Clinical trial NCT03468985
Conditions: Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Recurrent Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7
Keywords: Nivolumab Cabozantinib Ipilimumab NSCLC
Sponsor: National Cancer Institute (NCI)
Start date: 2018-05-07; Completion date: 2022-12-21
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To demonstrate whether combination therapy of nivolumab and cabozantinib s-malate (cabozantinib), or of nivolumab and cabozantinib, and ipilimumab as compared to nivolumab alone, extends progression-free survival (PFS) for this patient population with non-squamous non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To estimate the overall survival for each arm of the trial. II. To estimate the best overall response rate for each arm of the trial. III. To estimate the progression free survival of the targeted therapy arm of the trial.

IV. To describe the toxicity profile of monotherapy with nivolumab, and the combination of nivolumab and cabozantinib, and the combination of nivolumab and cabozantinib and ipilimumab, in this patient population with non-squamous NSCLC.

CORRELATIVE OBJECTIVES:

I. To adjust progression free survival for each arm based on PD-L1 tumor status.

IMAGING OBJECTIVES:

I. To describe time point tumor response assessment, overall best response and progression-free survival using the conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and the exploratory uni-dimensional immune response criteria (iRRC) and the imaging (i)RECIST criteria with all measurements performed by the central review.

II. To compare RECIST 1.1 imaging response assessment measurements (time point response assessment and overall best response) assess by site study personnel to those performed by central review.

EXPLORATORY TOBACCO USE OBJECTIVES:

I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications).

II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.

III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.

IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.

OUTLINE: Patients are randomized to 1 of 3 arms. Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement are assigned to Arm T.

ARM A: Patients receive nivolumab at 480 mg intravenously (IV) over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nivolumab at 480 mg IV over 60 minutes on day 1 and cabozantinib s-malate at 40 mg orally (PO) daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive nivolumab at 480 mg IV over 60 minutes on day 1, cabozantinib s-malate at 40 mg PO daily on days 1-28, and ipilimumab at 1 mg/kg IV over 90 minutes every 8 weeks. Cycles for nivolumab and cabozantinib s-malate repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM T: Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement receive nivolumab at 480 mg IV over 60 minutes on day 1 and cabozantinib s-malate at 40 mg PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Arms: arm 1: Patients receive nivolumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive nivolumab IV over 60 minutes on day 1, cabozantinib s-malate PO daily on days 1-28, and ipilimumab IV over 90 minutes every 8 weeks. Cycles for nivolumab and cabozantinib s-malate repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cabozantinib intervention 2: Ipilimumab intervention 3: Nivolumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
April 4, 2019
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #4 to EA5152, A Randomized Phase II Trial of Nivolumab, Cabozantinib 
Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients with Previously 
Treated Non-Squamous NSCLC.
This addendum is in response to Dr. John Wright’s March 29, 2019 Request for Rapid 
Amendment for cabozantinib.
Please replace your current copy of the protocol and Informed Consent document (if ICD 
changed) with this (these) updated version(s).  We recommend that each institution maintain a 
file containing the original protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
An expedited review by the IRB can be considered for this amendment. However, please 
consult your local IRB’s standard operating procedures, since their requirements may differ and 
require a full board review. It is the decision of the local IRB whether or not subjects are to be 
re-consented.
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the CIRB 
posting of this notice.
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed 
consent changes must be approved by local IRBs within 90 days of distribution of this notice. If 
your local IRB has different SOPs, they must be available at future E-A audit.
The following are ECOG-ACRIN’s responses to CTEP review comments from the “Review of
Amendment #03 of Protocol # EA5152”, dated August 30, 2018. Please note that the Principal 
Investigator’s comments appear in bold below.
I.
Recommendations:
#
Section
Comments
1.
Protocol:
8.1.5
Information about the permitted temperature excursion is valuable to the sites.  
Strongly recommend to updating it in your next amendment request.
“Storage:  Store intact bottles at controlled room temperature 200 C to 250C (680 F
to 770 F); temperature excursions are permitted between 150 C and 300 C (590 F to 
860 F) [see USP Controlled Room Temperature].


ii 
# 
Section 
Comments 
If a storage temperature excursion is identified, promptly return XL184 
(Cabozantinib) to 200 to 250C (680 to 770 F) and quarantine the 
supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.” 
PI Response: This change has been made. 
2. 
Protocol: 
8.2.6 
Replace current section with the following: 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose, USP so as not to exceed a 
total infusion volume of 120 160 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. 
PI Response: This change has been made. 
3. 
Protocol: 
8 
In the first paragraph, change the following sentence as indicated: 
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, Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF). 
PI Response: This change has been made. 
4. 
Protocol: 
8 
Change the third paragraph as indicated: 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can sSubmit agent requests through the 
PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password. For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
PI Response: This change has been made. 
 
The following are ECOG-ACRIN’s responses to CTEP review comments from the “Review of 
Amendment #02 of Protocol # EA5152”, dated July 13, 2018. Please note that the Principal 
Investigator’s comments appear in bold below. 
I. 
Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
5. 
General 
No further details of the analysis nor statistical plan are provided. No early 
stopping point is noted. These must all be provided prior to possible approval. 
These will also require statistical assessment. Therefore these changes cannot 
be approved currently. 
PI Response: Thank you for the suggestion. Since the study is suspended 
and is likely to be terminated soon, due to slow accrual, further design 
changes are no longer being implemented. 


iii 
# 
Section 
Comments 
6. 
General 
Please provide the specific reasons for doing the comparative imaging at the 
indicated timepoints per the published literature. 
PI Response: Thank you for the suggestion. Since the study is suspended 
and is likely to be terminated soon, due to slow accrual, further design 
changes are no longer being implemented. 
7. 
Protocol: 
9.2 
Discusses study endpoints but not in detail. 
Statistical considerations in section 9 will have to be assessed by others. In 
particular anything that would relate to the exploratory imaging study. 
PI Response: Thank you for the suggestion. Since the study is suspended 
and is likely to be terminated soon, due to slow accrual, further design 
changes are no longer being implemented. 
II. Comments Requiring a Response – Administrative & Editorial Issues: 
# 
Section 
Comments 
8. 
Protocol: 
8.1.5 
The drug storage has been updated to include permitted temperature 
excursion.  Please update in your next amendment request. 
“Storage:  Store intact bottles at controlled room temperature 200 C to 250C 
(680 F to 770 F); temperature excursions are permitted between 150 C and 300 
C (590 F to 860 F) [see USP Controlled Room Temperature]. 
If a storage temperature excursion is identified, promptly return 
XL184 (Cabozantinib) to 200 to 250C (680 to 770 F) and quarantine 
the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.” 
PI Response: This change has been made. 
9. 
Protocol: 
8 
Replace “Useful Links and Contacts” with the following: 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/   
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov   
• 
IB Coordinator:  IBCoordinator@mail.nih.gov   
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) 
PI Response: This change has been made. 


iv 
# 
Section 
Comments 
10. 
ICF: 
“What possible 
risks can I expect 
from taking part in 
this study?” 
What are the risks? 
Add Group C to the possible side effects of cabozantinib table, or remove all 
references to study groups. 
PI Response: This change has been made. 
The following revisions to EA5152 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Global 
Various minor administrative edits made throughout. 
2. 
Cover Page 
Updated version date. 
3. 
3.1.1 
Revised language for eligibility criteria clarification. 
4. 
5.2 
Revised language for clarification of adverse event reporting. 
5. 
5.2.2 
Added section for clarification of adverse event reporting. 
6. 
5.2.3 
Added section for clarification of adverse event reporting. 
7. 
5.3.1 
Updated CAEPR to version 2.4, December 17, 2018. 
8. 
5.4.14 
Removed grade 4 fatigue as it does not exist in CTCAE. 
9. 
6.1.4.4 
Updated remark in table to be consistent with section 6.1.4.1. 
10. 7.1 
Added language to footnote 4 for screening TSH and reflex free T4. 
11. 8 
Revised language per CTEP recommendations. Updated useful links and 
contacts information. 
12. 8.1.5 
Updated storage information for cabozantinib. 
13. 8.2.4 
Added description section for nivolumab. 
14. 8.2.5 
Updated storage information for nivolumab. 
15. 8.2.7 
Updated preparation information for nivolumab. 
16. 8.2.8 
Updated route of administration information for nivolumab. 
17. 8.2.10 
Updated availability information for nivolumab. 
18. 8.3.4 
Added description section for ipilimumab. 
19. 8.3.7 
Updated preparation information for ipilimumab. 
20. 8.3.8 
Updated route and method of administration information for ipilimumab. 
21. 8.3.9 
Added availability information for ipilimumuab. 
22. 8.3.11 
Updated nursing/patient implications information for ipilimumab. 
23. Appendix VI 
Updated language of pregnancy reporting to be more consistent with 
current version of template. 
24. Appendix VIII 
Removed CTCAE incorrect version number. 


v 
The following revisions to EA5152 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Page 1 
Updated version date. 
2. 
“What possible risks 
can I expect from 
taking part in this 
study?” 
Added group C to heading for tables describing “possible side effects of 
cabozantinib.” Updated cabozantinib risk profile per CAEPR version 2.4, 
December 17, 2018. 
If you have any questions regarding this addendum, please contact Elanna Radomyshelsky at 
eradomyshelsky@ecog-acrin.org or 617-632-3610. 
We request review and approval of this addendum to EA5152 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
Enclosure 
CC: Joel Neal, MD, PhD 
Heather Wakelee, MD 
Suresh Ramalingam, MD 
Suzanne Dahlberg, PhD 
Zhuoxin Sun, PhD 
Seena Aisner, MD 
Sharyn Katz, MD 
Christine Lovly, MD, PhD 
Becky Fillingham 
Donna Marinucci 
 
Carol Chami 
Melinda Flood 
Bruce Giantonio, M.D. 
Kerry Higgins, MPH 
Gayle Ipock 
Jean MacDonald, MPH 
Jeffrey Zhang 
Elanna Radomyshelsky 
Lauren Lambert 
Sarah Archambault 
Kelly Redmond 
 
 


EA5152
1
A Randomized Phase II Trial of Nivolumab, Cabozantinib 
Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus 
Ipilimumab in Patients with Previously Treated Non-
Squamous NSCLC
STUDY CHAIR:
Joel Neal, M.D., Ph.D.
STUDY CO-CHAIR:
Heather Wakelee, M.D.
STUDY STATISTICIAN:
Suzanne Dahlberg, Ph.D.
IMAGING STATISTICAN
Zheng Zhang, Ph.D.
THORACIC COMMITTEE CHAIR:
Suresh Ramalingam, M.D.
PATHOLOGY CO-CHAIR:
Seena Aisner, M.D.
IMAGING CO-CHAIR
Sharyn Katz, M.D 
BIOLOGY CO-CHAIR:
Christine M. Lovly, MD, Ph.D.
Version Date: April 4, 2019
STUDY PARTICIPANTS
ACTIVATION DATE
ALLIANCE / Alliance for Clinical Trials in 
Oncology
March 1, 2018
NRG / NRG Oncology
Addendum #1
SWOG / SWOG
Addendum #2
Addendum #3
US Sites Only 
Addendum #4
NCTN GROUP STUDY CHAMPIONS
ALLIANCE: Muhammad Furqan, MD
Agents
IND#
NSC#
Supply
XL184 (Cabozantinib)
761968
DCTD
BMS-936558 (Nivolumab, MDX-1106)
748726
DCTD
Ipilimumab (MDX-010)
732442
DCTD


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
2 
Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Background and antitumor effects of cabozantinib, nivolumab, and 
ipilimumab in NSCLC ................................................................................. 7 
1.2 
Combination Data ................................................................................... 10 
1.3 
Preclinical and clinical rationale for the combination of cabozantinib, 
nivolumab, and ipilimumab in NSCLC ..................................................... 11 
1.4 
Evidence for using cabozantinib as a targeted therapy in NSCLC ........... 12 
1.5 
Cabozantinib (XL184) - Further information ........................................... 12 
1.6 
Nivolumab and ipilimumab – further information ................................. 19 
1.7 
Imaging of therapy response to immune checkpoint inhibition............. 23 
1.8 
Rationale for Tobacco Use Assessment .................................................. 24 
2. Objectives ......................................................................................................... 26 
2.1 
Primary Endpoint .................................................................................... 26 
2.2 
Secondary Endpoints ............................................................................... 26 
2.3 
Correlative Endpoints .............................................................................. 26 
2.4 
Imaging Endpoints ................................................................................... 26 
2.5 
Exploratory Tobacco Use Objectives ....................................................... 26 
3. Selection of Patients ......................................................................................... 28 
3.1 
Eligibility Criteria for Step 0 .................................................................... 28 
3.2 
Eligibility Criteria for Step 1 .................................................................... 29 
4. Registration and Randomization Procedures ................................................... 36 
4.1 
Preregistration (Step 0) ........................................................................... 39 
4.2 
Randomization/Registration (Step 1) ...................................................... 40 
4.3 
Submission of Images for Central Review ............................................... 42 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment42 
5. Treatment Plan ................................................................................................. 43 
5.1 
Administration Schedule ......................................................................... 43 
5.2 
Adverse Event Reporting Requirements ................................................. 43 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ........... 55 
5.4 
Dose Modifications ................................................................................. 72 
5.5 
Supportive Care and Concomitant Treatments ...................................... 98 
5.6 
Patient Reported Outcome Measures: Tobacco Use Assessment ........ 100 
5.7 
Duration of Therapy .............................................................................. 102 
5.8 
Duration of Follow-up ........................................................................... 102 
6. Measurement of Effect ................................................................................... 103 
6.1 
Antitumor Effect – Solid Tumors ........................................................... 103 
6.2 
Exploratory imaging correlatives: ......................................................... 111 
6.3 
Submission of Images for Central Review ............................................. 116 
7. Therapeutic Parameters ................................................................................. 117 
7.1 
Step 1: Therapeutic Parameters ........................................................... 117 


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
3 
8. Drug Formulation and Procurement ............................................................... 120 
8.1 
Cabozantinib (NSC 761968 .................................................................... 121 
8.2 
Nivolumab (NSC 748726) ...................................................................... 124 
8.3 
Ipilimumab (NSC 732442) ..................................................................... 126 
9. Statistical Considerations ................................................................................ 129 
9.1 
Study Design and Objectives ................................................................. 129 
9.2 
Study Endpoints .................................................................................... 129 
9.3 
Statistical Analysis Plan ......................................................................... 130 
9.4 
Sample Size Considerations .................................................................. 130 
9.5 
Projected Accrual .................................................................................. 131 
9.6 
Gender and Ethnicity ............................................................................ 131 
9.7 
Randomization Scheme......................................................................... 131 
9.8 
Monitoring Plan .................................................................................... 132 
9.9 
Tobacco Use Assessment ...................................................................... 132 
10. Specimen Submissions .................................................................................... 133 
10.1 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) ........................................................................................ 133 
10.2 ECOG-ACRIN Sample Tracking System .................................................. 134 
10.3 Use of Specimens in Research .............................................................. 135 
10.4 Sample Inventory Submission Guidelines ............................................. 135 
11. Laboratory Research Studies .......................................................................... 136 
11.1 Reference PD-L1 Testing and Correlation with Outcome. .................... 136 
11.2 Lab Data Transfer Guidelines ................................................................ 137 
12. Electronic Data Capture .................................................................................. 138 
13. Patient Consent and Peer Judgment .............................................................. 138 
14. References ...................................................................................................... 138 
Appendix I  Pathology Submission Guidelines ...................................................... 145 
Appendix II  Patient Thank You Letter ................................................................... 149 
Appendix III  Patient Pill Calendar ......................................................................... 150 
Appendix IV  CRADA/CTA ...................................................................................... 152 
Appendix V  ECOG Performance Status................................................................. 154 
 Appendix VI  Instructions for Reporting Pregnancies on a Clinical Trial .............. 155 
Appendix VII  Prohibited Medications and Medications to Use with Caution ...... 158 
Appendix VIII  Ancillary for Tobacco Use Assessment: EAQ16T ............................ 160 
 
 
 


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
4 
STUDY CHAIR 
Joel Neal, M.D., Ph.D. 
Stanford University/Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
Phone: (650) 725-3081 
Fax: (650) 498-5800 
Email: jwneal@stanford.edu 
 
STUDY CO-CHAIR 
Heather Wakelee, M.D. 
Stanford University/Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
Phone: (650) 736-7221 
Fax: (650) 724-3697 
Email: hwakelee@stanford.edu 
 
ALLIANCE STUDY CHAMPION 
Muhammad Furqan, M.B., B.S 
Assistant Professor, Department of Medicine 
Division of Hematology, Oncology, Blood & 
Marrow Transplant 
University of Iowa Hospitals and Clinics 
Telephone: +1-319-356-1527 
Fax: +1- 319-353-8383 
Email: Muhammad-furqan@uiowa.edu 
 


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments: 
For study data 
submission:  
For image submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-
tab under the Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 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 through 
Medidata Rave and the 
ECOG-ACRIN Systems for 
Easy Entry of Patient 
Reported Outcomes 
(EASEE-PRO) system. 
Please see the data 
submission section of the 
protocol for further 
instructions.  
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
All CT and FDG-PET/CT imaging 
data obtained for patients 
participating in this clinical trial at 
baseline and through the first 3 
follow-up imaging time points will be 
de-identified and uploaded from the 
study site to the ACR Imaging Core 
Laboratory within 48 hrs. of 
completion using TRIAD software. 
See the section “Image Submission 
for Central Review” in this protocol 
for further information. 
For questions regarding TRIAD 
installation, please contact the 
TRIAD helpdesk at TRIAD-
Support@acr.org or 
https://triadhelp.acr.org/clinicaltrials 
The most current version of the study protocol and all supporting documents must be downloaded from the protocol-specific Web page of 
the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM 
username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the Coordinating Group. 
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 Web site is located at   https://www.ctsu.org 
 
Rev. Add2 


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
6 
Schema 
ARM A
Nivolumab 
480mg IV every 4 weeks
R
A
N
D
O
M
I
Z
A
T
I
O
 N2
Stratification Factor
· Known PD-L1 IHC
· Negative
· Positive (> 1%)
· Unknown/not tested
N = 169
Cycle = 4 weeks
ARM B
Cabozantinib 
40mg PO Daily
Nivolumab 
480mg IV every 4 weeks
1.
Tumors must be known to be negative for EGFR or ALK mutations for patients with or without eligible molecular alterations. 
Patients with eligible molecular alterations (MET mutation, MET amplification, ROS1 rearrangement, RET rearrangement) must 
submit testing results per Section 4.2.4.
2.
1:1:1 Randomization across Arms A-C.
ARM C
Cabozantinib 
40mg PO Daily
Nivolumab 
480mg IV every 4 weeks
Ipilimumab 
1mg/kg IV every 8 weeks
ARM T
Cabozantinib 
40mg PO Daily
Nivolumab 
480mg IV every 4 weeks
P
R
E
-
R
E
G
I
S
T
R
A
T
I
O
N
Patients with only one prior 
line of platinum based 
therapy and no prior 
immunotherapy, without 
eligible molecular 
alterations outlined in 
Section 3.1.11
Patients with at least 
one prior line of 
therapy, and no prior 
immunotherapy, with 
eligible molecular 
alterations outlined in 
Section 3.1.11
Step 0
Step 1
Eligible for 
targeted cohort
Ineligible for 
targeted cohort
 
Rev. Add1 


ECOG-ACRIN 
EA5152 
Cancer Research Group 
Version Date: April 4, 2019 
7 
1. 
Introduction 
1.1 
Background and antitumor effects of cabozantinib, nivolumab, and ipilimumab in 
NSCLC 
Lung cancer remains the leading cause of cancer-related deaths in the United 
States, estimated to be responsible for over 160,000 deaths, and worldwide 
killing more than 1.3 million people annually.[1, 2] Non-small cell lung cancer 
(NSCLC) comprises 87% of all lung cancers. Despite many available treatment 
options, metastatic non-small cell lung cancer remains an incurable disease. 
First-line chemotherapy with a platinum-based doublet for advanced NSCLC has 
a response rate of only approximately 20% and a median overall survival of 8-10 
months.[3] Second-line chemotherapeutic agents such as docetaxel and 
pemetrexed confer response rates of approximately 10% and progression-free 
survival times of approximately 3 months.[4] The majority of patients with NSCLC 
receive multiple lines of therapy, including cytotoxic chemotherapy, targeted 
small molecule tyrosine kinase in selected patients, and increasingly 
immunotherapy with anti-PD-1 drugs.  
Activity of Cabozantinib in NSCLC 
Cabozantinib has demonstrated activity in patients with previously treated 
NSCLC. Recently, the ECOG-ACRIN group studied the use of cabozantinib, an 
oral small molecule inhibitor of MET, RET and VEGFR2, in previously treated 
patients with EGFR wild type NSCLC. Compared with the erlotinib control group, 
treatment with cabozantinib led to clinically relevant improvements in 
progression-free and overall survival.[6] In this study, 125 patients were 
randomized between erlotinib (E), cabozantinib (C), and the combination (EC). 
The study met its primary endpoints, demonstrating an improvement in 
progression-free survival for both of the cabozantinib-containing arms versus 
erlotinib, and also showed an improvement in overall survival (Figure, below). 


