biopathology Center 
Nationwide Children’s Hospital 
Protocol AREN1721 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*The room number is required. Packages not listing the room number 
will be denied and returned to the sender. 
 
15.1.3.5 Use of Banked Specimens 
Exploratory biomarker testing of banked specimens will not occur until 
an amendment to this treatment protocol (or separate correlative science 
protocol) is reviewed and approved in accordance with National Clinical 
Trials Network (NCTN) policies. Amendments to the protocol and/or 
proposals for use of banked tissue or blood samples will include the 
appropriate background, experimental plans with assay details, and a 
detailed statistical section. Samples for testing will not be released for 
testing until the appropriate NCI approvals have been obtained. 
 
 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
16.1 
Goals of Diagnostic Imaging 
Routine diagnostic imaging will be performed during treatment and follow-up, and at the 
time of suspected tumor progression/recurrence to detect and characterize sites of disease 
involvement as well as response. Investigators are encouraged to use a consistent modality 
for follow-up scans. 
 
16.2 
Timing of Diagnostic Imaging 
16.2.1 Required Imaging Time Points 
To document tumor, CT and/or MRI will be performed for all treatment arms, 
including after cross-over from Arm C to Arm A, according to following schedule: 
• 
Pre-treatment 
• 
After Cycles 2, 4, 6, 9, 12, and then every 4 cycles thereafter* 
• 
At 6-8 weeks (not less than 4 weeks) following initial documentation of 
objective response (per Section 10.2) 
• 
At any time where progressive disease is suspected 
• 
At the end of treatment 

 
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• 
At relapse 
• 
Follow-up assessments 
 
Note: Tumors will be evaluated using RECIST v1.1 criteria, with the exceptions 
described in Section 10.2.1 to account for possible “pseudoprogression”. 
 
* For patients who remain on protocol therapy despite increase in tumor size 
≥ 20%, imaging to include target lesions must occur every cycle, per Section 
10.2.1. For patients who cross-over from Arm C to Arm A at initial progression, 
the cycle number should restart for the purposes of imaging to ‘Cycle 1’. The first 
cycle of combination therapy after cross-over will be defined as the cycle for which 
> 14 days of axitinib is given, with Day 1 of Cycle 1 after cross-over defined as 
the day of first nivolumab dose during that cycle after axitinib is started or on the 
day axitinib is started if given concurrently. NOTE: The total protocol therapy 
received on AREN1721 (whether delivered on Arm A, Arm C, or Arm C+A) is 
not to exceed 26 cycles or 2 years, whichever comes first. 
 
16.3 
Required Imaging Studies 
16.3.1 CT or MRI of the abdomen and pelvis 
CT and MRI guidelines are available on the COG Member site at: 
https://members.childrensoncologygroup.org/_files/reference/RefMaterial/Diagn
osticImagingGuidelines_MRI&CT.pdf 
 
CT of the abdomen and pelvis should be collimated to at most 5 mm slice 
thickness. IV contrast in the portal venous phase (usually around 50s post-
injection) is required. Oral contrast is not necessary. 
 
MRI of the abdomen and pelvis should include T1 and T2 weighted images pre-
contrast and post-contrast dynamic T1-weighted images through the kidneys. 
Diffusion weighted images are strongly recommended. Recommended b values for 
diffusion weighted imaging are b 50, 500, 1000 mm/s2. Post contrast T1 weighted 
images through the kidneys should be acquired dynamically in the arterial (~20s), 
portal venous (~50s) and delayed phase. Note: The same imaging parameters 
should be used at each evaluation. 
 
16.3.2 CT of the chest 
CT of the chest should have enhanced lung windows. IV contrast is encouraged at 
diagnosis to assess for possible mediastinal adenopathy. Slice thickness should be 
5 mm or less. 
 