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Based on these results, cabozantinib appears to be an active drug in the 
treatment of NSCLC. Furthermore, MET IHC testing was performed and does not 
appear to be correlated with PFS benefit. We do not believe that the additional 
contribution of erlotinib in the combination is a meaningful difference that should 
be pursued, particularly as the indication for erlotinib in EGFR wild-type NSCLC 
has recently been rescinded by the FDA.[7]
The current FDA approved dose of nivolumab is 240 mg IV every 2 weeks 
(recently changed from 3 mg/kg IV every 2 weeks). However, an alternative 
dosing strategy of 480 mg IV every 4 weeks is being pursued for approval as 
well. In anticipation of this, we will plan to administer nivolumab at the every 4 
week schedule on this trial.
Activity of Nivolumab in NSCLC
Nivolumab, a monoclonal anti-PD-1 immunotherapeutic checkpoint inhibitor, is 
FDA approved for the treatment of squamous and non-squamous NSCLC. Of the 
second line treatment options currently available, immunotherapies more often 
result in prolonged benefit for a population of patients, with about 20% of patients 
having >12 month PFS. There is excitement about this new platform of therapy, 
but there is an unmet need to find drugs which synergize immunologically to 
allow a larger proportion of patients to benefit long term from therapy.
Nivolumab is also active in the second line treatment of non-squamous NSCLC, 
as demonstrated in the trial Phase III, Randomized Trial (CheckMate 057) of 
Nivolumab versus Docetaxel in Advanced Non-squamous (non-SQ) Cell Non-
small Cell Lung Cancer (NSCLC) “.[8] In this trial, nivolumab had an overall 
survival benefit compared with docetaxel. 


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Nivolumab 
(n = 292) 
Docetaxel 
(n = 290) 
mOS, mo 
12.2 
9.4 
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015 
mPFS, mo 
2.3 
4.2 
HR = 0.92 (95% CI: 0.77, 1.11); P = 0.3932 
The question of whether positive PD-L1 testing is necessary to predict benefit is 
currently an area of active investigation. With FDA approval of nivolumab, an 
optional “complementary diagnostic” of PD-L1 testing was also released. This 
diagnostic may help predict the likelihood of response, but is not required for 
treatment. 
Activity of Nivolumab and Ipilimumab in NSCLC 
Nivolumab and ipilimumab is an FDA approved combination therapy in 
melanoma, and is being extensively tested in NSCLC. In the CheckMate-012 
study published in Lancet Oncology, four dose regimens were tested of 
nivolumab and ipilimumab.[9] In the two arms potentially suitable for moving 
forward, the treatment responses were as follows:  
 
Nivolumab 3 mg/kg q2 
weeks + Ipilimumab 1 
mg/kg q 6 weeks (n = 38) 
Nivolumab 3 mg/kg q2 
weeks + Ipilimumab 1 
mg/kg q 12 weeks (n = 
39) 
Response rate 
38% 
47% 
Median progression free 
survival 
3.9 months 
8.1 months 
1 year overall survival 
69% 
Not calculated 
These numbers suggest that this combination could compete with first line 
platinum based therapy in the treatment of NSCLC. Grade 3 or higher adverse 
events occurred in 28% of patients (5% GI, 5% endocrine, 5% hepatic, 3% 
pulmonary, and others not reported), suggesting that this combination does have 
more toxicity than nivolumab alone.  
There are two large ongoing trials using nivolumab and ipilimumab. The 
CheckMate-568 trial (NCT02659059) is a single arm phase 2 study treating 340 
patients with advanced NSCLC using first line nivolumab and ipilimumab. This 
study will identify whether efficacy of the combination is numerically better than 
historical controls with chemotherapy. Separately, the CheckMate 227 study 
(NCT02477826) is being conducted in 1980 patients with NSCLC assigning 
previously untreated patients to nivolumab, nivolumab plus ipilimumab, 
nivolumab plus platinum-doublet chemotherapy, or platinum doublet 
chemotherapy as the comparator arm in patients with advanced NSCLC. 
Therefore, there is justification for using the combination of cabozantinib, 
nivolumab, and ipilimumab as one of the investigational arms of this randomized 
3-arm trial. 


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1.2 
Combination Data  
Based on these data, using ipilimumab either every 6 weeks or every 12 weeks 
is reasonable, and the every 12 week dosing was numerically even a bit better. 
Therefore, we have chosen to dose every 8 weeks for this protocol to match with 
intended radiographic assessment frequency. Safety of the combination of 
cabozantinib, nivolumab, and ipilimumab 
The combination of nivolumab and cabozantinib is currently being tested for 
safety of dose in a phase I study, “Cabozantinib Plus Nivolumab (CaboNivo) 
Alone or in Combination With Ipilimumab (CaboNivoIpi) in Patients With 
Advanced/Metastatic Urothelial Carcinoma and Other Genitourinary Tumors” 
(NCT02496208). Preliminary results were presented in 2017, with a 30% overall 
response rate and toxicity information presented below.[10] The recommended 
phase II doses described were cabozantinib 40 mg + nivolumab 3 mg/kg every 3 
weeks, and cabozantinib 40 mg + nivolumab 3 mg/kg every 3 weeks + 
ipilimumab 1mg/kg every 3 weeks (for 4 doses total). We anticipate additional 
information regarding safety of this combination will continue to become available 
as this trial is conducted. 
Adverse Event 
CaboNivo N=30 
CaboNivoIpi N=18 
Any 
Grade 
N (%) 
Grade 3 
N (%) 
Grade 4 
N (%) 
Any 
Grade 
N (%) 
Grade 3 
N (%) 
Grade 4 
|N (%) 
Alanine Aminotransferase 
Increased 
20 (67) 
0 
0 
8 (44) 
1(6) 
0 
Fatigue 
19 (63) 
2 (7) 
0 
13 (72) 
2 (13) 
0 
Diarrhea 
18 (60) 
2 (7) 
0 
11 (61) 
0 
0 
Hypothyroidism 
17 (57) 
0 
0 
5 (28) 
0 
0 
Aspartate 
Aminotransferase 
Increased 
15 (50) 
0 
0 
4 (22) 
0 
0 
Anorexia 
14 (47) 
0 
0 
11 (61) 
1 (6) 
0 
Hoarseness 
12 (40) 
0 
0 
4(22) 
0 
0 
Mucositis 
12 (40) 
0 
0 
6 (33) 
0 
0 
Hypocalcemia 
12 (40) 
0 
0 
4 (22) 
0 
0 
Hyponatremia 
11 (37) 
1 (3) 
0 
5(28) 
2 (13) 
0 
Hypophosphatemia 
11 (37) 
4 (13) 
0 
8(44) 
3 (17) 
0 
Palmar Plantar 
Erythrodysesthesia 
11 (37) 
0 
0 
5 (28) 
0 
0 
Thrombocytopenia 
11 (37) 
1 (3) 
1 (3) 
6 (33) 
0 
0 
Dysgeusia 
9 (30) 
0 
0 
8 (44) 
0 
0 
Hypoalbuminemia 
9 (30) 
0 
0 
3(17) 
0 
0 
Myalgia 
9 (30) 
0 
0 
3(17) 
0 
0 
Nausea 
9 (30) 
0 
0 
7(39) 
2(13) 
0 
Rash€ 
8 (27) 
0 
0 
6(33) 
1 (6) 
0 
Neutropenia 
8 (27) 
5 (17) 
0 
4(22) 
0 
0 
Dry mouth 
7 (23) 
0 
0 
6(33) 
0 
0 


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Adverse Event 
CaboNivo N=30 
CaboNivoIpi N=18 
Any 
Grade 
N (%) 
Grade 3 
N (%) 
Grade 4 
N (%) 
Any 
Grade 
N (%) 
Grade 3 
N (%) 
Grade 4 
|N (%) 
Dry skin 
7 (23) 
0 
0 
4 (22) 
0 
0 
Vomiting 
7 (23) 
1 (3) 
0 
4 (22) 
0 
0 
Hypertension 
7 (23) 
3 (10) 
0 
3(17) 
3 (17) 
0 
Hypomagnesemia 
7 (23) 
0 
0 
2(11) 
0 
0 
Proteinuria 
7 (23) 
1 (3) 
0 
2 (11) 
0 
0 
Headache 
7 (23) 
0 
0 
0 
0 
0 
Anemia 
6 (20) 
1 (3) 
0 
4(22) 
0 
0 
Weight loss 
6 (20) 
0 
0 
5 (28) 
0 
0 
Abdominal Pain 
5 (17) 
0 
0 
3(17) 
0 
0 
Hypokalemia 
5 (17) 
0 
0 
4(22) 
0 
0 
Lipase increase 
5 (17) 
2 (7) 
2 (7) 
8 (44) 
2 (13) 
1 (6) 
Cough 
3 (10) 
0 
0 
5 (28) 
0 
0 
Dehydration 
3 (10) 
2 (7) 
0 
3 (17) 
0 
0 
Hyperthyroidism 
3 (10) 
1 (3) 
0 
2 (11) 
0 
0 
Amylase increase 
4 (13) 
1 (3) 
0 
1(6) 
0 
0 
Thromboembolic Event 
1 (3) 
1 (3) 
0 
0 
0 
0 
Colitis 
0 
0 
0 
1 (6) 
1 (6) 
0 
Aseptic meningitis 
1 (3) 
1 (3) 
0 
0 
0 
0 
1.3 
Preclinical and clinical rationale for the combination of cabozantinib, nivolumab, 
and ipilimumab in NSCLC 
There is emerging preclinical evidence that the combination of nivolumab and 
cabozantinib might offer synergistic activity. In a publication from Jim Hodges’ lab 
at the NCI, it was observed that cabozantinib changes both the tumor and the 
immune system in a mouse model to be more permissive for immune-mediated 
tumor killing, both in cell culture and in murine cell line grafts.[11] Mice were 
implanted with the MC38-CEA murine colon carcinoma cell line, which expresses 
VEGFR2 and MET. When a poxviral-based colon cancer vaccine was 
administered, the observed T cell tumor infiltration was modest, but cabozantinib 
significantly boosted this effect for CD3, CD4, and CD8-positive T cells. 
Additionally, cytokine production was markedly higher with the combination. In 
another report, these authors observe regression of tumors in 5/10 mice treated 
with the combination of vaccine and cabozantinib, but 0/10 mice with vaccine or 
cabozantinib alone:[12]  In another study, Patnaik et al used a murine mouse 
endogenous prostate cancer model to study the effects of cabozantinib on the 
immune system. [13] Cabozantinib induced tumor regression via an 
inflammatory, not apoptotic, mechanism. There was evidence of potent infiltration 
of polymorphonuclear leukocytes and release of a neutrophil chemoattractant, 
HMGB1. Tumor regression could be blocked by dexamethasone or an anti-Ly6G 
antibody which depleted neutrophils. This appeared to be a MET-inhibitor 
independent effect. Finally, early clinical support for the combination of 
cabozantinib and anti-PD-1 therapy comes from a phase II trial in which 


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treatment with cabozantinib has been shown to upregulate PD-L1 expression on 
regulatory T cells in patients with metastatic urothelial carcinoma, which may 
confer sensitivity to anti-PD-1 therapy.[14] Together, these studies suggest that 
cabozantinib has a pro-inflammatory mechanism of action and support the use of 
cabozantinib in combination with a checkpoint inhibitor. Based on these pre-
clinical observations, and the clinical efficacy of these two agents independently 
in NSCLC, we propose to conduct a randomized phase 2 study in advanced 
NSCLC. 
Clinically, based on the observed activity of cabozantinib and nivolumab 
independently in the second and third line treatment of NSCLC, and the potential 
immunostimulatory activity of cabozantinib observed in the preclinical setting, we 
propose that combining these drugs together may lead to superior outcome 
compared with nivolumab alone. Furthermore, given the efficacy data leading to 
the FDA approval in melanoma[15, 16] and the promising phase 2 evidence for 
the combination of nivolumab and ipilimumab in NSCLC,[9] we propose also 
testing the safety and efficacy of cabozantinib/nivolumab/ipilimumab as well 
1.4 
Evidence for using cabozantinib as a targeted therapy in NSCLC 
In addition to the activity against VEGFR2, cabozantinib is active as a MET 
inhibitor, ROS1 inhibitor, and RET inhibitor. MET exon 14 splice mutations 
comprise up to 3% of NSCLC, and are highly sensitive to the MET inhibitor 
crizotinib.[17-19] Reported confirmed response rates have been as high as 
43%.[20]  Additionally, they have been reported to be sensitive to 
cabozantinib.[18] Because cabozantinib is a type II MET inhibitor, which is still 
active after acquired resistance solvent front mutations develop, it may even 
work after resistance to crizotinib has developed.[21] One patient with CNS 
progression after crizotinib with a response to cabozantinib has been 
described.[22]  
MET amplification is likely found in less than 1% of NSCLC, but these tumors are 
also highly sensitive to MET inhibitors even independently of the presence of 
MET exon 14 splice alterations.[23] It is reported that the highest level of MET 
amplification, characterized by a fluorescence in situ hybridization MET/CEP7 
ratio of 5 or higher defines the "MET-amplified" group.[23]  
RET gene rearrangements occur in about 1% of NSCLC. Responses to the RET 
inhibitor cabozantinib have been reported by many groups, with a response rate 
of 28% or higher.[24] [25] 
Finally, ROS1-rearranged NSCLC, which is highly sensitive to the FDA approved 
drug crizotinib, also develops acquired resistance that may respond to 
cabozantinib.[26, 27] 
A single arm phase II study ongoing examining the effect of single agent 
cabozantinib in many of these targeted patient populations is currently ongoing 
(NCT01639508).  However, the combination of cabozantinib and nivolumab in 
this targeted population is novel and may exceed the response expected from 
either cabozantinib or nivolumab alone. Therefore, we propose an exploratory 
targeted therapy to test the response to the combination of these agents.  
1.5 
Cabozantinib (XL184) - Further information 
Cabozantinib (XL184) is an inhibitor of multiple receptor tyrosine kinases (RTKs). 
It is provided as both capsules and tablets, but the two formulations are not 


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interchangeable. Cometriq® (cabozantinib capsules, 140 mg) was approved by 
the United States Food and Drug Administration (FDA) on 29 November 2012 for 
the treatment of patients with progressive, metastatic medullary thyroid cancer 
(MTC). On 21 March 2014, cabozantinib capsules were approved by the 
European Commission for the treatment of adult patients with progressive, 
unresectable locally advanced or metastatic MTC. Cabometyx™ (cabozantinib 
tablets, 60 mg) was approved by FDA on 25 April 2016 for patients with 
advanced renal cell carcinoma (RCC) who have received prior anti angiogenic 
therapy and by the European Commission on 09 September 2016 for the 
treatment of advanced RCC in adults who have received prior vascular 
endothelial growth factor (VEGF) targeted therapy. 
The targets of cabozantinib include several RTKs known to play important roles 
in tumor cell proliferation and/or tumor neovascularization, namely MET 
(hepatocyte growth factor [HGF] receptor), vascular endothelial growth factor 
receptor 2 (VEGFR2, also known as KDR), AXL, and RET. Other recognized 
targets of cabozantinib include ROS1, TRKA, TRKB, TYRO3, MER, two 
additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely 
related RTKs KIT and FLT-3. In vivo pharmacodynamic activity of cabozantinib 
against MET, VEGFR2, AXL, and RET has been demonstrated in preclinical 
studies and has been associated with tumor growth inhibition and tumor 
regression. In preclinical studies, cabozantinib treatment has also been shown to 
inhibit tumor angiogenesis and tumor invasiveness and metastasis. 
In nonclinical toxicology studies of cabozantinib in rodents and non-rodents, 
histopathological changes associated with cabozantinib administration were 
observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, 
adrenal, and reproductive tract tissues, and secondary changes were observed 
in bone and pancreas. Cabozantinib tested negative in bacterial and mammalian 
cell genotoxicity assays in vitro. In reproductive toxicity studies, cabozantinib was 
embryotoxic in rats, produced fetal soft tissue changes in rabbits, produced fetal 
external malformations in rats, and decreased fertility in male and female rats. 
The metabolite present at highest concentrations in humans administered 
cabozantinib, EXEL-1644, was negative in an in vitro bacterial genotoxicity 
bioassay and caused no systemic tissue toxicity in rats. In a 2 year rat 
carcinogenicity study, cabozantinib-related neoplastic findings consisted of an 
increased incidence of benign pheochromocytoma, alone or in combination with 
malignant pheochromocytoma/complex malignant pheochromocytoma of the 
adrenal medulla in both sexes. No clinical cases of pheochromocytoma have 
occurred to date. No carcinogenic signal has was observed in a rasH2 transgenic 
mouse model following cabozantinib dosing for 26 weeks. 
Nonclinical Development of XL184   
In Vivo Activity 
Inhibition of VEGF signaling pathway was previously shown to result in more 
invasive tumors in the transgenic RIP-Tag2 mouse model of pancreatic 
neuroendocrine cancer that spontaneously develops aggressive tumors (Paez-
Ribes et al., 2009).  In RIP-Tag2 transgenic mice, tumors treated with XL184 
were smaller (P <0.05) than in mice treated with vehicle or an anti-VEGF 
antibody, but were also less invasive (P <0.05) and had no liver metastases 
(Sennino et al., 2009). All mice treated with XL184 (n = 6) survived until 20 
weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) 


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reached that endpoint. Tumor vascularity decreased after treatment, with 
reductions ranging from 67% at 3 mg/kg to 83% at 30 mg/kg for 7 days (You et 
al., 2011).  Tumors were 35% smaller after XL184 treatment than corresponding 
values for vehicle control mice. c-Met protein expression in tumors was slightly 
decreased, but phosphorylated c-Met was markedly reduced after treatment for 7 
days.   
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered 
four oral doses of 100 mg/kg (Yakes et al., 2011).  XL184 increased tumor 
hypoxia (13-fold) and apoptosis (TUNEL; 2.5-fold) at 8 and 4 hours after the first 
and second doses, respectively, when compared to vehicle-treated tumors.  In 
addition, XL184 disrupted tumor vasculature by inducing endothelial cell death 
that negatively affected tumor viability.  XL184 treatment resulted in significant 
tumor growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 
30, or 60 mg/kg) when compared to vehicle-treated tumors.  Dose-dependent 
inhibition was observed for the 3 and 10 mg/kg doses (P <0.01), and complete 
inhibition was observed at the 30 and 60 mg/kg doses.  A single 100 mg/kg dose 
resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days after 
which tumors began growing at a rate similar to vehicle-treated control tumors.  
In addition, XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat 
C6 glioma cell line for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with 
vehicle-treated tumors.  The 3 mg/kg and 10 mg/kg doses resulted in significant 
tumor regression (62% and 85%, P <0.0001) when compared with predose tumor 
weights.  Subchronic administration of XL184 was well tolerated in mice and rats 
with no signs of toxicity, as determined by stable and/or increasing body weights 
during the treatment period. 
ARCaP-M is a human prostate cancer model which expresses both c-Met and 
VEGF co-receptor NP-1 used in a human prostate tumor xenograft study in 
mouse bone (Zhang et al., 2010).  ARCaP-M cells were injected into the tibia of 
nude mice on Day 1, and on Day 31 animals with established bone lesions were 
randomized to receive XL184 or vehicle daily (qd) for 7 weeks of treatment 
(Investigator’s brochure, 2017).  Tibiae from vehicle-treated animals exhibited 
both osteoblastic and osteolytic lesions, whereas tibiae from XL184 treated 
animals appeared mostly normal.  Thus, XL184 treatment blocked both 
osteoblastic and osteolytic progression of ARCaP-M xenograft tumors in bone. 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was 
achieved at well tolerated doses of XL184 and at plasma exposures comparable 
to exposure observed in clinical trials (Investigator’s Brochure, 2017).  XL184 
produced prolonged inhibition of receptor phosphorylation, such as sustained 
inhibition of c-Met and VEGFR2 for 10 hours after administration of a single dose 
of XL184.  This extended inhibition occurred in a manner that was generally 
predicted by plasma exposure, i.e., inhibition was diminished when plasma levels 
fell below approximately 20 μM for c-Met, 5 μM for VEGFR2, and 23 μM for TIE-
2. 
Once daily administration of XL184 resulted in significant inhibition of c-Met 
phosphorylation in TT tumors, relative to tumors from vehicle control-treated 
mice, with maximal inhibition of 70% seen at 60 mg/kg (Investigator’s Brochure, 
2016).  Dose-dependent inhibition of phosphorylation of c-Met and RET was 
observed among the 3, 10, and 30 mg/kg dose groups as well.   


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c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 
2–8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that 
harbor constitutively phosphorylated c-Met (Yakes et al., 2011).  This effect was 
reversible, as c-Met phosphorylation returned to basal levels by 48 hours after 
treatment.   
Toxicology 
In rodents and non-rodents, histopathological changes associated with XL184 
administration were observed in gastrointestinal (GI) tract, bone marrow, 
lymphoid tissues, kidney, and adrenal and reproductive tract tissues 
(Investigator’s Brochure, 2017).  Histopathological changes present in the bone 
and pancreas were considered secondary to XL184 administration. Adverse 
effects following oral exposure to XL184 were generally dose-related, clinically 
monitorable, and self-resolving upon discontinuation of dosing. In 6-month 
chronic toxicity studies, treatment-related changes were present only in kidney 
(rats) and reproductive tissues (dog).  In reproductive/developmental toxicity 
studies, XL184 administration resulted in decreased fertility in male and female 
rats, in embryotoxicity when given to pregnant rats, and in a visceral tissue 
malformation (small spleen) when given to pregnant rabbits. The no-observable-
adverse-effect-levels (NOAELs) for the chronic toxicity and 
reproductive/developmental toxicity studies occurred at plasma exposures (AUC) 
below steady-state values measured in subjects with solid tumors administered 
175 mg XL184 capsule form daily (Study XL184-001). 
In definitive genotoxicity bioassays, XL184 was negative in an S. 
typhimurium/E.coli bacterial mutagenicity study, an in vitro chromosome 
aberration study using human peripheral blood lymphocytes, and an in vivo 
mouse bone marrow micronucleus study (Investigator’s Brochure, 2017).  In 
safety pharmacology studies, no adverse effects occurred on neurobehavioral or 
respiratory functions in XL184-treated rats or on cardiovascular function in 
XL184-treated dogs. 
Summary of Clinical Trials 
This document summarizes 17 clinical studies of cabozantinib for oncology 
indications including four Phase 1 studies, one Phase 1b/2 study, four Phase 2 
studies, five Phase 3 studies (a placebo controlled study in subjects with MTC, 
two active-controlled studies in subjects with CRPC, one ongoing open-label, 
active-controlled study in subjects with RCC, and one ongoing and enrolling 
double-blinded placebo-controlled study in subjects with hepatocellular 
carcinoma [HCC]), one ongoing and enrolling Phase 4 study in MTC, one 
ongoing maintenance “roll over” study, and one expanded access study. In 
addition, there are eleven clinical pharmacology studies; nine were conducted in 
healthy subjects alone, one study was conducted that included healthy subjects 
and subjects with renal impairment, and one study was conducted that included 
healthy subjects and subjects with hepatic impairment. In addition to these 
company-sponsored clinical studies, twenty-nine externally-sponsored studies 
(ESSs; previously referred to as investigator-sponsored trials [ISTs]) and 
seventeen National Cancer Institute (NCI)-Cancer Therapy Evaluation Program 
(CTEP) trials have enrolled subjects in oncology indications. 
A pooled analysis of safety data in 2467 subjects with cancer treated with 
cabozantinib in company-sponsored single-agent studies (XL184 001, XL184 
008, XL184 201, XL184 203, XL184 205, XL184 301, XL184 306, XL184 307, 


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XL184 308, and XL184-401) has been performed. For ongoing studies, serious 
adverse event (SAE) data are presented through February 28, 2017. 
Clinical study protocols have expressed cabozantinib dose as either the malate 
salt weight or the freebase equivalent (FBE) weight. In this Investigator’s 
Brochure, dose strengths are expressed as the FBE weight. For the dosage 
form, formulation, and dosage strengths used in a particular study, please refer 
to the study protocol. 
Cabozantinib is administered as either capsules or tablets. In a bioequivalence 
study comparing capsules with tablets in healthy adult subjects (Study XL184-
010), the geometric mean ratios for both AUC parameters (AUC0-t and AUC0-
inf) comparing 140 mg cabozantinib doses of the tablet formulation with the 
capsule formulation were 108% (90% confidence interval [CI]%: 101, 117). The 
ratio of geometric means for Cmax (119%; 90% CI%: 107, 132) had a 90% CI 
upper bound that slightly exceeds the standard accepted limit of 125%. 
Therefore, bioequivalence of the cabozantinib capsule and tablet formulations 
cannot be concluded, and the two formulations are not interchangeable. 
The single agent maximum tolerated dose (MTD) of the capsule in a daily dosing 
schedule based on 28 days of dosing in Study XL184-001 was determined to be 
140 mg. The 140 mg capsule dose level was evaluated in placebo-controlled 
Phase 3 Study XL184-301 in subjects with MTC. Dose modifications (reductions 
or interruptions) occurred frequently in the cabozantinib arm of this study. Lower 
doses of cabozantinib have been explored in other indications. A tablet dose of 
60 mg once daily (qd) was evaluated in two Phase 3 studies in prostate cancer, 
and is being evaluated in two ongoing Phase 3 studies, one in RCC and one in 
HCC. Ongoing double-blind Study XL184-401 compares the efficacy and safety 
of cabozantinib 140 mg qd (capsule formulation) with cabozantinib 60 mg qd 
(tablet formulation) in subjects with MTC. Common to all studies is the titration of 
the dose to individual patient tolerability. 
Clinical Experience 
As of February 29, 2016, 3447 patients have been studied in 28 completed or 
ongoing Exelixis-sponsored clinical trials with XL184 treatment. There are 17 
clinical studies of cabozantinib for oncology indications including four Phase 1 
studies, one Phase 1b/2 study, four Phase 2 studies, five Phase 3 studies ( a 
placebo-controlled study in subjects with MTC, two active-controlled studies in 
subjects with castration-resistant prostate cancer [CRPC], one ongoing open-
label, active-controlled study in subjects with RCC, and one ongoing and 
enrolling double-blinded placebo-controlled study in subjects with hepatocellular 
carcinoma [HCC]), one ongoing and enrolling Phase 4 study in MTC, one 
ongoing maintenance “roll-over” study, and one expanded access study   
Detailed information for each of these studies, including pharmacokinetic data, 
can be found in the Investigator’s Brochure (2016). Safety and efficacy 
information, from the 2016 Investigator’s Brochure, is summarized below.  
Adverse Events 
As of February 28, 2017, AE data are available for 3002 subjects who have been 
dosed with XL184 (2410 in single-agent studies and 592 in combination studies 
of XL184 with erlotinib, rosiglitazone, or TMZ ± radiation) (Investigator’s 
Brochure, 2017).  Data from the 2410 subjects who received single-agent XL184 
show that the most frequently (> 20%) observed AEs regardless of causality 


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were diarrhea, fatigue, decreased appetite, nausea, constipation, palmar-plantar 
erythrodysesthesia (PPE) syndrome, vomiting, dysphonia, and hypertension.  
Effects that may be related to the inhibition of VEGF, including hypertension, 
thromboembolic events, GI perforation, fistula formation, hemorrhage, wound 
dehiscence, and proteinuria, have been observed in the single-agent and 
combination XL184 studies. The most commonly reported SAEs that were 
assessed as related to study treatment with XL184 (as a single-agent or 
combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein 
thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound 
dehiscence, and PPE syndrome. 
Thirty-three (34) subjects with Grade 5 AEs had events assessed as related to 
the study treatment. The only related Grade 5 AEs that occurred more than once 
were pulmonary embolism (n=4), death (unspecified; n=3), hemorrhage (n=2), 
respiratory failure (n=2), and sudden death (n=2).  (Investigator’s Brochure, 
2017). 
Pharmacokinetics 
Following oral administration of cabozantinib capsules or tablets, median time to 
maximum plasma concentrations (Tmax) for cabozantinib ranged from 2 to 5 h 
post-dose. The terminal half life (for predicting drug washout) was approximately 
120 h. Repeat daily dosing of cabozantinib capsules at 140 mg for 19 days 
resulted in 4- to 5-fold higher mean cabozantinib accumulation (based on area 
under the plasma concentration-vs-time curve [AUC]) compared with a single 
dose administration; steady state was achieved by Day 15. Cabozantinib is 
highly protein bound in human plasma (≥ 99.7%).  
Two population pharmacokinetics (PopPK) analyses have been conducted using 
cabozantinib clinical data. The first included data from subjects with MTC, 
glioblastoma (GB), and other solid tumors who received repeated oral daily 
dosing of cabozantinib capsules at 140 mg. From this analysis, the predicted 
effective half-life was approximately 55 h, the oral apparent volume of distribution 
(V/F) was approximately 349 L, and the oral apparent clearance (CL/F) at 
steadystate was estimated to be 4.4 L/h. The analysis did not identify clinically 
relevant differences in clearance of cabozantinib between females and males or 
between Whites (89%) and non-Whites (11% [<4% were Asian]). Cabozantinib 
pharmacokinetics (PK) was not affected by age (20-86 years).  
A second PopPK analysis was conducted in subjects with RCC who received 
repeated oral daily cabozantinib tablet dosing at 60 mg (with protocol-permitted 
dose reductions to 40 mg and 20 mg) combined with healthy subjects who 
received a single oral cabozantinib tablet dose of 20, 40, or 60 mg. This analysis 
indicated that for a White male subject the predicted terminal plasma half-life of 
cabozantinib was approximately 99 h; the terminal phase volume of distribution 
(Vz) was approximately 319 L; and the CL/F at steady-state was estimated to be 
approximately 2.2 L/h. Female gender and Asian race were significant covariates 
on CL/F, and while the attributes were statistically significant, they were not 
deemed clinically meaningful given the magnitude of the effects. Further 
evaluation of the differences in the two PopPK analyses revealed that compared 
with other cancer subject groups (ie, RCC, castrationresistant prostate cancer 
[CRPC], GB), MTC subjects cleared cabozantinib faster and thus had lower 
dose-normalized steady-state plasma exposures. Several possible factors may 


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underlie the higher cabozantinib clearance observed in MTC subjects in the first 
PopPK analysis; however, an exact cause has yet to be identified.  
Within a 48-day collection period after a single dose of 14C-cabozantinib in 
healthy subjects, approximately 81% of the total administered radioactivity was 
recovered with 54% in feces and 27% in urine.   
Results from a PK study of cabozantinib in subjects with renal impairment 
indicated that the ratios of geometric least squares (LS) mean for maximum 
plasma concentration (Cmax) and AUCs (AUC from 0 h to the last sampling time 
point [AUC0-t] and AUC from 0 h to infinity [AUC0-inf]) were 19% and 30% 
higher, respectively, for subjects with mild renal impairment compared to subjects 
with normal renal function. For subjects with moderate renal impairment, both 
Cmax and AUCs appeared to be similar when compared with subjects with 
normal renal function (differences: < 3% and < 7%, respectively). Results from a 
PK evaluation of cabozantinib in subjects with hepatic impairment indicated that 
exposure (AUC0-inf) to cabozantinib was increased by about 81% and 63% in 
subjects with mild and moderate hepatic impairment, respectively. There are no 
PK data in subjects with severe renal or hepatic impairment.  
A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively, 
relative to fasted conditions in healthy subjects administered a single 140-mg oral 
cabozantinib capsule dose.   
 Cabozantinib is a substrate of cytochrome P450 (CYP)3A4 in vitro. Inhibition of 
CYP3A4 reduced the formation of the cabozantinib N-oxide metabolite by > 80%. 
Inhibition of CYP2C9 had a minimal effect on cabozantinib N-oxide metabolite 
formation (ie, a < 20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib N-
oxide metabolite formation. In healthy subjects, cabozantinib plasma AUC0-inf 
was increased 38% with coadministration of the strong CYP3A4 inhibitor 
ketoconazole and decreased 77% with coadministration of the strong CYP3A4 
inducer rifampin (rifampicin).  
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-
type inhibitor of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 
μM), and a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in 
human liver microsome (HLM) preparations. Concentration associated with 50% 
inhibition (IC50) values > 20 μM were observed for CYP1A2, CYP2D6, and 
CYP3A4 isozymes in both recombinant and HLM assay systems. Cabozantinib 
at steady-state plasma concentrations (≥ 100 mg/day daily dosing for a minimum 
of 21 days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) 
plasma exposure (Cmax and AUC) in subjects with solid tumors.  
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations 
(ie, 75-100% of CYP1A1 positive control β-naphthoflavone induction) but not of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or 
isozyme-associated enzyme activities.   
Concomitant administration of proton pump inhibitor (PPI) esomeprazole resulted 
in no clinically relevant effect on cabozantinib plasma PK in healthy subjects.  
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-
glycoprotein (P-gp) transport activities in a bi-directional assay system using 
MDCK-MDR1 cells. In addition, cabozantinib was shown to be a substrate of 


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drug transporter multidrug resistance-associated protein 2 (MRP2) in an in vitro 
assay. 
1.6 
Nivolumab and ipilimumab – further information 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human 
monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for 
human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell 
surface membrane receptor (Investigator Brochure, 2016).  PD-1 is a negative 
regulatory molecule that is expressed transiently following T-cell activation and 
on chronically stimulated T cells characterized by an “exhausted” phenotype.  
Nivolumab binds to cynomolgus monkey PD-1 but not mouse, rat, or rabbit 
molecules.  Clinical activity of nivolumab has been observed in patients with 
melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).  
The combination of nivolumab and ipilimumab (anti-cytotoxic T lymphocyte 
associated antigen-4 [anti-CTLA-4]) in a phase 1/2 trial showed markedly 
enhanced clinical activity with an acceptable safety profile in melanoma patients 
(Wolchok et al., 2013). 
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has 
provided transformative information on the nature of the immune system and 
cancer.  An emerging picture suggests that endogenous immune responses can 
mediate effective tumor regression and/or improved survival even in patients with 
large volume tumors resistant to other forms of therapy.  Some of the unique 
features of this type of therapy, based largely on experience in advanced 
melanoma, include:  improved overall survival (OS) with or without radiographic 
responses or improved progression-free survival (PFS); responses that may be 
delayed or occur after radiographic disease progression; combinations of 
immune modulators with enhanced or novel activities (in the example of 
ipilimumab and nivolumab); and toxicity that is almost exclusively immune or 
inflammatory in nature.  It is not yet clear what factors determine responses and 
which components of the immune system are needed for this to occur.  It seems 
likely that both memory helper and effector cells would be needed to sustain 
long-term responses. Increasing emphasis has been placed on understanding 
the relationships of the tumor, cellular infiltrate, and immunologic milieu 
surrounding each tumor. 
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family 
of T-cell co-stimulatory receptors that include Ig super family member CD28, 
CTLA-4, inducible co-stimulator (ICOS), and B and T lymphocyte attenuator 
(BTLA) (Investigator Brochure, 2016).  PD-1 is transiently but highly expressed 
on activated T cells functioning to limit immune effectors at the site of activation.  
Chronic stimulation may prevent the re-methylation of the PD-1 gene leading to 
continuous expression and characterizes a state of “exhausted” T cells that lose 
function and proliferative capacity while enhancing a suppressive tumor 
microenvironment.  PD-1 may act together with other T-cell modulating 
molecules, including CTLA-4, TIM-3, lymphocyte-activation gene 3 (LAG-3) as 
well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-1), cytokines, and 
transforming growth factor beta (TGF-beta).   
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also 
known as B7-H1 or CD274, expressed on tumor, antigen-presenting cells 
[APCs], and dendritic cells [DCs]) and PD-L2 (also known as B7-DC or CD273, 
expressed on endothelial cells).  The interaction of PD-1 with PD-L1 and PD-L2 