 
17.0 
RADIATION THERAPY GUIDELINES 
No radiation therapy is planned for this study. 
 
 

 
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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored 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 at https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete 
their annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such as 
the  Roster Update Management System (RUMS), OPEN, Rave, acting as a primary site contact, 
or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
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 
Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs must list all 
clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 

 
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered at the 
enrolling site with a participating organization.  
 
Additional 
information 
is 
located 
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. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU members’ 
website. Permission to view and download this protocol and its supporting documents is restricted based 
on person and site roster assignment. To participate, the institution and its associated investigators and staff 
must be associated with the LPO or a Protocol Organization (PO) on the protocol. One way to search for a 
protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and protocol 
number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
 
Protocol-Specific Requirements For 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) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory Submission 
Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the Regulatory 
section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
 

 
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Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol Status, 
and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as outlined 
within the protocol. It does not reflect compliance with protocol requirements for individuals participating 
on the protocol or the enrolling investigator’s status with NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this trial/study. 
Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus (AP) 
registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer 
to 
https://ctep.cancer.gov/investigatorResources/default.htm 
for 
registration 
types 
and 
documentation required. 
 
Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
Integration enables evaluation of post-baseline Adverse Events (AE) entered in Rave to determine whether 
they require expedited reporting, and facilitates entry in CTEP-AERS for those AEs requiring expedited 
reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event form, which is 
available for entry at each treatment or reporting period and used to collect AEs that start during the period 
or persist from the previous reporting period. CRA will enter AEs that occur prior to the start of treatment 
on a baseline form that is not included in the Rave-CTEP-AERS integration. AEs that occur prior to 
enrollment must begin and end on the baseline Adverse Events form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the following on the 
Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA modifies an AE, 
it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules evaluation by 
completing the Expedited Reporting Evaluation form. Both NCI and protocol-specific reporting rules 

 
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evaluate the AEs submitted for expedited reporting. A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements. The CRA completes the report by 
accessing CTEP-AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be made to CTEP by 
telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour notification that was phoned 
in must be entered immediately into CTEP-AERS using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
• 
Study specific documents: Protocols > Documents> Education and Promotion; and   
• 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU Operations 
Information> User Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries and 
form delinquencies, monitor data quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home section 
displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, DQP 
Delinquent Forms and the DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff 
that have Rave study access can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP Queries, 
and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the DQP. A 
protocol must have the Calendar functionality implemented in Rave by the Lead Protocol Organization for 
delinquent form details and reports to be available on the DQP. Site staff should contact the LPO Data 
Manager for their protocol regarding questions about Rave Calendaring functionality.   
 
 
 

  
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APPENDIX V: BRISTOL MYERS SQUIBB NIVOLUMAB TREATMENT GUIDELINES 
ALGORITHM 
 

  
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Note: The dosing of any medications above are provided for patients ≥ 18 years of age. 
 

  
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APPENDIX VI: CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
pexidartinib 
rifabutin 
rifapentin 
 
 
 

  
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everolimus5 
felodipine5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 

  
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tadalafil5 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2 Refer to Section 4.2 regarding use of corticosteroids.  
3 The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4 Narrow therapeutic range substrates 
5 Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 
 
 

  
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APPENDIX VII: GLOMERULAR FILTRATION RATE (GFR) CALCULATIONS 
 
Measurement of GFR should be undertaken at the recommended timepoints as indicated in the required 
observations. GFR may be obtained via nuclear Tc99 method, 24 hour urine collection method, OR 
estimated using the formulas below. 
 
GFR tests should not be done when the patient is receiving IV hydration as the result will not be reliable. 
Repeat assessments should use the same technique, as per local practices. 
 
 
Updated Schwartz’s Formula (0-18 years) 
According to new bedside Schwartz’s formula,75 GFR (eGFR) can be estimated from single serum samples: 
 
• 
Normal 120 
• 
Normal range 90-120 
 
 
For adult patients (> 18 years of age) 
The Modification of Diet in Renal Disease (MDRD) equation76 should be used to calculate eGFR: 
 
 
 
PLEASE NOTE: These formulas have not been confirmed in patients receiving repeated cycles of intensive 
chemotherapy. GFR may be overestimated by these methods due to tubular section of creatinine. 
 