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results in negative regulatory stimuli that down-modulate the activated T-cell 
immune response through SHP-1 phosphastase. 
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c).  In transplantable tumor models that 
expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual 
anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors 
that were largely resistant to single antibody treatment (Woo et al., 2012).  
Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout 
mice, dual knockout mice abrogated self-tolerance with resultant autoimmune 
infiltrates in multiple organs, leading to eventual lethality. 
PD-L1 expression is found on a number of tumors, and is associated with poor 
prognoses based on OS in many tumors, including melanoma (Taube et al., 
2012), renal (Thompson et al., 2004; Thompson et al., 2005; Thompson et al., 
2006), esophageal (Ohigashi, et al. 2005), gastric (Wu et al., 2006), ovarian 
(Dong et al., 2003), pancreatic (Nomi, et al., 2007), lung (Zitvogel, et al., 2006), 
and other cancers (Investigator Brochure, 2016). 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C 
virus (HCV) and human immunodeficiency virus (HIV).  In these cases, high 
expression levels of PD-1 were found in viral-specific CD8+ T cells that also 
display a non-responsive or exhausted phenotype.  Non-responsive PD-1-high T 
cells were observed in simian immunodeficiency virus (SIV) infection in rhesus 
macaques.  Treatment of SIV-infected macaques with an anti-PD-1 mAb (3 
mg/kg x4) resulted in decreased viral loads and increased survival along with 
expanded T cells with increased T-cell functionality.   
Nonclinical Development of Nivolumab 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, 
nivolumab alone was well tolerated (Investigator Brochure, 2016).  Combination 
studies have highlighted the potential for toxicity when combined with ipilimumab, 
MDX-1408, and BMS-986016.  Nivolumab bound specifically to PD-1 (and not to 
related members of the CD28 family such as CD28, ICOS, CTLA-4, and BTLA) 
with a Kd = 3.06 nM.  A surrogate rat anti-mouse PD-1 antibody (4H2) was 
derived and expressed as chimeric IgG1 murine antibody.  Antitumor activity was 
seen for several tumor models, including colon carcinoma and fibrosarcoma. 
Clinical Development of Nivolumab 
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic 
chemotherapy, other immunotherapy (such as ipilimumab), anti-angiogenesis 
therapy, and targeted therapies in completed and ongoing BMS-sponsored 
clinical trials in NSCLC, melanoma, RCC, hepatocellular carcinoma (HCC), 
gastrointestinal (GI) malignancies including microsatellite instability (MSI) in 
colorectal cancer, and triple-negative breast cancer (TNBC) with an expanding 
group of indications (Investigator Brochure, 2016).  In addition, two investigator-
sponsored trials (ISTs) of nivolumab in combination with a peptide vaccine in 
melanoma are being conducted in the adjuvant setting and advanced disease.  
Seven nivolumab studies were conducted in Japan, including six studies in 
advanced solid tumors and recurrent or unresectable stage III/IV melanoma 
sponsored by Ono Pharmaceuticals Co. Ltd., and one IST in recurrent or 
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Pharmacokinetics 
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, 
with dose-proportional increases in maximum serum concentration (Cmax) and 
area under the concentration-time curve from time zero to infinity (AUC0-∞), with 
low to moderate inter-subject variability observed at each dose level (Investigator 
Brochure, 2016).  Clearance of nivolumab is independent of dose in the dose 
range (0.1 to 10 mg/kg) and tumor types studied.  Body weight normalized 
dosing showed approximately constant trough concentrations over a wide range 
of body weights.  The mean terminal elimination half-life of BMS-936558 is 17 to 
25 days consistent with the half-life of endogenous IgG4.   
Efficacy 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 
mg/kg dose was chosen for expanded cohorts. Among 236 patients, objective 
responses (ORs) (complete or partial responses [CR or PR]) were seen in 
NSCLC, melanoma, and RCC.  ORs were observed at all doses (Sznol et al., 
2013).  Median OS was 16.8 months across doses and 20.3 months at the 3 
mg/kg dose.  Median OS across all dose cohorts was 9.2 months and 9.6 months 
for squamous and non-squamous NSCLC, respectively (Brahmer et al., 2013).  
In the RCC cohort, median duration of response was 12.9 months for both doses 
with 5 of the 10 responses lasting ≥1 year (Drake et al., 2013).   
In an advanced melanoma phase 1 study, nivolumab and ipilimumab were 
administered IV every 3 weeks for 4 doses followed by nivolumab alone every 3 
weeks for 4 doses (concurrent regimen) (Wolchok et al., 2013).  The combined 
treatment was subsequently administered every 12 weeks for up to 8 doses.  In a 
sequenced regimen, patients previously treated with ipilimumab received 
nivolumab every 2 weeks for up to 48 doses.  In the concurrent regimen (53 
patients), 53% of patients had an OR at doses 1 mg/kg nivolumab and 3 mg/kg 
ipilimumab, with tumor reduction of 80% or more (modified World Health 
Organization [mWHO] criteria).  In the sequenced-regimen (33 patients), the 
objective response rate (ORR) was 20%. 
In a phase 1 study of nivolumab plus platinum-based doublet chemotherapy (PT-
doublet) in chemotherapy-naïve NSCLC patients, 43 patients were treated with 
nivolumab + PT-doublet (Rizvi et al., 2013).  No dose-limiting toxicities (DLTs) 
were reported and total/confirmed ORRs were 43/33%, 40/33%, and 31/31% in 
nivolumab/gemcitabine/cisplatin, nivolumab/pemetrexed/cisplatin, and 
nivolumab/carboplatin/paclitaxel arms, respectively. 
Toxicology 
A maximum tolerated dose (MTD) of nivolumab was not defined (Topalian et al., 
2012).  Serious adverse events (SAEs) occurred in 32 of 296 patients (11%) 
similar to the immune-related inflammatory events seen with ipilimumab:  
pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis (with noted 
pulmonary toxicity resulting in 3 deaths. Renal failure, symptomatic pancreatic 
and DM, neurologic events, and vasculitis have also been reported.).   In 
combination with ipilimumab in the concurrent-regimen group (Wolchok et al., 
2013), grade 3 or 4 treatment-related events were noted in 53% of patients.  Skin 
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Pharmacodynamics/Biomarkers 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination 
with ipilimumab with the use of IHC staining and pharmacodynamics changes in 
the peripheral-blood absolute lymphocyte count (Wolchok et al., 2013).  With PD-
L1 positivity defined as expression in at least 5% of tumor cells, biopsy 
specimens from 21 of 56 patients (38%) were PD-L1–positive.  Among patients 
treated with the concurrent regimen of nivolumab and ipilimumab, ORs were 
observed in patients with either PD-L1–positive tumor samples (6 of 13 patients) 
or PD-L1–negative tumor samples (9 of 22).  In the sequenced regimen cohorts, 
a higher number of overall responses was seen among patients with PD-L1–
positive tumor samples (4 of 8 patients) than among patients with PD-L1–
negative tumor samples (1 of 13) suggesting the possibility that these tumors 
have higher response rates to the combination. The relationship between PDL-1 
expression and responses may not be present in patients treated with the 
combination.  Tissue expression of PDL-2, interferon-γ (IFN- γ), IDO, and T cell 
CD8+ are of current interest.  Until more reliable data based on standardized 
procedures for tissue collection and assays are available, PD-L1 status cannot 
be used to select patients for treatment at this time.   
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4, YervoyTM) is a fully human 
monoclonal immunoglobulin (Ig) G1κ specific for human cytotoxic T lymphocyte 
antigen 4 (CTLA-4, CD152), which is expressed on a subset of activated T cells 
(Ipilimumab Investigator Brochure, 2017).  CTLA-4 is a negative regulator of T-
cell activation.  Ipilimumab binds to CTLA-4 and inhibits its interaction with 
ligands on antigen-presenting cells (APCs).  The proposed mechanism of action 
for ipilimumab’s effects in subjects with melanoma is indirect, possibly through T-
cell potentiation and mediation of antitumor immune responses. 
Ipilimumab has been approved for the treatment of unresectable metastatic 
melanoma in over 40 countries including the United States (US, March 2011), the 
European Union (July 2011), and Australia (July 2011). 
BMS and Medarex (acquired by BMS in Sep-2009) have co-sponsored an 
extensive clinical development program for ipilimumab, encompassing > 13,800 
subjects in several cancer types in completed and ongoing studies, including a 
compassionate use program (Ipilimumab Investigator Brochure, 2017).  The 
focus of the clinical program is in melanoma, prostate cancer, and lung cancer, 
with advanced melanoma being the most comprehensively studied indication.  
Ipilimumab is being investigated both as monotherapy and in combination with 
other modalities such as chemotherapy, radiation therapy, and other 
immunotherapies. 
CTEP’s clinical development of ipilimumab focuses on cervical, gastrointestinal, 
ovarian, prostate cancer, chronic lymphocytic leukemia, head and neck 
squamous cell carcinoma, solid tumors, Hodgkin and non-Hodgkin lymphomas, 
melanoma, and myelodysplastic syndrome. 
While the toxicity and clinical responses overlap, mechanisms of immune 
activation and range of responses appear to be different for each of the single 
agents.  
Preclinical data support the combinations of nivolumab and ipilimumab (Curran et 
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The combination of ipilimumab with nivolumab has been reported to result in 
improved responses in advanced melanoma marked by time to response, 
number of responses, depth and duration of responses, PFS, and OS compared 
to single agent ipilimumab (Wolchok et al., 2013).  
For RCC results have been reported (Hammers et al., 2014). 
The combination is being evaluated in other disease settings typically with 
3mg/kg nivolumab and 1mg/kg ipilimumab q 3 weeks x 4 induction doses. 
The rationale for the doses selected in this trial is outline in Section 1.2, above.  
1.7 
Imaging of therapy response to immune checkpoint inhibition 
Therapy with immune checkpoint inhibitors can lead to unconventional tumor 
responses resulting from immune activation [90,91,92]. Radiologic 
pseudoprogression describes an unconventional imaging pattern of tumor 
response where tumors initially exhibit features of progression, including tumor 
enlargement and/or development of new lesions, with subsequent radiologic 
tumor response evident on serial imaging with sustained therapy [90]. Several 
new imaging response criteria have been proposed for measurement of tumor 
response in solid tumors undergoing immune checkpoint inhibitor therapy 
including the immune related response criteria (irRC) [90], an adaption of the 
irRC termed the uni-dimensional iRRC [93] and, most recently, the iRECIST 
criteria [94]. These immune criteria have been put forth with the goal of more 
accurately classifying unconventional tumor responses as non-progression. 
However, it is yet unclear if any of these new criteria present a benefit over the 
conventional Response Evaluation in Solid Tumor (RECIST) 1.1 [95] for use as 
an imaging endpoint in clinical trials of immune checkpoint inhibition in solid 
tumors. Here we propose an explorative correlative imaging aim to define tumor 
response assessed by RECIST1.1, unidimensional irRC and iRECIST, assessed 
by central review. The hypothesis for this imaging aim will be that significant 
differences exist in the calculation of best overall response and progression-free 
survival amount the examined tumor response criteria. Interpretation of the 
response data will be performed noting the bias in the availability patient imaging 
for analysis with immune criteria since only patients maintained on therapy 
beyond imaging evidence of progression (ie. clinically suspected of radiologic 
pseudoprogression) will have the required imaging data (subsequent re-imaging 
to confirm suspected progression). While this is a limitation to the interpretation 
to the immune criteria imaging response data, the data obtained is felt to be 
valuable in better understanding the application of these imaging criteria to 
clinical trials of immunotherapeutics. 
Finally, this clinical trial utilizes a study site calculation of RECIST1.1 response 
for patients enrolled in this study. Typically these measurements are calculated 
by study personnel that are trained in RECIST1.1 measurement but are not 
radiologists. This strategy is employed in many clinical trials that do not include a 
central reading of imaging response. Here we will compare the RECIST1.1 
calculations determined at the study sites to those generated by central review to 
determine if there are significant differences in the measurements obtained 
between these two imaging assessment approaches. The hypothesis will be that 
no significant difference exists between measurements of RECIST1.1 between 
study imaging site and central review. 


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1.8 
Rationale for Tobacco Use Assessment 
NOTE: 
Please refer to Appendix VIII for EAQ16T references. 
A significant proportion of cancer patients are current smokers at the time of 
cancer diagnosis, [1-5] and there are known risks associated with continued 
smoking following cancer diagnosis. These include decreased survival time; 
increased complications from surgery, radiation, and chemotherapy; and 
increased risk of second primary tumors [6,-11] As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer 
Research (AACR) and the American Society of Clinical Oncology (ASCO) have 
identified persistent smoking as a modifiable risk factor and recommend 
cessation counseling for cancer patients who smoke. Although evidence-based 
guidelines for treating tobacco dependence exist, [12] they have not yet been 
well-integrated into cancer care settings. Moreover, knowledge regarding the 
scope and patterns of tobacco use among cancer patients is limited. 
Tobacco use following a cancer diagnosis compromises treatment outcomes but 
is not well understood. About 10% to 30% of cancer patients are smoking at the 
time of diagnosis, [1-4, 14, 1 5] and the majority of cancer patients who smoke at 
diagnosis continue to smoke following diagnosis [3, 16]. Quitting smoking upon 
cancer diagnosis may improve cancer treatment effectiveness, reduce risk of 
recurrence and of developing new primary tumors, [9,11,17-21] and improve 
chances of survival [1,22-24]. Conversely, continuing to smoke may result in 
diminished QOL [1, 25, 26], treatment delays and increased treatment 
complications [2, 6–8, 22, 27–34]. 
Tobacco use following a cancer diagnosis may compromise patient reported 
outcomes. It is hypothesized that smoking may be used as a means of reducing 
symptom burden among cancer patients, which may be a barrier to smoking 
cessation. Relatedly, research has shown that cancer patients who are smoking 
experience more difficulty with physical and psychological symptom control, 
compared to nonsmokers [35–38]. Research is needed to examine how symptom 
levels differ, by tobacco use and exposure and how tobacco use changes may 
affect reported symptom burden. 
National initiatives emphasize the importance of identifying tobacco use in cancer 
care settings.  Smoking status was designated as a core objective in the 2010 
federal government “Meaningful Use” electronic health record documentation [39, 
40]. In 2013, the American Association for Cancer Research (AACR) released 
guidelines emphasizing the provision of tobacco cessation services to cancer 
patients [41]. The American Society of Clinical Oncology (ASCO) recommends 
cessation counseling to all smokers by their second oncology visit as a core 
quality indicator [42]. The National Comprehensive Cancer Network (NCCN) 
published Smoking Cessation guidelines to formalize these initiatives [43]. 
Integrated, evidence-based services are needed during cancer care. The USPHS 
Practice Guidelines recommend that evidence-based tobacco treatment be 
delivered to all smokers in health care settings, yet little progress has been made 
to integrate these guidelines into cancer care [44]. This is unfortunate, as 
cessation closer to the time of diagnosis results in a higher likelihood for 
continued abstinence [1,45-48] effective interventions exist, [1,45-48] and many 
cancer patients who smoke want to quit smoking[45,46,49,50]. Little work has 
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racial/ethnic minority cancer patients who are at elevated risk of continued 
smoking [51-53]. 
Tobacco use is often not being assessed or intervened upon during cancer care.  
Recent surveys of oncologists and of clinical practices at comprehensive cancer 
centers and community oncology settings demonstrate that assessment of 
tobacco dependence is lacking [54-57]. During treatment, most cancer patients 
do not get assistance with smoking cessation support.58–60 Tobacco use 
assessments and cessation support have not been incorporated in most 
cooperative group clinical trials [61]. No one has assessed cancer patients’ 
reports of their oncology providers’ assistance behaviors. 
The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force developed 
the Cancer Patient Tobacco Use [1-4,13,14]. Questionnaire (C-TUQ). We 
propose that administering selected C-TUQ items to participants enrolling in 8 
Phase II and Phase III ECOG ACRIN (EA) therapeutic trials will add value to 
parent trial research questions by advancing the field. Specifically, among 
patients with varied cancers (tobacco-related and non tobacco-related) and 
cancer treatments, we will administer C-TUQ questions at EA trial enrollment and 
3 and 6 month follow-up. 
We have the following aims: 
1. Treatment toxicity: To determine the effects of tobacco, operationalized as 
combustible tobacco (1a), other forms of tobacco (1b), and environmental 
tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose modifications). 
2. Symptom burden: To determine the effects of tobacco on patient-reported 
physical symptoms and psychological symptoms. 
3. Cessation patterns and treatment: To examine quitting behaviors and 
behavioral counseling/support and cessation medication utilization. 
4. Trial outcomes: To explore the effect of tobacco use and exposure on 
treatment duration and relative dose intensity, and on therapeutic benefit, of 8 
selected EA trials. 
The findings will advance the nascent field of tobacco use in the context of 
cancer care by: 1) longitudinal assessment of cigarette smoking, other forms of 
tobacco use and secondhand smoke exposure at trial enrollment and at 3 and 6 
month follow-up; 2) increase knowledge about the effects of tobacco use and 
exposure on treatment toxicity, physical and psychological symptoms and 3) 
oncology provider delivery,  and 4) patient’s perceptions of stigma and utilization 
of behavioral and pharmacological treatment of tobacco dependence.   Finally, 
the use of this assessment would provide a unique additional value to the 
hypothesis of this trial, by allowing investigation of previously unanswered 
questions about the effects of tobacco use and exposure on trial adherence and 
outcomes among patients with smoking-related and non-smoking related 
cancers. 
 


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2. 
Objectives 
2.1 
Primary Endpoint 
2.1.1 
The primary objective of this trial is to demonstrate whether 
combination therapy of nivolumab and cabozantinib, or of nivolumab 
and cabozantinib, and ipilimumab as compared to nivolumab alone, 
extends progression-free survival (PFS) for this patient population 
with non-squamous NSCLC. 
2.2 
Secondary Endpoints 
2.2.1 
To estimate the overall survival for each arm of the trial  
2.2.2 
To estimate the best overall response rate for each arm of the trial 
2.2.3 
To estimate the progression free survival of the targeted therapy arm 
of the trial 
2.2.4 
To describe the toxicity profile of monotherapy with nivolumab, and 
the combination of nivolumab and cabozantinib, and the combination 
of nivolumab and cabozantinib and ipilimumab, in this patient 
population with non-squamous NSCLC. 
2.3 
Correlative Endpoints  
2.3.1 
To adjust progression free survival for each arm based on PD-L1 
tumor status  
2.4 
Imaging Endpoints 
2.4.1 
To describe time point tumor response assessment, overall best 
response and progression-free survival using the conventional 
RECIST1.1 criteria and the exploratory uni-dimensional immune 
response criteria (iRRC) and the iRECIST criteria with all 
measurements performed by the central review. 
2.4.2 
To compare RECIST1.1 imaging response assessment 
measurements (time point response assessment and overall best 
response) assess by site study personnel to those performed by 
central review. 
2.5 
Exploratory Tobacco Use Objectives 
2.5.1 
To determine the effects of tobacco, operationalized as combustible 
tobacco (1a), other forms of tobacco (1b), and environmental tobacco 
exposure (ETS) (1c) on provider-reported cancer-treatment toxicity 
(adverse events (both clinical and hematologic) and dose 
modifications). 
2.5.2 
To determine the effects of tobacco on patient-reported physical 
symptoms and psychological symptoms. 
2.5.3 
To examine quitting behaviors and behavioral counseling/support and 
cessation medication utilization. 
2.5.4 
To explore the effect of tobacco use and exposure on treatment 
duration, relative dose intensity, and therapeutic benefit. 
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NOTE: 
Tobacco Use objectives described above are ancillary for the 
Tobacco Use Assessment project approved by NCI. A combined 
analysis of the data from the selected ECOG-ACRIN trials is planned. 
Data collected from the tobacco use assessment in each parent study 
will not be analyzed and reported in the clinical study report. 
 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria for Step 0 
3.1.1 
Patients with tumors with the following molecular alterations must 
submit testing results via Medidata Rave to determine eligibility to Arm 
T. The Study Chair, Co-Chair, Biology Co-Chair, or a delegate must 
review the molecular testing and agree that the testing meets one of 
the molecular eligibility criteria outlined below (please see Section 
4.2.4 for instructions): 
· 
ROS1 gene rearrangement by FISH or DNA analysis (may have 
progressed on prior crizotinib therapy) 
· 
MET exon 14 splice mutations on DNA analysis (may have 
progressed on prior crizotinib therapy) 
· 
MET high amplification by FISH or DNA analysis or other MET 
mutations predicted to be sensitive to MET inhibitor (no prior 
targeted therapy allowed) 
· 
RET gene rearrangement by FISH or DNA analysis (no prior 
targeted therapy allowed) 
Institutions will be notified of the patient’s eligibility status for Arm T 
within two (2) business days of submission of the molecular testing 
reports. 
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If patients do not have tumors with the above molecular alterations 
noted proceed directly to Step 1. 
3.2 
Eligibility Criteria for Step 1 
3.2.1 
For patients with known molecular alterations, institution has been 
notified that patient is deemed eligible for Arm T per review of 
molecular testing reports 
3.2.2 
Pathologically confirmed non-squamous non-small cell lung 
carcinoma (NSCLC) 
3.2.3 
Stage IV disease (includes M1a, M1b, or recurrent disease), 
according to the 7th edition of the lung cancer TNM classification 
system. 
3.2.4 
Predominant non-squamous histology (patients with NSCLC NOS are 
eligible). Mixed tumors will be categorized by the predominant cell 
type. If small cell elements are present the patient is ineligible.  
3.2.5 
Tumors must be tested and known negative for EGFR TKI sensitizing 
mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and 
ALK gene rearrangements by routine CLIA-certified clinical testing 
methods. Negative circulating tumor DNA results alone are not 
acceptable. Prior testing for tumor PD-L1 status is not required. 
3.2.6 
Patients must have progressed radiographically following first line 
platinum-based chemotherapy, No additional lines of therapy are 
permitted.  
NOTE: 
Prior adjuvant chemotherapy for early stage disease does 
not count as one line of therapy if 12 months or greater 
elapsed between completion of adjuvant therapy and 
initiation of first-line systemic therapy. If less than 12 
months elapsed, adjuvant chemotherapy counts as one 
line of therapy.  
Exception for targeted therapy sub-study (Arm T): At least 
one line of prior chemotherapy or targeted therapy is 
required, but there is no limit on number of prior 
treatments.  
3.2.7 
Patients must have measurable disease as defined by RECIST v1.1 
criteria in Section 6. Baseline measurements and evaluation of ALL 
sites of disease must be obtained within 4 weeks prior to registration 
3.2.8 
No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-
1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, 
pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as 
ipilimumab). No prior allergic reaction to small molecule tyrosine 
kinase inhibitors or monoclonal antibodies. 
Exception for targeted therapy sub-study (Arm T): Prior crizotinib may 
be allowed depending on the gene alteration (see Section 3.1.1) 
3.2.9 
Any prior chemotherapy (based on administration schedule) must 
have been completed in greater than or equal to the following times 
prior to registration: 
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Chemotherapy/ targeted oral therapy administered in a daily or weekly 
schedule must be completed ≥ 1 week prior to registration;  
Any chemotherapy administered in an every 2 week or greater 
schedule must be completed ≥ 2 weeks prior to registration. 
Additionally, patients should be recovered to equal to or less than 
grade 1 toxicities related to any prior treatment, unless AE(s) are 
clinically nonsignificant and/or stable on supportive therapy. 
3.2.10 
No prior radiation therapy for bone metastasis within 2 weeks, any 
other radiation therapy within 4 weeks prior to registration. 
3.2.11 
Patients with no known brain metastasis must have baseline brain 
imaging within 12 weeks prior to study registration not demonstrating 
brain metastases. 
OR 
Patients with known brain metastases must have baseline brain 
imaging within 4 weeks prior to study registration and meet all of the 
following criteria: 
3.2.11.1 
Have completed treatment to all symptomatic brain 
metastases (with whole brain radiation or radiosurgery) ≥ 4 
weeks prior to registration, or have undergone complete 
neurosurgical resection ≥ 3 months prior to registration. 
3.2.11.2 
Be clinically stable from brain metastases at time of 
screening, if no treatment was administered. 
3.2.11.3 
Known leptomeningeal disease is not allowed. 
3.2.12 
Patients must have ECOG performance status 0-1 
NOTE: 
Participants with impaired decision-making capacity 
(IDMC) should not be allowed to participate in this study 
due to its complexity. 
3.2.13 
Patients must have anticipated life expectancy greater than 3 months. 
3.2.14 
Patients must have acceptable bone marrow, renal hepatic, and 
coagulation function within 2 weeks prior to registration as defined 
below: 
ULN = institutional upper limit of normal    LLN=institutional lower limit 
of normal 
· 
Absolute neutrophil count ≥ 1,500/ mm3 
Absolute neutrophil count ≥ 1,500/ mm3? (Yes/No)_____  
Date of Test______ 
· 
Platelets ≥ 100,000/mm3 
Platelets ≥ 100,000/mm3? (Yes/No)______ Date of Test______ 
· 
Hemoglobin ≥ 9 g/dL 
Hemoglobin ≥ 9 g/dL? (Yes/No)______ Date of test______ 
· 
Subject has prothrombin time (PT)/INR and partial thromboplastin 
time (PTT) test ≤ 1.3 x the laboratory ULN 
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· 
PT/INR ≤ 1.3 x ULN? (Yes/No)_______ Date of test______ 
PTT ≤ 1.3 x ULN? (Yes/No)____Date of test_____ 
· 
Total bilirubin ≤ 1.5 × ULN 
Total bilirubin ≤ 1.5 × ULN? (Yes/No)____ Date of Test_____ 
· 
AST (SGOT) and ALT(SGPT) ≤ 3 X ULN 
AST (SGOT) ≤ 3 X ULN? (Yes/No)______ Date of Test______ 
ALT (SGPT) ≤ 3 X ULN? (Yes/No)_______ Date of Test______ 
· 
Serum albumin ≥ 2.8g/dL 
Serum albumin ≥ 2.8g/dL? (Yes/No)______ Date of test______ 
· 
Serum calcium (absolute or albumin corrected), magnesium and 
potassium ≥ LLN 
Ca (absolute or albumin corrected), Mg, K ≥ LLN?  
(Yes/No)______ Date of test______ 
NOTE: 
Serum calcium, magnesium and potassium can be 
replaced if values are below LLN.  
· 
Creatinine ≤1.5 X ULN 
(or) 
Calculated (Crockoft-Gault formula) or measured creatinine 
clearance ≥ 50 mL/min/1.73m2 (normalized to BSA) for patients 
with creatinine levels greater than 1.5 times the institutional 
normal Creatinine ≤ 1.5 X ULN or creatinine clearance  
≥ 50ml/min/1.73m2? 
(Yes/No)______ Date of test______ 
· 
Screening urine dipstick must equal 0 or “trace.” If urine dipstick 
results are ≥ 1+, or if dipstick was not performed, calculation of 
Urine Protein Creatinine (UPC) is required and patients must have 
a UPC ratio ≤ 1 to participate in the study. 
Urine dipstick = 0 or “trace?” (Yes/No)______ Date of test______ 
If no, UPC ratio ≤ 1? (Yes/No)______ Date of test______ 
3.2.15 
No history of the following: 
· 
Clinically-significant gastrointestinal bleeding within 6 months prior 
to registration.  
· 
Hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood within 3 
months prior to registration. 
· 
Drug induced pneumonitis within 3 months prior to registration  
· 
Signs indicative of pulmonary hemorrhage within 3 months before 
the first dose of study treatment 
· 
Radiographic evidence of cavitating pulmonary lesion(s) 
· 
Tumor invading any major blood vessels 
· 
Evidence of tumor invading the GI tract (esophagus, stomach, 
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endotracheal or mainstem endobronchial tumor within 28 days 
before the first dose of cabozantinib 
3.2.16 
No concomitant anticoagulation with oral anticoagulants (eg, warfarin, 
direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, 
clopidogrel). Allowed anticoagulants are the following: 
· 
Low-dose aspirin for cardioprotection (per local applicable 
guidelines) is permitted. 
· 
Low molecular weight heparins (LMWH) or unfractionated heparin 
is permitted. 
· 
Anticoagulation with therapeutic doses of LMWH is allowed in 
subjects without known brain metastases who are on a stable 
dose of LMWH for at least 6 weeks before first dose of study 
treatment, and who have had no clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor. 
3.2.17 
No concomitant treatment of strong CYP3A4 inducers (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, and St. John’s Wort). 
3.2.18 
No cardiovascular disorders including: 
a) Congestive heart failure (CHF): New York Heart Association 
(NYHA) Class III (moderate) or Class IV (severe) at the time of 
screening 
b) Concurrent uncontrolled hypertension defined as sustained BP > 
150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days prior to registration 
c) Any of the following within 6 months prior to registration: 
· 
unstable angina pectoris 
· 
clinically-significant cardiac arrhythmias 
· 
stroke (including TIA, or other ischemic event) 
· 
myocardial infarction 
3.2.19 
No gastrointestinal disorders associated with a high risk of perforation 
or fistula formation within 3 months prior to registration: 
· 
active peptic ulcer disease, 
· 
inflammatory bowel disease (including ulcerative colitis and 
Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis or appendicitis 
· 
known malabsorption syndrome 
· 
bowel obstruction or gastric outlet obstruction 
· 
PEG tube placement 
3.2.20 
No gastrointestinal disorders associated with a high risk of perforation 
or fistula formation within 6 months prior to registration: 
· 
abdominal fistula 
· 
gastrointestinal perforation 
· 
intra-abdominal abscess. Note: Complete resolution of an intra-
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with cabozantinib even if the abscess occurred more than 6 
months prior to registration. 
3.2.21 
None of the following conditions: 
a) Grade 3 or greater infection, or infection requiring intravenous 
systemic treatment within 28 days prior to registration. Patients 
should be off antibiotics at the time of registration. 
b) serious non-healing wound/ulcer/bone fracture within 28 days 
prior to registration 
c) history of organ transplant 
d) concurrent symptomatic untreated hypothyroidism within 7 days 
prior to registration 
e) history of surgery as follows: 
· 
Major surgery (as an example, surgery requiring anesthesia 
and a > 24 hour hospital stay) within 3 months prior to 
registration , with wound healing at least 28 days prior to 
registration.  
· 
Minor surgery within 28 days prior to registration with complete 
wound healing at least 10 days prior to registration.   
· 
Minor procedures within 7 days prior to registration such as 
thoracentesis, paracentesis, or 18g or smaller needle biopsy of 
tumor 
· 
Patients with clinically relevant ongoing complications from 
prior surgery are not eligible.  
3.2.22 
Patients must have corrected QT interval calculated by the Fridericia 
formula (QTcF) ≤ 500 ms within 28 days before registration.  
QTcF = QT divided by cube root of the RR interval (QT/RR0.333) 
3.2.23 
Patients must be able to swallow tablets. 
3.2.24 
No currently active other malignancies which require systemic 
treatment  
3.2.25 
No patients that have a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug 
administration.  Inhaled or topical steroids and adrenal replacement 
doses ≤ 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease.  Patients are permitted to use 
topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).  Physiologic 
replacement doses of systemic corticosteroids are permitted, even if  
< 10 mg/day prednisone equivalents. A brief course of corticosteroids 
for prophylaxis (e.g., contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g., delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
3.2.26 
No patients with known active autoimmune disease or known history 
of autoimmune disease for which recurrence may affect vital organ 
function or require immune suppressive treatment including systemic 


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corticosteroids.  These include but are not limited to patients with a 
history of immune related neurologic disease,  multiple sclerosis, 
autoimmune (demyelinating)  neuropathy, Guillain-Barre syndrome, 
myasthenia gravis; systemic autoimmune disease such as SLE, 
connective tissue diseases, scleroderma, inflammatory bowel disease 
(IBD), Crohn’s, ulcerative colitis, autoimmune hepatitis. Patients with a 
history of toxic epidermal necrolysis (TEN), Stevens-Johnson 
syndrome, or phospholipid syndrome should be excluded because of 
the risk of recurrence or exacerbation of disease.  Patients with 
vitiligo, endocrine deficiencies including type I diabetes mellitus or 
thyroiditis managed with replacement hormones including physiologic 
corticosteroids are eligible. Patients with rheumatoid arthritis and 
other arthropathies, Sjögren’s syndrome and psoriasis controlled with 
topical medication and patients with positive serology, such as 
antinuclear antibodies (ANA), anti-thyroid antibodies should be 
evaluated for the presence of target organ involvement and potential 
need for systemic treatment but should otherwise be eligible. 
3.2.27 
Age ≥ 18 years on day of consent. Because no dosing or adverse 
event data are currently available on the use of cabozantinib, 
nivolumab, or ipilimumab in patients < 18 years of age, children are 
excluded from this study. 
3.2.28 
No ongoing major illness or psychosocial issues that would limit 
compliance with the protocol.  
3.2.29 
Women must not be pregnant or breast-feeding due to 
contraindications with the study agents.  
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. 
A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Women of childbearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.2.30 
Women of childbearing potential (WOCBP) and males who are 
sexually active with WOCBP must use an accepted and effective 
method of contraception or abstain from sexual intercourse for at least 
one week prior to the start of treatment, and continue for 5 months 
after the last dose of protocol treatment for women of childbearing 
potential and 7 months after the last dose of protocol treatment for 
males who are sexually active with WOCBP. 
3.2.31 
Patients with known HIV disease taking antiretroviral therapy are 
excluded, because there are no safety data with the combination of 


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antiretroviral therapy and cabozantinib or ipilimumab or nivolumab 
with ipilimumab. 
Patients with known chronic active hepatitis B (defined as a positive 
hepatitis B surface antigen and/or hepatitis B viral load in the last 12 
months) are excluded, regardless of antiviral treatment. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 


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4. 
Registration and Randomization Procedures 
CTEP Registration Procedures 
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 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
· 
Added to a site roster 
· 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
· 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at <TBD>. 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). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
· 
An active Federal Wide Assurance (FWA) number 
· 
An active roster affiliation with the Lead Network or a participating organization 
· 
A valid IRB approval 
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· 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
· 
Active registration status 
· 
The IRB number of the site IRB of record listed on their Form FDA 1572 
· 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory For 
sites using the CIRB, IRB approval information is received from the CIRB and applied to 
the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent 
to open the study locally. The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Downloading Site Registration Documents:  
Site registration forms may be downloaded from the EA5152 protocol page located on 
the CTSU members’ website.   
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Protocols tab in the upper left of your screen 
· 
Either enter the protocol # in the search field at the top of the protocol tree, or  
· 
Click on the By Lead Organization folder to expand 
· 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA5152 
· 
Click LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.  
Requirements For EA5152 Site Registration:  
· 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation 
and IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects 
Assurance Identification/IRB Declaration of Exception Form, or combination is 
accepted) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
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. 