 
 
eGFR (mL/min/1.73m2) =   × height (cm)/Scr (mg/dL) 
eGFR (mL/min/1.73m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) 

  
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APPENDIX VIII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AREN1721 
(for children from 7 through 12 years of age) 
 
A study to compare treatments for a type of kidney cancer called tRCC 
 
1. We have been talking with you about your cancer. tRCC is a type of cancer that grows in the 
kidneys. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have tRCC. A research study is 
when doctors work together to try out new ways to help people who are sick. At this time, there is 
no treatment that is typical for tRCC. In this study, we are trying to learn more about how to treat 
it by using 2 different drugs. We do not know how well these drugs will work in children, teens, 
and young adults with tRCC. That is why we are doing this study. 
 
3. Children who are part of this study will be treated in 1 of 2 ways. You will get either the one drug 
by itself, or two drugs together. There is a 50:50 chance you will receive one drug or two-drug 
treatment. You will also have tests to see if the cancer is getting worse, staying the same, or 
getting better. If you have treatment with one drug and your cancer gets worse, then you may be 
able to switch to the two-drug treatment.  
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is getting rid 
of the cancer for a long time, but we don’t know for sure if there is any benefit of being part of 
this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatments may cause bad 
side effects. There is also the risk that the treatments may not work and that your cancer keeps 
growing. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood, urine and tumor samples. We want to 
see if there are ways to tell how the cancer will respond to treatment. These samples would be 
taken when other standard blood tests or surgery are being performed, so there would be no extra 
procedures. You can still take part in this study even if you don't allow us to collect the extra 
blood, urine or tumor samples for research. 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY AREN1721 
(for teens from 13 through 17 years of age) 
 
A study to compare treatments for a type of kidney cancer called tRCC 
 
1. We have been talking with you about your cancer. tRCC is a type of cancer that grows in the 
kidneys. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have tRCC. A research study is 
when doctors work together to try out new ways to help people who are sick. At this time, there is 
no treatment that is typical for tRCC. In this study, we are trying to learn more about how to treat 
it by using 2 drugs called axitinib and nivolumab. We do not know how well these drugs will 
work in children, teens, and young adults with tRCC. That is why we are doing this study. 
 
3. Children and teens who are part of this study will be treated in 1 of 2 ways. You will get either 
nivolumab by itself, or axitinib and nivolumab together. There is a 50:50 chance you will receive 
nivolumab by itself, or axitinib and nivolumab together. You will also have imaging tests to see if 
the cancer is getting worse, staying the same, or getting better. If you have treatment with 
nivolumab by itself and your cancer gets worse, then you may have the option to receive axitinib 
and nivolumab together. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is getting rid 
of the cancer for a long time, but we don’t know for sure if there is any benefit of being part of 
this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatments may cause bad 
side effects. There is also the risk that the treatments may not work and that your cancer keeps 
growing. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood, urine and tumor samples. We want to 
see if there are ways to tell how the cancer will respond to treatment. These samples would be 
taken when other standard blood tests or surgery are being performed, so there would be no extra 
procedures. You can still take part in this study even if you don't allow us to collect the extra 
blood, urine or tumor samples for research. 
 
 
 