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Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an assurance 
number. 
· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 
· 
Date of review. 
· 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
· 
Click on the Regulatory tab  
· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type.  
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
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patient in the Rave Database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
· 
All eligibility criteria have been met within the protocol stated timeframes, including 
verifying availability of tumor tissue as per eligibility criteria.  
· 
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. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Preregistration (Step 0) 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification 
· 
Institution and affiliate name 
· 
Investigator’s name 
4.1.3 
Patient Identification 
· 
Patient’s initials (first and last) 
· 
Patient’s Hospital ID and/or Social Security number 
· 
Patient demographics 
· 
Gender 
· 
Birth date (mm/yyyy) 
· 
Race 
· 
Ethnicity 
· 
Nine-digit ZIP code 
· 
Method of payment 
· 
Country of residence 
4.1.4 
Additional Requirements 
4.1.4.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.1.4.2 
Patients with tumors with known molecular alternations 
being considered for Arm T must have molecular testing 
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send de-identified molecular testing information via 
Medidata Rave. 
Institutions will be notified of the patient’s eligibility status 
for Arm T within two (2) business days of submission of the 
molecular testing report. 
4.2 
Randomization/Registration (Step 1) 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
· 
Institution and affiliate name 
· 
Investigator’s name 
4.2.3 
Patient Identification 
· 
Patient’s initials (first and last) 
· 
Patient’s Hospital ID and/or Social Security number 
· 
Patient demographics 
· 
Gender 
· 
Birth date (mm/yyyy) 
· 
Race 
· 
Ethnicity 
· 
Nine-digit ZIP code 
· 
Method of payment 
· 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.  
Targeted Therapy (Arm T) Registration: Patients considered for Arm T 
must have molecular testing results reviewed by the Study Chair or 
delegate. Please submit de-identified molecular testing information via 
Medidata Rave. Institutions will be notified of the patient’s eligibility 
status for Arm T within two (2) business days of submission of the 
molecular testing reports.   
4.2.5 
Stratification Factors 
Known PD-L1 status (negative vs. positive (≥1%) vs. unknown by 
IHC/not tested). Any clinically validated testing platform is allowed, for 
example platforms using but not restricted to the antibodies 28-8, 
22C3, SP142, SP263. 
4.2.6 
Additional Requirements  
4.2.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
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4.2.6.2 
Pathology materials must be submitted for defined 
laboratory research studies as indicated in Section 10. 
4.2.6.3 
Data collection for this study will be done through the 
Medidata Rave clinical data management system. Access 
to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active 
CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave 
role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or, 
Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. To the hold Rave 
CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an 
NPIVR or IVR. Associates can hold read-only roles in 
Rave. 
Upon initial site registration approval for the study in RSS, 
all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select 
Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata 
screen. 
Users that have not previously activated their 
iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive 
a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by 
e-mail at ctsucontact@westat.com. 
4.2.7 
ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO) System: 
When patients consent to participate, they will be asked to provide a 
contact email address and that address along with their registration 
information will be sent directly from the parent trial’s registration 
system to EASEE-PRO, and the patient will be automatically 
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registered into EASEE-PRO for participation.  To activate their 
account for self-directed web entry of surveys, the system will send an 
activation message to the   contact email address that will explain how 
to activate their account for self-directed web entry of surveys.  After 
their account is activated, the patient will be able to complete 
questionnaires using a secure browser interface from any web 
enabled computer, tablet, or mobile device. 
4.3 
Submission of Images for Central Review 
Each participating site is required to submit all acquired diagnostic and follow-up 
images of study participants to the ACR Imaging Core Laboratory. Imaging 
should be submitted to the ACR Imaging Core Lab via TRIAD 4 and any 
associated data forms should be completed within 48 hours of acquisition. 
Prompt submission of all image data is essential to ensure adequate image 
quality assessment. 
TRIAD® is ACR’s proprietary image exchange application that will be used as 
the sole method of data transfer to the ACR Clinical Research Center Core 
Laboratory for this trial. The TRIAD application can then be configured as a 
DICOM destination on either scanner(s) and/or PACS system for direct network 
transfer of study related images into the TRIAD directory. 
4.3.1 
TRIAD Access Requirements: 
Staff who will submit images through TRIAD will need to be registered 
with The Cancer Therapy Evaluation Program (CTEP) and have a 
valid and active CTEP Identity and Access Management (IAM) 
account. Please refer to the beginning of Section 4 for instructions on 
how to request a CTEP-IAM account. 
To submit images, the user must be assigned the 'TRIAD site user' 
role on the relevant Group or CTSU roster. ECOG-ACRIN users 
should contact your site Lead RA to be added to your site roster. 
4.3.2 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. Support and information on 
installation of TRIAD can be found at 
https://triadhelp.acr.org/clinicaltrials. The TRIAD helpdesk can be 
reached at TRIAD-Support@acr.org. This process can be done in 
parallel to obtaining your CTEP-IAM account username and 
password. 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave and EASEE-PRO according to the schedule in the EA5152 Forms 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Treatment should start within seven working days after registration.  
Cycle = 4 weeks (28 days)  
Cabozantinib will be dispensed every cycle. 
NOTE: 
Cabozantinib should be taken on an empty stomach (i.e. do not eat 2 
hours before or 1 hour after each dose of cabozantinib. Do not crush 
or chew. No not take missed dose within 12 hours of the next dose. 
Please refer to Appendix VII for more information.  
Patients will continue receiving treatment until disease progression is observed 
or an adverse event requiring discontinuation occurs. 
All therapy should start on the same day, but cabozantinib may start the morning 
following infusional therapy if morning dosing is desired. 
5.1.1 
ARM A 
Nivolumab 480 mg IV over 60 minutes every 4 weeks, ongoing 
5.1.2 
ARM B 
Nivolumab 480 mg IV over 60 minutes every 4 weeks, ongoing 
Cabozantinib 40 mg PO daily, ongoing 
5.1.3 
ARM C 
Nivolumab 480 mg IV over 60 minutes every 4 weeks, ongoing 
Cabozantinib 40 mg PO daily, ongoing 
Ipilimumab 1 mg/kg over 90 minutes every 8 weeks, ongoing 
NOTE:  
On days when both nivolumab and ipilimumab are 
administered, nivolumab is administered prior to 
ipilimumab.  
5.1.4 
Targeted therapy arm (ARM T) 
Nivolumab 480 mg IV over 60 minutes every 4 weeks, ongoing 
Cabozantinib 40 mg PO daily, ongoing 
5.2 
Adverse Event Reporting Requirements 
All toxicity grades described throughout this protocol and all reportable 
adverse events will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
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 (http://ctep.cancer.gov). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required  part of every clinical trial, are done so investigators and 
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regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents 
5.2.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4 of the protocol for more information 
on how to access the Medidata Rave system and the EA5152 forms 
packet for instructions on where, when and what adverse events are 
to be reported routinely on this protocol. 
5.2.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The remainder of this section provides information 
and instructions regarding expedited adverse event reporting. 
5.2.4 
Terminology 
· 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
· 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
· 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
· 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
· 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
· 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
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· 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
· 
Death  
· 
A life-threatening adverse event  
· 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
· 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
· 
A congenital anomaly/birth defect.  
· 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered a serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
· 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported expeditiously if the grade being reported exceeds the 
grade listed in the parentheses next to the event. Since some 
arms on this protocol use multiple investigational agents, if an AE 
is listed on multiple SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
5.2.5 
Mechanisms for Adverse Event Reporting 
Routine reporting: Adverse events are reported in a routine manner 
at scheduled times during a trial using the Medidata Rave clinical data 
management system. Please refer to Section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EA5152 forms packet for instructions on where and when adverse 
events are to be reported routinely. 
Expedited reporting: In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The remainder of this section 
provide information and instructions regarding expedited adverse 
event reporting 
5.2.6 
Expedited Adverse Event Reporting Procedure 
Adverse Events requiring expediting reporting will use CTEP’s 
Adverse Event Reporting System (CTEP-AERS). CTEP’s guidelines 
for CTEP-AERS can be found at http://ctep.cancer.gov. 
For this study, all adverse events requiring expedited reporting 
must initially be reported on the Adverse Event Form in the 
appropriate Treatment Cycle folder in Medidata Rave.  The CTEP-
AERS report must then be initiated directly from the Adverse 
Event Form in Medidata Rave. Do not initiate the CTEP-AERS 
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report via the CTEP-AERS website. Once the event is reported in 
CTEP-AERS, ECOG-ACRIN, the NCI, and all appropriate regulatory 
agencies will be notified of the event in an expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the AE Team at ECOG-ACRIN (857-504-2900) 
· 
the NCI (301-897-7497)  
An electronic CTEP-AERS report MUST be initiated via Medidata 
Rave immediately upon re-establishment of internet connection 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.7 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
· 
the phase (0, 1, 2, or 3) of the trial  
· 
whether the patient has received an investigational or commercial 
agent or both 
· 
the seriousness of the event 
· 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
· 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
· 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
· 
the relationship to the study treatment (attribution) 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA5152 and outline 
the specific expedited adverse event reporting requirements for 
study EA5152. 
5.2.8 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arms A, B, C, T  
5.2.8.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
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NOTE: 
For this study, all adverse events requiring 
expedited reporting must initially be 
reported on the Adverse Event Form in the 
appropriate Treatment Cycle folder in 
Medidata Rave. Once the adverse event is 
entered into Rave, the Rules Engine will 
confirm whether or not the adverse event 
requires expedited reporting. The CTEP-AERS 
report must then be initiated directly from the 
Adverse Event Form in Medidata Rave. Do not 
initiate the CTEP-AERS report via the CTEP-
AERS website. We encourage all sites to 
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Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the 
six criteria in the top portion of the 
table below in Section 5.2.9. 
Yes 
No 
Identify the type and 
grade of the event 
using the CTCAE. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
Refer to Section 5.2.10 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
event in CTEP-AERS 
accessed via Medidata
Refer to Section 5.2.10 to 
determine if the event meets the 
protocol specific reporting 
requirements for this study. If so, 
report the event in CTEP-AERS 
accessed via Medidata Rave 
Is the event 
reportable? 
No 
Yes 
Refer to Section 5.2.10 to determine if the event meets the 
criteria as an exception to reporting on this protocol. If it 
does not, report the event in CTEP-AERS accessed via 
Medidata Rave. 
With this information, review 
the chart in Section 5.2.9 to 
determine if event requires 
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5.2.8.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
NOTE: 
For this study, all adverse events requiring 
expedited reporting must initially be 
reported on the Adverse Event Form or Late 
Adverse Event Form in the appropriate 
Treatment Cycle or Post Registration folder 
in Medidata Rave.  Once the adverse event is 
entered into Rave, the Rules Engine will 
confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS 
report must then be initiated directly from the 
Adverse Event/Late Adverse Event Form in 
Medidata Rave.  Do not initiate the CTEP-
AERS report via the CTEP-AERS website. We 
encourage all sites to confirm the Rules Engine 
assessment with the requirements outlined 
below. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.9, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
· 
All Grade 3, 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported expeditiously even if the patient is 
off study.   
Expedited 10 calendar day reports for: 
· 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.2.9 
Expedited Reporting Requirements for Arm A, B, C, and T on protocol 
EA5152 
Investigational Agents: Nivolumab, Cabozantinib, Ipilimumab  
Commercial Agents: None  
Phase 1 and Early Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
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NOTE: 
Footnote 1 instructs how to report serious adverse events 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
in CTEP-AERS accessed via Medidata Rave within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
· 
“24-Hour; 5 Calendar Days” – The AE must initially be reported in CTEP-AERS accessed via 
Medidata Rave within 24 hours of learning of the AE, followed by a complete expedited report within 
5 calendar days of the initial 24-hour report. 
· 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
· 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
· 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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5.2.10 
Additional instructions, requirements and exceptions for protocol 
EA5152 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com  or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
Reporting a death on study:  A death occurring while on study or 
within 30 days of the last dose of treatment requires both routine 
and expedited reporting, regardless of causality.  Attribution to 
treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be reported 
as a Grade 5 “Disease progression” under the System 
Organ Class (SOC) “General disorder and 
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. 
 
EA5152 specific expedited reporting requirements: 
· 
Colitis:  Any grade 3-5 colitis that is considered treatment 
related must be reported in CTEP-AERS accessed via 
Medidata Rave within 24 hours of learning of the event, 
followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
· 
Pneumonitis:  Any grade 3-5 pneumonitis that is considered 
treatment related must be reported in CTEP-AERS accessed 
via Medidata Rave within 24 hours of learning of the event, 
followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
· 
Infusion Reactions:  Any grade 3-5 infusion reaction must be 
reported in CTEP-AERS accessed via Medidata Rave within 
24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour 
report. 
· 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the subject is on 
Cabozantinib, Nivolumab or Ipilimumab, or within 28 days of 
the subject’s last dose of Cabozantinib, Nivolumab or 
Ipilimumab, are considered immediately reportable events. The 
pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported in CTEP-AERS accessed via 
Medidata Rave within 24 hours of the Investigator’s 
knowledge.  Please refer to Appendix VI for detailed 
instructions on how to report the occurrence of a pregnancy as 
well as the outcome of all pregnancies. 
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EA5152 specific expedited reporting exceptions: 
For study arms A, B, C, T, the adverse events listed below do not 
require expedited reporting 
· 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported 
expeditiously if the grade being reported exceeds the grade 
listed in the parentheses next to the event. Since some arms 
on this protocol use multiple investigational agents, if an AE is 
listed on multiple SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
5.2.11 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be require expedited reporting must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.12 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
· 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol). Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
· 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis expeditiously by initially reporting it on 
the Adverse Event Form or Late Adverse Event Form in the 
appropriate Treatment Cycle or Post Registration folder in 
Medidata Rave. The CTEP-AERS report must then be initiated 
Rev. Add1 
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directly from the Adverse Event/Late Adverse Event Form in 
Medidata Rave.  Do not initiate the CTEP-AERS report via the 
CTEP-AERS website. 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted in  CTEP-AERS or by the ECOG-ACRIN 
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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
5.3.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
XL184 (Cabozantinib s-malate, NSC 761968) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 3219patients. Below is the CAEPR for XL184 (Cabozantinib 
s-malate). 
NOTE: 
If an AE meets the reporting requirements of the protocol, 
and it is listed on the SPEER, it should ONLY be reported 
expeditiously if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  Since 
some arms on this protocol use multiple investigational 
agents, if an AE is listed on multiple SPEERs, use the 
lower of the grades to determine if expedited reporting is 
required. 
Version 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal 
hemorrhage3 
  
 
 
Gastrointestinal 
perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased 
(Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Generalized 
muscle 
weakness 
 
  
 
Muscle cramp 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Intracranial hemorrhage    
 
 
Ischemia cerebrovascular   
 
 
Reversible 
posterior 
leukoencephalopathy 
syndrome 
  
 
 
Stroke 
  


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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Transient ischemic attacks   
RENAL AND URINARY DISORDERS 
  
 
Hematuria 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Pneumothorax6 
  
 
 
Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
 
Voice alteration 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hair color changes 
 
 Hair color changes (Gr 1) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 3) 
 
Rash maculo-papular 
 
 Rash 
maculo-papular 
(Gr 3) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL 
DISORDERS SOC. 
3 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
4 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
5 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
6 Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating 
patients with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases. 


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7 Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
8 Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. 
9 Thromboembolic event includes pulmonary embolism which may be life-threatening. 
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that XL184 
(Cabozantinib) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile 
neutropenia; Hemolytic uremic syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left 
ventricular systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine 
disorders - Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; 
Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal 
pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; 
Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other 
(pneumoperitoneum); Gastrointestinal pain; Gingival pain; Hemorrhoids; Ileus; Pancreatitis; 
Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; 
Edema face; Fever; Gait disturbance; General disorders and administration site conditions - 
Other (general physical health deterioration); General disorders and administration site 
conditions - Other (implant site inflammation); Hypothermia; Malaise; Multi-organ failure; Non-
cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; 
Hepatobiliary disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic 
cirrhosis); Hepatobiliary disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other 
(hepatitis toxic); Hepatobiliary disorders - Other (hepatorenal syndrome); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and 
procedural complications - Other (post procedural hemorrhage); Injury, poisoning and 
procedural complications - Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Creatinine increased; 
Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Investigations - Other (D-dimer); Investigations - Other (urine ketone body present); 
Lymphocyte count decreased; Neutrophil count decreased; Serum amylase increased; Thyroid 
stimulating hormone increased; White blood cell decreased 


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METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; 
Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition 
disorders - Other (failure to thrive); Metabolism and nutrition disorders - Other 
(hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; 
Chest wall pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective 
tissue disorder - Other (muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; 
Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral 
cavity cancer); Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; 
Dysarthria; Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous 
system disorders - Other (hemiparesis); Nervous system disorders - Other (vocal cord 
paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; 
Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; 
Glucosuria; Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system 
and breast disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; 
Vaginal inflammation; Vaginal perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; 
Oropharyngeal pain; Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; 
Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - 
Other (nasal septum perforation); Respiratory, thoracic and mediastinal disorders - Other 
(pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); Sore 
throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; 
Pain of skin; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, 
sloughing of skin and erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); 
Skin hypopigmentation; Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular 
disorders - Other (bleeding varicose vein); Vasculitis 
NOTE: 
XL184 (Cabozantinib) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 


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5.3.2 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
BMS-936558 (Nivolumab, MDX-1106, NSC 748726) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/aeguidelines.pdf for further clarification. Frequency is provided 
based on 2069 patients. Below is the CAEPR for BMS-936558 
(Nivolumab, MDX-1106). 
NOTE: 
If an AE meets the reporting requirements of the protocol, 
and it is listed on the SPEER, it should ONLY be reported 
expeditiously if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  Since 
some arms on this protocol use multiple investigational 
agents, if an AE is listed on multiple SPEERs, use the 
lower of the grades to determine if expedited reporting is 
required. 
Version 2.3, June 18, 20181 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hypophysitis3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision  
  
 
 
Dry eye 
  
Rev. Add1 
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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Eye disorders - Other 
(diplopia)3 
  
 
 
Eye disorders - Other 
(Graves ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Gastritis 
  
 
 
 Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 
2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release 
syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting 
of allotransplant)3,6  
  
 
 
Immune system disorders - 
Other (sarcoid granuloma)3  
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related 
reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3)  
 
Aspartate 
aminotransferase 
increased3 
 
 Aspartate 
aminotransferase 
increased3 (Gr 3)  


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Blood bilirubin 
increased3 
 
 Blood bilirubin increased3 
(Gr 2)  
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 2) 
  
Neutrophil count 
decreased 
 
  
 
Platelet count 
decreased 
 
  
 
Serum amylase 
increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic 
syndrome) 
  


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 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Peripheral motor 
neuropathy 
  
 
 
Peripheral sensory 
neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (bronchiolitis 
obliterans with organizing 
pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2)  
 
Rash maculo-papular3  
 Rash maculo-papular3 (Gr 
2)  
 
 
Skin and subcutaneous 
disorders -Other (bullous 
pemphigoid)  
  
 
Skin and subcutaneous 
disorders - Other 
(Sweet’s Syndrome)3 
 
  
 
Skin hypopigmentation3  
  
 
 
 Stevens-Johnson 
syndrome 
  
 
 
 Toxic epidermal necrolysis   
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
3 BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the inhibition of 
“immune checkpoints”, may result in severe and possibly fatal immune-mediated adverse events 
probably due to T-cell activation and proliferation.  This may result in autoimmune disorders that can 
include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune 
response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune 
neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug 
rash with eosinophilia systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve 
paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and 


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hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, 
autoimmune hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, 
myasthenia gravis, polymyositis, and Guillain-Barre syndrome. 
4 Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
5 Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
6 Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving BMS-936558 (Nivolumab, MDX-1106).  
These complications may occur despite intervening therapy between receiving BMS-936558 (Nivolumab, 
MDX-1106) and allo-SCT. 
7 Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
Adverse events reported on BMS-936558 (Nivolumab, MDX-1106) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that 
BMS-936558 (Nivolumab, MDX-1106) 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; 


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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: 
BMS-936558 (Nivolumab, MDX-1106) 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. 


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5.3.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Ipilimumab (MDX-010, NSCs 732442 and 720801) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted 
below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/aeguidelines.pdf  for further clarification. Frequency is provided 
based on 2678 patients. Below is the CAEPR for Ipilimumab (MDX-
010). 
NOTE: 
If an AE meets the reporting requirements of the protocol, 
and it is listed on the SPEER, it should ONLY be reported 
expeditiously if the grade being reported exceeds the 
grade listed in the parentheses next to the event.  Since 
some arms on this protocol use multiple investigational 
agents, if an AE is listed on multiple SPEERs, use the 
lower of the grades to determine if expedited reporting is 
required. 
NOTE: 
For Arm C, although colitis appears in the SPEER list 
below as an exception to expedited reporting, all grades 
3-5 colitis that are considered treatment related must 
be reported in CTEP-AERS accessed via Medidata 
Rave because it is a protocol specific requirement, as 
outlined in Section 5.2.10. 
Version 2.9, December 20, 20171 
 
Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic 
system disorders - 
Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
Rev. Add1 
Rev. Add3 


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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other 
(episcleritis)2 
 
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
 
General disorders and 
administration site 
conditions - Other 
(systemic inflammatory 
response syndrome 
[SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - 
Other (hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system 
disorders - Other 
(GVHD in the setting of 
allotransplant)4 
  


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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
INFECTIONS AND INFESTATIONS 
  
 
 
Infections and 
infestations - Other 
(aseptic meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
 
Lymphocyte count 
decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
 
Metabolism and 
nutrition disorders - 
Other (exacerbation of 
pre-existing diabetes 
mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle 
weakness 
  
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
 Ataxia 
  
 
Facial nerve disorder 
 
  
 
Guillain-Barre syndrome2 
 
  
 
Headache 
 
  
 
Myasthenia gravis2 
 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - 
Other (mental status 
changes) 
  


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Adverse Events with Possible 
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - 
Other (granulomatous 
tubulointerstitial nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
 Respiratory failure 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(bronchiolitis obliterans 
with organizing 
pneumonia) 
  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other (lung 
infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-
papular 
 
 
 Rash maculo-papular (Gr 
3)  
 
Skin and subcutaneous 
disorders - Other (Sweet’s 
syndrome) 
 
  
 
 
Stevens-Johnson 
syndrome 
  
 
 
Toxic epidermal 
necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, 
autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic 
colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, and adrenal insufficiency), ocular manifestations (e.g., uveitis, iritis, 
conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and 
Guillain-Barre syndrome.  The majority of these reactions manifested early during treatment; however, a 
minority occurred weeks to months after discontinuation of ipilimumab especially with the initiation of 
additional treatments. 


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3 Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
4 Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receiving 
allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010). These complications may occur 
despite intervening therapy between receiving Ipilimumab (MDX-010) and allo-SCT. 
5 In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
6 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
7 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ipilimumab 
(MDX-010) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment 
changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal 
disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; 
Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of 
motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; 
Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 


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NOTE: 
Ipilimumab (MDX-010) 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. 


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5.4 
Dose Modifications  
5.4.1 
Cabozantinib Dose Levels 
Dose Level 
Cabozantinib Dosage 
0 
40 mg daily 
-1 
20 mg daily 
Missed or vomited doses of cabozantinib should be considered 
missed and not made up.  
5.4.2 
Nivolumab and Ipilimumab Dose Levels 
Missed doses of nivolumab and ipilimumab drugs should not be made 
up if not administered within the window specified by the protocol. 
Administration of nivolumab and ipilimumab should remain 
synchronized for patients on both drugs. No dose levels or schedule 
changes exist for nivolumab and ipilimumab – the drugs are either 
administered (together for the combination arm) or held at each given 
time. If held they may be given at the next specified interval in the 
protocol. 
If all treatment is held for more than 56 days (8 weeks), the 
patient must be permanently discontinued from study therapy 
unless study chair approval is obtained for unusual 
circumstances. 
5.4.3 
General principles for management of toxicity with combination 
therapy 
The combinations of cabozantinib and immunotherapy are still 
investigational, and unanticipated or synergistic side effects may be 
observed. Toxicity from combination therapy may be difficult to 
attribute to cabozantinib versus nivolumab (with or without 
ipilimumab). Guidance is provided below in defining attribution by 
holding cabozantinib, or by empirically starting corticosteroids.   
As a general approach, it is suggested that AEs be treated with 
supportive care when possible at the earliest signs of toxicity. The 
below management guidelines are provided based on what is known 
individually about cabozantinib and nivolumab/ipilimumab, with 
additional guidance in the areas of overlap. They are not mandatory 
and investigator discretion may be used 
There are many circumstances in which the instructions below dictate 
permanent discontinuation of therapy. If an investigator feels that it is 
in the patient’s best interest to continue on study therapy, study chair 
approval may be obtained prior to restarting drug.  
Table of relative likelihood of cabozantinib-related and immune-
related toxicities.   
++ More common  
+ Less common 
- 
Infrequent 
Rev. Add1 
Rev. Add3 


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Toxicity 
Cabozantinib-
related 
Immune-
related 
Protocol 
management 
section 
Diarrhea 
++ 
++ 
5.4.6 
Nausea and Vomiting 
++ 
+ 
5.4.7 
Oral mucositis 
++ 
- 
5.4.8 
Hand-foot syndrome (palmar-plantar 
erythrodysesthesia syndrome) 
++ 
- 
5.4.8 
Skin Rash 
+ 
+ 
5.4.8 
Transaminitis (AST/ALT increased) 
+ 
++ 
5.4.9 
Hyperbilirubinemia (bililrubin increased) 
- 
+ 
5.4.9 
Amylase/lipase increased; pancreatitis 
+ 
- 
5.4.9 
Pneumonitis 
+ 
++ 
5.4.10 
Hypothyroidism 
++ 
++ 
5.4.11 
Adrenal insufficiency 
- 
+ 
5.4.11 
Neurologic events 
- 
+ 
5.4.12 
Renal dysfunction 
- 
- 
5.4.13 
Proteinuria 
+ 
- 
5.4.13 
Fatigue 
++ 
++ 
5.4.14 
Fever 
- 
- 
5.4.15 
Infusion reaction 
N/A 
- 
5.4.16 
Thrombosis/embolism 
+ 
- 
5.4.17 
Hypertension 
++ 
- 
5.4.18 
Cardiomyopathy/myocarditis 
- 
+ 
5.4.19 
Hemorrhagic events 
+ 
- 
5.4.20 
Fistula formation/perforation 
+ 
- 
5.4.21 
Wound healing problems 
+ 
- 
5.4.22 
Osteonecrosis of the jaw 
+ 
- 
5.4.23 
Cardiac QTc prolongation 
+ 
- 
5.4.24 
5.4.4 
Cabozantinib-associated adverse events 
Most adverse events related to cabozantinib should start to improve 
within 1-2 weeks of drug hold with supportive management. For 
patients with possible cabozantinib toxicity of any grade, the 
investigator has the option to hold cabozantinib to determine whether 
the toxicity resolves (therefore it is more likely from cabozantinib) or 
the toxicity persists (therefore it is more likely from immunotherapy). If 
the toxicity is more likely from cabozantinib, the investigator has the 
option to continue cabozantinib, or dose reduce one level. If 
cabozantinib has already been dose reduced and toxicity recurs, it 


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may be permanently discontinued while the other study drug(s) are 
continued, if appropriate.  
5.4.5 
Immune-related adverse events 
Immune-related adverse events can happen with any onset in 
relationship to immune therapy administration, even months after 
discontinuation of therapy. Corticosteroids are the mainstay of therapy 
for immune-related adverse events. Most should improve or resolve 
with an adequate dose of steroids. Prior to starting corticosteroids or 
hormone replacement for any reason, appropriate endocrine testing 
including cortisol, ACTH, TSH and reflex T4 to document baseline is 
strongly recommended. 
Please note that in some cases the treatment algorithms recommend 
steroids if symptoms do not resolve in 7 days. However, this 
recommendation is not meant to delay steroid treatment at any time it 
is clinically indicated.  Any patient started on corticosteroids initially 
who is determined to not require steroid treatment for an autoimmune 
adverse event may resume therapy after an observation period 
without further symptoms at the discretion of the investigator. Any 
patients who require additional immune suppressive treatment beyond 
steroids should go off immune therapy study treatment (but may 
continue cabozantinib as appropriate).  
If AE’s are felt to be immune related and drugs are held, nivolumab 
and ipilimumab should either be given together or both held. 
Cabozantinib may be either continued, or held, as felt appropriate by 
the investigator depending on the particular toxicity. The study chair 
may be contacted for individual circumstances to provide additional 
guidance.   
5.4.6 
Diarrhea 
Overall management of diarrhea: 
Management of diarrhea may be challenging for patients on 
combination therapy on this protocol, because cabozantinib and 
immune-related diarrhea have different etiologies and management.  
In general, cabozantinib-associated diarrhea tends to be more crampy 
(not painful) and generally mild in nature. If there is bloody colitis, or 
abdominal pain, also consider the likelihood of immune-related colitis. 
For patients on cabozantinib containing arms, it is suggested they 
hold for grade 2 and higher diarrhea to monitor for clinical 
improvement. Antidiarrheals may be used. If the diarrhea is refractory 
to 1 week or more of drug hold, a trial of steroid therapy may be 
indicated according to the immune-mediated management algorithm 
below. Rechallenge may be considered for grade 3 and below 
diarrhea after resolution to grade 1, but for grade 4 diarrhea study 
chair approval is required after resolution before rechallenge. 
Management of cabozantinib-associated diarrhea:  
Subjects should be instructed to notify their physician immediately at 
the first signs of poorly formed or loose stool or an increased 


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frequency of bowel movements. Guidelines for the evaluation and 
management of diarrhea are shown in the table below. Administration 
of antidiarrheal/antimotility agents can be considered for diarrhea as 
initial management, but are not generally recommended for immune 
related colitis. Some subjects may require concomitant treatment with 
more than one antidiarrheal agent. When therapy with antidiarrheal 
agents does not control the diarrhea to tolerable levels, cabozantinib 
should be temporarily interrupted or dose reduced. When the diarrhea 
is controlled, retreatment with cabozantinib may be acceptable per 
investigator decision. In addition, general supportive measures should 
be implemented such as continuous oral isotonic hydration, correction 
of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or 
perianal skin erosions which increase the risk for anal abscesses, 
fistulas, or proctitis. Good personal hygiene should be emphasized. 
Regular examinations of the perianal region should be performed 
whenever diarrhea has occurred during treatment with cabozantinib. 
Infections of the perianal region should be treated per local guidelines. 
 
5.4.7 
Nausea and Vomiting  
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Antiemetic agents are recommended as clinically appropriate for 
treatment or prophylaxis of nausea and vomiting, along with 
supportive care. Dehydration and electrolyte abnormalities may be 
associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. The dose 
modification guidance should be followed for non-hematologic events 
(Section 5.4.25). 
The 5-HT3 receptor antagonists are recommended over chronic use 
of NK-1 receptor antagonists and dexamethasone (NK-1 receptor 
antagonists can induce or inhibit CYP3A4, and glucocorticoids induce 
CYP3A4 and thus could lower cabozantinib exposure.)   
Immune-related nausea and vomiting 
Other GI N-V  
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
No change in dose.  
Grade 2 
Hold pending evaluation for gastritis duodenitis and other 
immune adverse events or other causes.  Resume at 
same dose level after resolution to ≤ Grade 1.   
Grade 3 
Hold pending evaluation until ≤ Grade 1.  Resume at 
same dose level. If symptoms do not resolve within 7 
days with symptomatic treatment  patients should go off 
protocol therapy 
Grade 4 
Off protocol therapy 
Patients with grade 2 or 3 N-V should be evaluated for upper GI 
inflammation and other immune related events.   
5.4.8 
Stomatitis, Mucositis, and Skin Rash 
Management of cabozantinib-associated stomatitis/mucositis: 
Preventive measures may include a comprehensive oral examination 
to identify and treat any potential risk for complications before study 
treatment is initiated. Appropriate correction of local factors should be 
instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis. During treatment with cabozantinib, 
good oral hygiene and standard local treatments such as non 
traumatic and non-irritating cleansing, and oral rinses (eg, with a weak 
solution of salt and baking soda) should be maintained. Lips should 
be kept moisturized with lip balm. The use of lipstick, lip-gloss, and 
Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. 
Obtain bacterial/viral culture if oral infection is suspected and treat 
infection as clinically indicated. 
Management of cabozantinib-associated skin conditions:   
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as 
hand-foot syndrome), skin rash (including blister, erythematous rash, 
macular rash, skin exfoliation, dermatitis acneiform, and papular 
rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia 
have been reported with cabozantinib. All subjects on study should be 


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advised on prophylactic measures including the use of emollients, 
removal of calluses, avoidance of exposure of hands and feet to hot 
water leading to vasodilatation, protection of pressure-sensitive areas 
of hands and feet, and use of cotton gloves and socks to prevent 
injury and keep the palms and soles dry. 
Early manifestations include tingling, numbness, mild hyperkeratosis, 
and symmetrical red and swollen areas on the palms and soles. The 
lateral sides of the fingers or periungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin 
symptoms such as blisters, desquamations, ulcerations, or necrosis of 
affected areas. Analgesics may be required for pain control. 
Treatment guidelines for stomatitis and other general skin reactions 
should be followed as in Section 5.4.25 
Treatment guidelines for hand-foot reactions related to study 
treatment are presented in the table below. 
Cabozantinib associated Hand-Foot Reactions  
CTCAE 
Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current 
dose if PPES is clinically insignificant and tolerable. 
Otherwise, cabozantinib should be reduced to the next 
lower dose level.a Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Reassess at least 
weekly; if PPES worsens at any time or does not improve 
after 2 weeks, proceed to the intervention guidelines for 
Grade 2. 
Grade 2  
Cabozantinib treatment may be continued if PPES is 
tolerated. Cabozantinib should be dose reduced or 
interrupted if PPES is intolerable. Continue urea 20% 
cream twice daily AND high potency steroid cream (eg, 
clobetasol 0.05%) once daily and add analgesics (eg, 
NSAIDs/gamma-aminobutyric acid agonists) for pain 
control if needed. Reassess at least weekly; if PPES 
worsens or affects self-care, proceed to the intervention 
guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to 
Grade 1 or 0. Continue treatment of skin reaction with high 
potency steroid cream (eg, clobetasol 0.05%) twice daily 
AND analgesics. Resume study drug at a reduced dose if 
PPES recovers to Grade ≤ 1. Discontinue subject from 
study treatment if PPES does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, 
non-steroidal anti-inflammatory drug; PPES, palmar plantar 
erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory 
drugs; PPE, palmar-plantar erythrodysesthesia 
Rev. Add3 


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Immune-related skin rash and oral lesions 
Skin Rash and 
Oral Lesions 
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
No change in dose * 
Grade 2 
Hold* until 1≤ Grade resolved.  Resume at same dose 
level.  
Grade 3 
Hold* until ≤ Grade 1.  Resume at same level at 
investigator discretion  
Grade 4 
Off protocol therapy 
* Patients with purpuric or bullous lesions must be evaluated for vasculitis, 
Steven-Johnson syndrome, TEN, and autoimmune bullous disease including 
oral lesions of bullous pemphigus/pemphagoid.  Pruritus may occur with or 
without skin rash and should be treated symptomatically if there is no 
associated liver or GI toxicity.  Note skin rash typically occurs early and may 
be followed by additional events particularly during steroids tapering.   
Recommended management:  See Skin AE management Algorithm  
 


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5.4.9 
Hepatobiliary Disorders 
Management of cabozantinib-associated hepatobiliary disorders: 
The following tables should be used for dose modifications for 
AST/ALT elevations and/or bilirubin elevations: 
Cabozantinib associated Transaminase and/or Bilirubin Elevations 
 
Notes 
In general, it is recommended that subjects with elevation of ALT, AST, 
and/or bilirubin have more frequent laboratory monitoring of these 
parameters, i.e. 2 or more times per week. If possible, hepatotoxic 
concomitant medications and alcohol should be discontinued in subjects 
who develop elevated transaminases. 
Transaminase elevation 
Grade 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib and consider weekly monitoring of liver function 
tests (LFTs) until stable. Then resume the standard protocol-defined 
monitoring of LFTs. 
Grade 2 
Continue cabozantinib with weekly monitoring of LFTs for 6 weeks. If LFTs 
continue to rise within Grade 2, hold cabozantinib treatment. Then continue 
with weekly LFTs until resolution to Grade ≤ 1. Study treatment may then 
be resumed at a one-dose-level reduction of cabozantinib 
Grade 3  
Hold cabozantinib treatment and monitor with twice weekly LFTs until 
Grade ≤ 2. Then continue with weekly LFTs until resolution to Grade ≤ 1. 
Cabozantinib may then be resumed at a one-dose-level reduction. 
Grade 4 
Discontinue all study treatment permanently. LFTs should be monitored as 
clinically indicated, at least 2-3 times per week, until resolution to Grade ≤ 
1. If the subject was unequivocally deriving clinical benefit, the subject may 
be able to resume treatment at a lower dose of cabozantinib as determined 
by the investigator and Study Chair but only with Study Chair approval. 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline 
≥ 50% increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with weekly monitoring of LFTs for 8 
weeks. If LFTs continue to rise, hold all study treatment. Then continue with 
weekly LFTs until resolution to Grade ≤ 1. Study treatment may then be 
resumed at a one-dose-level reduction of cabozantinib. 
≥ 50% increase of AST 
or ALT and at least one 
of AST or ALT is Grade 
3 (i.e. AST or ALT > 5.0 
but ≤ 20.0 x ULN) 
Hold all study treatment and monitor with twice weekly LFTs until Grade  
≤ 2.Then continue with at least weekly LFTs until resolution to Grade ≤ 1. 
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
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Cabozantinib associated asymptomatic Lipase or Amylase Elevations 
NOTES: Amylase and lipase elevations have been observed in clinical studies with cabozantinib.  The 
clinical significance of asymptomatic elevations of enzymes is not known but in general have 
not been associated with clinically apparent sequelae.  It is recommended that subjects with 
lipase elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of 
lipase and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be 
treated with standard supportive measures. 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
Hold all study treatment 
Monitor lipase and amylase twice weekly 
Upon resolution to Grade ≤ 1 or baseline, study treatment may be restarted at 
the same dose or at a reduced dose provided that this occurs within 4 weeks. 
If retreatment following Grade 3 lipase or amylase elevation is at the same 
cabozantinib dose and Grade 3 or Grade 4 elevations recur, then all study 
treatment must be held again until lipase and amylase  levels have resolved to 
Grade ≤ 1 or baseline and retreatment must be at a reduced dose. 
Grade 4 
Hold all study treatment 
Monitor lipase and amylase twice weekly 
Upon resolution to Grade ≤ 1 or baseline and if resolution occurred within 4 
days, cabozantinib may be restarted at the same dose or a reduced dose.  If 
resolution took more than 4 days, the dose must be reduced upon retreatment 
provided that resolution occurred within 4 weeks. 
If retreatment following Grade 4 lipase or amylase elevation is at the same 
cabozantinib dose and Grade 3 or 4 elevations recur, then all study treatment 
must be held again until lipase and amylase have resolved to Grade ≤ 1 or 
Grade 4  
Discontinue all study treatment permanently. LFTs should be 
monitored as clinically indicated, i.e. 2 times per week or more, 
until resolution to Grade ≤ 1. If the subject was unequivocally 
deriving clinical benefit, the subject may be able to resume 
treatment with cabozantinib at a lower dose as determined by the 
investigator and Study Chair but only with Study Chair approval. 
 
Bilirubin elevation Grade 
Intervention 
Grade 2 Bilirubin 
Continue study treatment. Consider more frequent monitoring of 
bilirubin, i.e weekly or more 
Grade 2 or greater Bilirubin (and 
> 2.0 ULN), with Grade 3 or 
greater transaminase elevation, 
without evidence of biliary 
obstruction (i.e. elevation of 
alkaline phosphatase) or 
alternative explanation 
Permanently discontinue all study treatment due to likely signal of 
severe liver injury 
Grade 3 Bilirubin (> 3.0 ULN), 
isolated 
Hold all study treatment until recovered to Grade ≤ 1 or baseline, 
INR < 1.5 ULN or baseline, and aminotransferases Grade ≤ 1 or 
baseline. Cabozantinib may then be resumed at a one-dose-level 
reduction. 
Grade 4 Bilirubin (> 10.0 ULN) 
Permanently discontinue cabozantinib 


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baseline and retreatment must be at a reduced dose. 
Cabozantinib-associated Pancreatitis 
Pancreatitis 
Grade 3 
Hold cabozantinib treatment. Radiographic evaluation is recommended.  
Monitor lipase and amylase weekly. 
Upon resolution to Grade ≤ 1 or baseline, cabozantinib may be restarted at a reduced dose. 
Grade 4 
Permanently discontinue all study treatment. However, if the subject was unequivocally 
deriving benefit from therapy, cabozantinib treatment may resume at a reduced at a reduced 
dose agreed to by the investigator and Study Chair but only with Study Chair approval. 
Immune-related hepatobiliary disorders 
Liver Function AST, 
ALT, Bilirubin   
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
Hold until UNL or baseline.   Resume at same dose level. 
Grade 2 
Hold until UNL or baseline.  Resume at same dose level.  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing inflammation.  Holding drug to 
evaluate LFT changes and early treatment are recommended.   
LFT changes may occur during steroid tapers from other events and may occur together with other GI events 
including cholecystitis/pancreatitis.  
Recommended management:  see Hepatic AE management algorithm 
 
Pancreatitis Amylapse/Lipase  
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
May continue at same dose level if asymptomatic; consider liver 
ultrasound and/or abdominal CT scan if no resolution.  
Grade 2 
May continue at same dose level if asymptomatic; consider liver 
ultrasound and/or abdominal CT scan if no resolution. 
Grade 3 
May continue at same dose level if asymptomatic; consider liver 
ultrasound and/or abdominal CT scan if no resolution. 
Grade 4 
Hold drug. Perform liver ultrasound and/or abdominal CT scan to rule 
out radiographic pancreatitis.  Resume at same dose level if 
asymptomatic and no radiographic clinical concerns. Patients who 
develop symptomatic pancreatitis or DM should be taken off treatment  
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and DKA.  Lipase elevation 
may occur during the period of steroid withdrawal and with other immune mediated events or associated with colitis, 
hepatitis, and patients who have asymptomatic lipase elevation typically have self-limited course and may be 
retreated.  
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse Event 
Management Algorithm  
 


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5.4.10 
Pneumonitis 
Management of cabozantinib associated pneumonitis 
Pneumonitis has been associated with cabozantinib, nivolumab, and 
ipilimumab therapies individually. In general it is difficult to definitively 
diagnose and can be life threatening. Patients with proven 
symptomatic clinically proven pneumonitis refractory to management 
guidelines for nivolumab +/- ipilimumab (below) should have 
cabozantinib permanently discontinued, if they were on cabozantinib 
therapy.  