  
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REFERENCES 
 
1. 
Argani P,Ladanyi M: Translocation carcinomas of the kidney. Clin Lab Med 25:363-78, 2005 
2. 
Argani P,Ladanyi M: The evolving story of renal translocation carcinomas. Am J Clin Pathol 
126:332-4, 2006 
3. 
Ramphal R, Pappo A, Zielenska M, et al.: Pediatric renal cell carcinoma: clinical, pathologic, and 
molecular abnormalities associated with the members of the mit transcription factor family. Am J 
Clin Pathol 126:349-64, 2006 
4. 
Geller JI, Argani P, Adeniran A, et al.: Translocation renal cell carcinoma. Cancer 112:1607-1616, 
2008 
5. 
Geller JI, Ehrlich PF, Cost NG, et al.: Characterization of adolescent and pediatric renal cell 
carcinoma: A report from the Children's Oncology Group study AREN03B2. Cancer 121:2457-64, 
2015 
6. 
PF E, NG C, G K, et al.: A Description of the Surgical Experience in Children, Adolescents and 
Young Adults with Renal Cell Carcinoma: A Report from the Children's Oncology Group Study 
AREN 03B2. BJU International 110:18, 2012 
7. 
Zhong M, De Angelo P, Osborne L, et al.: Translocation renal cell carcinomas in adults: a single-
institution experience. Am J Surg Pathol 36:654-62, 2012 
8. 
Kauffman E, Gupta G, Cecchi F, et al.: Characterization of the Akt-mTOR pathway in TFE3-
Fusion Renal Cell Cancers and Implications for Targeted Therapy. The Journal of Urology 
187:e183-e184, 2012 
9. 
Choueiri TK, Lim ZD, Hirsch MS, et al.: Vascular endothelial growth factor-targeted therapy for 
the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer 116:5219-25, 
2010 
10. 
Malouf GG, Camparo P, Molinie V, et al.: Transcription factor E3 and transcription factor EB renal 
cell carcinomas: clinical features, biological behavior and prognostic factors. J Urol 185:24-9, 2011 
11. 
Camparo P, Vasiliu V, Molinie V, et al.: Renal translocation carcinomas: clinicopathologic, 
immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the 
literature. Am J Surg Pathol 32:656-70, 2008 
12. 
Choo MS, Jeong CW, Song C, et al.: Clinicopathologic Characteristics and Prognosis of Xp11.2 
Translocation Renal Cell Carcinoma: Multicenter, Propensity Score Matching Analysis. Clin 
Genitourin Cancer 15:e819-e825, 2017 
13. 
Ellis CL, Eble JN, Subhawong AP, et al.: Clinical heterogeneity of Xp11 translocation renal cell 
carcinoma: impact of fusion subtype, age, and stage. Mod Pathol 27:875-86, 2014 
14. 
Meyer PN, Clark JI, Flanigan RC, et al.: Xp11.2 translocation renal cell carcinoma with very 
aggressive course in five adults. Am J Clin Pathol 128:70-9, 2007 
15. 
Hung CC, Pan CC, Lin CC, et al.: XP11.2 translocation renal cell carcinoma: clinical experience 
of Taipei Veterans General Hospital. J Chin Med Assoc 74:500-4, 2011 
16. 
Dal Cin P, Stas M, Sciot R, et al.: Translocation (X;1) reveals metastasis 31 years after renal cell 
carcinoma. Cancer Genet Cytogenet 101:58-61, 1998 
17. 
Arnoux V, Long JA, Fiard G, et al.: [Xp11.2 translocation renal carcinoma in adults over 50 years 
of age: about four cases]. Prog Urol 22:932-7, 2012 
18. 
Geller JI, Khoury JD,Dome JS: Author’s Reply re: Letter to the Editor re: ‘Geller J and Dome J. 
Lymph Node Involvement Does Not Predict Poor Outcome in Pediatric Renal Cell Carcinoma, 
Cancer, 101:1575-1583, October 1, 2004. Cancer 103:1318-1318, 2005 
19. 
Aoyagi T, Shinohara N, Kubota-Chikai K, et al.: Long-term survival in a patient with node-positive 
adult-onset Xp11.2 translocation renal cell carcinoma. Urol Int 86:487-90, 2011 
20. 
Liu N, Gan W, Qu F, et al.: Does the Fuhrman or World Health Organization/International Society 
of Urological Pathology Grading System Apply to the Xp11.2 Translocation Renal Cell 
Carcinoma?: A 10-Year Single-Center Study. Am J Pathol 188:929-936, 2018 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AREN1721 
 
 
Version Date: 12/14/2021 
 
Page 138 
 
21. 
Rehli M, Den Elzen N, Cassady AI, et al.: Cloning and characterization of the murine genes for 
bHLH-ZIP transcription factors TFEC and TFEB reveal a common gene organization for all MiT 
subfamily members. Genomics 56:111-20, 1999 
22. 
Tsuda M, Davis IJ, Argani P, et al.: TFE3 fusions activate MET signaling by transcriptional up-
regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer 
Res 67:919-29, 2007 
23. 
Wagner AJ, Goldberg JM, Dubois SG, et al.: Tivantinib (ARQ 197), a selective inhibitor of MET, 
in patients with microphthalmia transcription factor-associated tumors: results of a multicenter 
phase 2 trial. Cancer 118:5894-902, 2012 
24. 
Malouf GG, Camparo P, Oudard S, et al.: Targeted agents in metastatic Xp11 translocation/TFE3 
gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol 
21:1834-8, 2010 
25. 
Parikh J, Coleman T, Messias N, et al.: Temsirolimus in the treatment of renal cell carcinoma 
associated with Xp11.2 translocation/TFE gene fusion proteins: a case report and review of 
literature. Rare Tumors 1:e53, 2009 
26. 
Massari F, Santoni M, Ciccarese C, et al.: PD-1 blockade therapy in renal cell carcinoma: current 
studies and future promises. Cancer Treat Rev 41:114-21, 2015 
27. 
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 
28. 
Liu YC, Chang PM, Liu CY, et al.: Sunitinib-induced nephrotic syndrome in association with drug 
response in a patient with Xp11.2 translocation renal cell carcinoma. Jpn J Clin Oncol 41:1277-81, 
2011 
29. 
Numakura K, Tsuchiya N, Yuasa T, et al.: A case study of metastatic Xp11.2 translocation renal 
cell carcinoma effectively treated with sunitinib. Int J Clin Oncol 16:577-80, 2011 
30. 
Hou MM, Hsieh JJ, Chang NJ, et al.: Response to sorafenib in a patient with metastatic xp11 
translocation renal cell carcinoma. Clin Drug Investig 30:799-804, 2010 
31. 
Pwint TP, Macaulay V, Roberts IS, et al.: An adult Xp11.2 translocation renal carcinoma showing 
response to treatment with sunitinib. Urol Oncol 29:821-4, 2011 
32. 
Choueiri TK, Mosquera JM,Hirsch MS: A case of adult metastatic Xp11 translocation renal cell 
carcinoma treated successfully with sunitinib. Clin Genitourin Cancer 7:E93-4, 2009 
33. 
Chowdhury T, Prichard-Jones K, Sebire NJ, et al.: Persistent complete response after single-agent 
sunitinib treatment in a case of TFE translocation positive relapsed metastatic pediatric renal cell 
carcinoma. J Pediatr Hematol Oncol 35:e1-3, 2013 
34. 
Ambalavanan M,Geller JI: Treatment of advanced pediatric renal cell carcinoma. Pediatr Blood 
Cancer 66:e27766, 2019 
35. 
Rini BI, Escudier B, Tomczak P, et al.: Comparative effectiveness of axitinib versus sorafenib in 
advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931-9, 2011 
36. 
Pfizer: Investigator's Brochure: Axitinib, 2013, pp 1-122 
37. 
Motzer RJ, Rini BI, McDermott DF, et al.: Nivolumab for Metastatic Renal Cell Carcinoma: 
Results of a Randomized Phase II Trial. J Clin Oncol 33:1430-7, 2015 
38. 
McDermott DF, Drake CG, Sznol M, et al.: Survival, Durable Response, and Long-Term Safety in 
Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin 
Oncol 33:2013-20, 2015 
39. 
Motzer RJ, Escudier B, McDermott DF, et al.: Nivolumab versus Everolimus in Advanced Renal-
Cell Carcinoma. N Engl J Med 373:1803-13, 2015 
40. 
Chang K, Qu Y, Dai B, et al.: PD-L1 expression in Xp11.2 translocation renal cell carcinoma: 
Indicator of tumor aggressiveness. Scientific Reports 7:2074, 2017 
41. 
Choueiri TK, Fay AP, Gray KP, et al.: PD-L1 expression in nonclear-cell renal cell carcinoma. Ann 
Oncol 25:2178-84, 2014 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AREN1721 
 
 
Version Date: 12/14/2021 
 
Page 139 
 
42. 
Amin A, Plimack ER, Infante JR, et al.: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in 
combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma 
(mRCC). Journal of Clinical Oncology 32:5010-5010, 2014 
43. 
Rini BI, Plimack ER, Stus V, et al.: Pembrolizumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N Engl J Med 380:1116-1127, 2019 
44. 
Motzer RJ, Penkov K, Haanen J, et al.: Avelumab plus Axitinib versus Sunitinib for Advanced 
Renal-Cell Carcinoma. N Engl J Med 380:1103-1115, 2019 
45. 
Rini BI, Tomita Y, Melichar B, et al.: Overall Survival Analysis From a Randomized Phase II 
Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma. 
Clin Genitourin Cancer 14:499-503, 2016 
46. 
Rini B, Melichar B, Fishman M, et al.: Axitinib dose titration: analyses of exposure, blood pressure 
and clinical response from a randomized phase II study in metastatic renal cell carcinoma. Ann 
Oncol 26:1372-7, 2015 
47. 
Choueiri TK, Plimack ER, Gupta S, et al.: Phase Ib Dose-Finding Study of Axitinib Plus 
Pembrolizumab in Treatment-Naïve Patients With Advanced Renal Cell Carcinoma. Presented at 
the Kidney Cancer Association 14th International Symposium, Miami, FL, November 6-7, 2015, 
2015 
48. 
Atkins MB, Gupta S, Choueiri TK, et al.: Phase Ib dose-finding study of axitinib plus 
pembrolizumab in treatment-naïve patients with advanced renal cell carcinoma. Journal for 
Immunotherapy of Cancer 3:P353-P353, 2015 
49. 
Geller J, Fox E, Turpin B, et al.: ADVL1315: A phase 1 study of the VEGF receptor tyrosine kinase 
inhibitor axitinib (INLYTA, IND# 123101) in children with recurrent or refractory solid tumors--
A Children's Oncology Group study. J Clin Oncol 34, 2016 
50. 
Teng MW, Ngiow SF, Ribas A, et al.: Classifying Cancers Based on T-cell Infiltration and PD-L1. 
Cancer Res 75:2139-45, 2015 
51. 
Senovilla L, Vacchelli E, Galon J, et al.: Trial watch: Prognostic and predictive value of the immune 
infiltrate in cancer. Oncoimmunology 1:1323-1343, 2012 
52. 
Meng X, Huang Z, Teng F, et al.: Predictive biomarkers in PD-1/PD-L1 checkpoint blockade 
immunotherapy. Cancer Treat Rev 41:868-76, 2015 
53. 
Nishino M, Ramaiya NH, Hatabu H, et al.: Monitoring immune-checkpoint blockade: response 
evaluation and biomarker development. Nat Rev Clin Oncol 14:655-668, 2017 
54. 
Tanaka A,Sakaguchi S: Regulatory T cells in cancer immunotherapy. Cell Research 27:109, 2016 
55. 
Pitt JM, Vetizou M, Daillere R, et al.: Resistance Mechanisms to Immune-Checkpoint Blockade in 
Cancer: Tumor-Intrinsic and -Extrinsic Factors. Immunity 44:1255-69, 2016 
56. 
Long GV, Weber JS, Larkin J, et al.: Nivolumab for Patients With Advanced Melanoma Treated 
Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. JAMA Oncol 3:1511-1519, 2017 
57. 
George S, Motzer RJ, Hammers HJ, et al.: Safety and Efficacy of Nivolumab in Patients With 
Metastatic Renal Cell Carcinoma Treated Beyond Progression: A Subgroup Analysis of a 
Randomized Clinical Trial. JAMA Oncol 2:1179-86, 2016 
58. 
Escudier B, Motzer RJ, Sharma P, et al.: Treatment Beyond Progression in Patients with Advanced 
Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025. Eur Urol 72:368-376, 2017 
59. 
Ishihara H, Takagi T, Kondo T, et al.: Nivolumab treatment beyond progression for metastatic renal 
cell carcinoma: New role of metastasectomy in the immune checkpoint inhibitor era? International 
Journal of Urology 27:691-692, 2020 
60. 
Shah AY, Kotecha RR, Lemke EA, et al.: Outcomes of patients with metastatic clear-cell renal cell 
carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors. Eur 
J Cancer 114:67-75, 2019 
61. 
Schwartz GJ,B G: A simple estimate of glomerula filtration rate in adolescent boys. J. Pediatr. 
106:522-6, 1985 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AREN1721 
 
 
Version Date: 12/14/2021 
 
Page 140 
 
62. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
63. 
Seymour L, Bogaerts J, Perrone A, et al.: iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol 18:e143-e152, 2017 
64. 
Flanigan RC, Salmon SE, Bluemenstein BA, et al.: Nephrectomy followed by interferon alfa-2b 
compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655-9, 
2001 
65. 
Mickisch GH, Garin A, van Poppel H, et al.: Radical nephrectomy plus interferon-alfa-based 
immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a 
randomised trial. Lancet 358:966-70, 2001 
66. 
Heng DY, Wells JC, Rini BI, et al.: Cytoreductive nephrectomy in patients with synchronous 
metastases from renal cell carcinoma: results from the International Metastatic Renal Cell 
Carcinoma Database Consortium. Eur Urol 66:704-10, 2014 
67. 
Hanna N, Sun M, Meyer C, P.,, et al.: Survival Analyses of Patients With Metastatic Renal Cancer 
Treated With Targeted Therapy With or Without Cytoreductive Nephrectomy: A National Cancer 
Data Base Study. Journal of Clinical Oncology 34:3267-3275, 2016 
68. 
Raval MV, Bilimoria KY, Bentrem DJ, et al.: Nodal evaluation in Wilms' tumors: analysis of the 
national cancer data base. Ann Surg 251:559-65, 2010 
69. 
Zhuge Y, Cheung MC, Yang R, et al.: Improved survival with lymph node sampling in Wilms 
tumor. J Surg Res 167:e199-203, 2011 
70. 
Kieran K, Anderson JR, Dome JS, et al.: Lymph node involvement in Wilms tumor: results from 
National Wilms Tumor Studies 4 and 5. J Pediatr Surg 47:700-6, 2012 
71. 
Indolfi P, Bisogno G, Cecchetto G, et al.: Local lymph node involvement in pediatric renal cell 
carcinoma: a report from the Italian TREP project. Pediatr Blood Cancer 51:475-8, 2008 
72. 
Crispen PL, Breau RH, Allmer C, et al.: Lymph node dissection at the time of radical nephrectomy 
for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical 
templates. Eur Urol 59:18-23, 2011 
73. 
Capitanio U, Becker F, Blute ML, et al.: Lymph node dissection in renal cell carcinoma. Eur Urol 
60:1212-20, 2011 
74. 
Edge SB, Byrd DR, Compton CC, et al.: AJCC Cancer Staging Manual, 7th ed. New York, 
Springer-Verlag  
75. 
Schwartz GJ, Munoz A, Schneider MF, et al.: New equations to estimate GFR in children with 
CKD. J Am Soc Nephrol 20:629-37, 2009 
76. 
Levey AS, Stevens LA, Schmid CH, et al.: A new equation to estimate glomerular filtration rate. 
Ann Intern Med 150:604-12, 2009