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Pneumonitis 
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
Hold dose pending evaluation and resolution to baseline including baseline pO2.  
Resume no change in dose after pulmonary and/or ID consultation excludes 
lymphocytic pneumonitis.  
Grade 2 
Hold dose pending evaluation. Resume no change in dose after pulmonary and/or ID 
consultation excludes ipilimumab and associated lymphocytic pneumonitis as the 
cause of the pneumonitis. Off study if steroids are required. ^  
Grade 3 
Hold dose pending evaluation. Resume no change in dose after pulmonary and/or ID 
consultation excludes ipilimumab and associated lymphocytic pneumonitis as the 
cause of the pneumonitis. Off study if steroids are required  
Grade 4 
Off protocol therapy 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do not 
respond to antibiotics and have no causal organism identified including influenza.  Most patients with 
respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be required and analysis 
of lavage fluid for lymphocytic predominance may be helpful.  Patients with new lung nodules should be 
evaluated for sarcoid like granuloma.  Please consider recommending seasonal influenza killed vaccine 
for all patients. 
Recommended management:  See Pulmonary Adverse Event Management Algorithm  
 


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5.4.11 
Endocrine Disorders 
Management of cabozantinib associated endocrine disorders:  
Prospective studies of markers of thyroid functions are currently 
ongoing in two single-agent studies to characterize the effects of 
cabozantinib on thyroid function. Preliminary data indicate that 
cabozantinib affects thyroid function tests (TFTs) in a high number of 
subjects (see Cabozantinib Investigator’s Brochure).  Routine 
assessments for signs and symptoms associated with thyroid 
dysfunction is recommended for subjects treated with cabozantinib.  
Management of thyroid dysfunction (e.g., symptomatic 
hypothyroidism) should follow accepted clinical practice guidelines. 
Other endocrine disorders such as hypocalcemia and hyperglycemia, 
and associated laboratory changes, have been observed in less than 
10% of subjects.  Monitoring with standard laboratory tests and 
clinical examination prior to initiation and during treatment with 
cabozantinib is required.   
Cabozantinib should be discontinued in subjects with severe or life-
threatening endocrine dysfunction. 
Immune-related endocrine disorders 
Endocrine Hypophysitis 
Adrenal Insufficiency  
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
Asymptomatic TSH elevation *  Consider thyroid replacement therapy and 
endocrine consult 
Grade 2 
Hold until patients are on a stable replacement hormone regimen.  If treated 
with steroids patients must be stable off steroids for two weeks. Resume at 
same dose level.  
Grade 3 
Off study treatment. 
Grade 4 
Off protocol therapy 
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but including 
severe headache or enlarged pituitary on MRI should be considered grade 3 events.  Isolated thyroid or 
testosterone deficiency may be treated as grade 2 if there are no other associated deficiencies and 
adrenal function is monitored.  
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine testing 
including cortisol, ACTH, TSH and T4 must be obtained to document baseline. 
* Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be evaluated to 
rule out pituitary disease prior to initiating thyroid replacement. 
- Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment. 
- Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with replacement 
hormones including thyroid hormone and physiologic doses of corticosteroids. 
- Please note that grading and for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic 
meningitis or encephalitis should be considered grade 3 events.  
Recommended management: See Endocrine Management Algorithm  
 


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5.4.12 
Neurologic Events 
Management of cabozantinib associated neurologic events: 
Neurologic events are unusual with cabozantinib. Reversible 
leukoencephalopathy syndrome (RPLS) can be considered, but 
generally immune related events should be excluded as well. If a 
diagnosis of RPLS is confirmed, cabozantinib should be permanently 
discontinued. 
Immune-related neurologic events 
Neurologic events  
Management/Next Dose for Nivolumab 
≤ Grade 1 
Hold dose pending evaluation and observation. Resume with no change in dose when 
resolved to baseline. 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1. Off protocol 
therapy if treatment with steroids is required.  Resume at same dose level for peripheral 
isolated n. VII (Bell’s palsy)^  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic hypophysitis, or myopathy, 
peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), GB syndrome, myasthenia 
gravis should be off study.   
Recommended management:  See Neurologic Adverse Event Management Algorithm  


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5.4.13 
Renal dysfunction and proteinuria 
Management of cabozantinib related proteinuria: Proteinuria has 
been reported with approved drugs that inhibit VEGF pathways as 
well as with cabozantinib.  Any level of proteinuria diagnosed by 
dipstick should be quantified by a UPCR(mg/dL protein / mg/dL 
creatinine).  When a UPCR exceeds 1, a repeat UPCR or a 24-hour 
urine protein and creatinine should be performed to confirm the result. 
Cabozantinib should be discontinued in subjects who develop 
nephrotic syndrome (proteinuria > 3.5 g/day in combination with 
hypoalbuminemia, edema and hyperlipidemia) or any other relevant 
renal disease.  Also, given the nephrotoxic potential of 
bisphosphonates, these agents should be used with caution in 
patients receiving treatment with cabozantinib.  Details of 
management are described in the next Table below  


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Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1mg/mmol) 
· 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5mg/mg 
(> 113.1 and  
< 395.9mg/mmol) 
· 
Consider confirming with a 24-h protein assessment within 7 days 
· 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 h on 24-h urine collection. 
· 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine 
collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider interrupting cabozantinib 
treatment if UPCR remains > 2 mg/mg despite a dose reduction until 
UPCR decreases to < 2 mg/mg. Restart cabozantinib treatment at a 
reduced dose after a dose interruption. 
· 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done 
within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 
1 month, check urine protein/creatinine per protocol or as clinically 
indicated. 
≥ 3.5mg/mg 
(≥ 395.9mg/mmol) 
· 
Interrupt cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-h urine protein.  
· 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until 
the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg 
and < 2 mg/mg for 1 month or is determined to be stable (< 20% 
change) for 1 month, check urine protein/creatinine per protocol or 
as clinically indicated. 
Nephrotic syndrome 
· 
Discontinue cabozantinib treatment 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 
 


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Immune-related renal dysfunction 
Renal 
Management/Next Dose for Nivolumab and Nivo/Ipi combination 
≤ Grade 1 
Continue study therapy 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever  
 
5.4.14 
Fatigue 
Management of cabozantinib associated fatigue: Fatigue is 
common with cabozantinib treatment and generally should resolve 
within 2 weeks of discontinuing therapy. Dose reduction can be 
considered.  
Immune-related fatigue 
Fatigue  
Management/Next Dose for Nivolumab+/-Ipilimumab 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose 
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Fatigue  
Management/Next Dose for Nivolumab+/-Ipilimumab 
Grade 3 
Hold until ≤ Grade 2.  Resume at same dose level. 
Fatigue is the most common adverse event associated with immune checkpoint therapy.  Grade 2 or 
greater fatigue should be evaluated for associated or underlying organ involvement including pituitary, 
thyroid, and hepatic, or muscle (CPK) inflammation. 
5.4.15 
Fever 
Management of cabozantinib associated fever. Fever is unusual 
with cabozantinib treatment. Infection and immune related etiologies 
should be considered. 
Immune related fever 
Fever  
Management/Next Dose for Nivolumab and Nivo/Ipi combination 
≤ Grade 1 
Evaluate and continue at same dose level 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 4 
Off treatment 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever  
5.4.16 
Infusion reactions 
Since nivolumab contains only human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions.  However, if such a reaction were to occur, 
it might manifest with fever, chills, rigors, headache, rash, urticaria, 
angioedema, pruritis, arthralgias, hypo- or hypertension, 
bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an SAE 
according to Section 5.2.9 if reporting criteria are met. Infusion 
reactions should be graded according to NCI CTCAE guidelines. 
Treatment recommendations are provided below and may be modified 
based on local treatment standards and guidelines as medically 
appropriate: 
Remain at bedside and monitor subject until recovery from symptoms  
For Grade 1 symptoms:  (Mild reaction; infusion interruption not 
indicated; intervention not indicated) 
Infusion rate may be slowed or interrupted and restarted 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.   
The following prophylactic premedications are recommended for 
future infusions:  diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
Rev. Add1 
Rev. Add3 


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before additional nivolumab administrations, slowing infusion rate as 
above. 
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 50 mg IV (or equivalent) 
and/or paracetamol 325 to 1000 mg (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 50 mg IV, and 
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 50 mg (or equivalent) and 
(acetaminophen) (or paracetamol) 325 to 1000 mg should be 
administered at least 30 minutes before additional nivolumab 
administrations.  If necessary, corticosteroids (recommended dose: up 
to 25 mg of IV hydrocortisone or equivalent) may be used. 
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 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of 
a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed.  Patient should be monitored until the 
investigator is comfortable that the symptoms will not recur.   
Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis.  Remain at bedside and monitor patient until 
recovery from symptoms.  


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In the case of late-occurring hypersensitivity symptoms (e.g., 
appearance of a localized or generalized pruritis within 1 week after 
treatment), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids).  Additional treatment prior to next 
dose as per guidelines above.  
Please note that late occurring events including isolated fever and 
fatigue may represent the presentation of systemic inflammation.  
Please evaluate accordingly. 
5.4.17 
Embolism and Thrombosis 
Management of cabozantinib associated embolism and 
thrombosis: Deep vein thrombosis and PE have been observed in 
clinical studies with cabozantinib; including fatal events (please refer 
to the Investigator Brochure). Subjects who develop a PE or DVT 
should have all study treatment held until therapeutic anticoagulation 
is initiated. 
Anticoagulation with warfarin is not allowed due to drug interactions 
with both cabozantinib; therefore ONLY heparins or low molecular 
weight heparin is allowed. Patients with brain metastases should be 
treated with caution and the investigator should consider the potential 
benefit to outweigh the risks. 
Grade 2-3 DVT or PE: All study treatment may be resumed without a 
dose-level reduction in subjects who have uncomplicated PE or DCT. 
During treatment with anticoagulants, subjects need to be monitored 
on an ongoing basis for bleeding risk and signs of bleeding. 
Grade 4 DVT or PE: Subjects with life-threatening PE or DVT should 
have cabozantinib discontinued unless toxicity can be managed and 
subject is deriving clear clinical benefit as determined by the 
investigator and agreed by the Study Chair.  Venous filters (e.g. vena 
cava filters) are not recommended due to the high incidence of 
complications associated with their use.  Once a subject is fully 
anticoagulated, cabozantinib can be restarted per investigator 
judgment at one dose lower.  Subjects should permanently 
discontinue cabozantinib after a second thrombotic event. Although 
routine prophylactic anticoagulation is not necessary for all subjects, 
prophylactic anticoagulation is allowed for individual subjects at the 
discretion of the investigator. 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial 
infarction) have been observed rarely in studies with cabozantinib.  
Cabozantinib should be discontinued in subjects who develop an 
acute MI or any other clinically significant arterial thromboembolic 
complication. 
5.4.18 
Hypertension 
Management of cabozantinib related hypertension: Hypertension 
is a relatively common complication of other VEGF-pathway inhibitors 
and has been observed in cabozantinib clinical studies. 
Guidelines for management are presented in the table below. 


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Table: Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic)a and < 160 mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm Hg 
· Optimize antihypertensive medications by adding new or 
additional antihypertensive medications and/or increase dose of 
existing medications. 
· Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does not 
result in BP < 150 mm Hg systolic or < 100 mm Hg diastolic 
· If subject is symptomatic interrupt cabozantinib treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
· Reduce cabozantinib by one dose level or interrupt cabozantinib 
treatment per investigator discretion 
· Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive therapy 
(usually to include 3 agents) does not result in BP < 150 mm Hg 
systolic or < 100 mm Hg diastolic, cabozantinib treatment 
should be dose reduced further or interrupted 
· Cabozantinib treatment should be dose interrupted if upper 
limits of systolic BP (≥ 160 mm Hg) are sustained and not 
adequately manageable or if systolic BP is > 180 mm Hg or 
diastolic BP > 110 mm Hg, or if subject is symptomatic 
· Re-start cabozantinib treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at < 150 mm Hg 
systolic and < 100 mm Hg diastolic 
Hypertensive emergencyb 
· Discontinue cabozantinib treatment 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP  
> 150 or diastolic BP > 100 based on their clinical judgment and assessment of the individual subject. 
b Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or 
impending end-organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, 
pulmonary edema, encephalopathy, kidney damage). 
5.4.19 
Myocarditis 
Management of cabozantinib related 
cardiomyopathy/myocarditis: Cardiomyopathy has been reported 
with VEGF-pathway inhibitors, but myocarditis is very infrequent at 
most. Therefore, immune related causes should be primarily 
suspected but cabozantinib should also be held while workup is 
ongoing. 
Management of immune related cardiomyopathy/myocarditis: 
Myocarditis, that may result in cardiomyopathy, has been increasingly 
reported as a complication of immunotherapy. 
Guidelines for management are presented in the table below. 
· 
Drug will be held for grade 2 cardiac dysfunction pending 
evaluation 
· 
Drug will be permanently discontinued for grade 3 or 4 cardiac 
dysfunction and grade 2 events that do not recover to baseline or 
that reoccur 
· 
Treatment with steroids as clinically indicated 


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Cardiac* 
Management/Next Dose for BMS-936558 (Nivolumab) + Ipilimumab Cardiac 
Toxicities  
≤ Grade 1 
Hold dose pending evaluation and observation** Evaluate for signs and symptoms of 
CHF, ischemia, arrhythmia or myositis. Obtain history EKG, CK (for concomitant 
myositis), CK-MB, Troponin I. Repeat troponin, CK and EKG 2-3 days. If troponin and 
labs normalize may resume therapy. If labs worsen or symptoms develop then treat as 
below. Hold pending evaluation. 
Grade ≥ 2 with 
suspected 
myocarditis 
Hold dose** Admit to hospital.  Cardiology consult.  Rule out MI and other causes of 
cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  Consider cardiac MRI and cardiac 
biopsy.  Initiate high dose methylprednisolone.  If no improvement within 24 hours, add 
either infliximab, ATG or tacrolimus. Consult algorithm for more details.  Resume therapy 
if there is a return to baseline and myocarditis is excluded or considered unlikely. 
Grade ≥ 2 with 
confirmed 
myocarditis 
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac Transplant 
Unit).  Treat as above.  Consider high dose methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off treatment. 
* Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
** Patients with evidence of myositis without myocarditis may be treated according as “other event”   
NOTE: The optimal treatment regimen for immune mediated myocarditis has not been established.  Since 
this toxicity has caused patient deaths, an aggressive approach is recommended.   
5.4.20 
Prevention and Treatment of Hemorrhagic Events 
Management of cabozantinib associated hemorrhagic events: 
Hemorrhagic events have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib.  As preventive 
measures, subjects should be evaluated for potential bleeding risk 
factors prior to initiating cabozantinib treatment and monitored for 
bleeding events with serial complete blood counts and physical 
examination while on study. 
Risk factors for hemorrhagic events may include (but may not be 
limited to) the following: 
· 
Tumor lesions with cavitations or tumor lesions which invade, 
encase, or abut major blood vessels.   
· 
Recent or concurrent radiation to the thoracic cavity. 
· 
Active peptic ulcer disease, ulcerative colitis, and other 
inflammatory GI diseases. 
· 
Underlying medical conditions which affect normal hemostasis 
(e.g., deficiencies in clotting factors and/or platelet function, or 
thrombocytopenia). 
· 
Concomitant medication with anticoagulants or other drugs which 
affect normal hemostasis. 
· 
History of clinically significant hemoptysis. 
Management: Cabozantinib should be discontinued in subjects with 
serious (Grade 3) and life-threatening (Grade 4) bleeding events or 
recent hemoptysis (≥ 0.5 teaspoon (2.5mL) of red blood).  Treatment 
with cabozantinib should be held if less severe forms of clinically 
significant hemorrhage occur and may be restarted after the cause of 
hemorrhage has been identified and the risk of bleeding has subsided 
at a dose agreed to by the Study Chair and the investigator.  Therapy 


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of bleeding events should include supportive care and standard 
medical interventions. 
Furthermore, subjects who develop tumors abutting, encasing, or 
invading a major blood vessel or who develop cavitation of their 
pulmonary tumors while on study treatment should be considered for 
discontinuation of cabozantinib treatment. 
5.4.21 
Rectal and Perirectal Abscess and GI and non-GI Perforation/Fistula 
Formation/ 
Management of cabozantinib-associated rectal and perirectal 
abscess: Rectal and perirectal abscesses have been reported, often 
in subjects with concurrent diarrhea. 
These should be treated with appropriate local care and antibiotic 
therapy. Cabozantinib should be held until adequate healing has 
taken place. 
Management of cabozantinib associated GI Perforation/Fistula: 
GI perforation/fistula and Non-GI fistula formation have been reported 
with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib. Carefully monitor for episodes of abdominal pain, 
especially in subjects with known risk factors for developing GI 
perforation/fistula or non-GI fistula, to allow for early diagnosis. 
Risk factors include the following: 
· 
Intra-abdominal tumor/metastases invading GI mucosa.  
· 
Active peptic ulcer disease, inflammatory bowel disease, 
ulcerative colitis, diverticulitis, cholecystitis or symptomatic 
cholangitis, or appendicitis 
· 
History of abdominal fistula, GI perforation, bowel obstruction, or 
intra-abdominal abscess 
· 
Prior GI surgery (particularly when associated with delayed or 
incomplete healing). Complete healing following abdominal 
surgery or resolution of intra abdominal abscess must be 
confirmed prior to initiating treatment with cabozantinib. 
· 
Radiation to the GI tract 
Additional risk factors include concurrent chronic use of steroid 
treatment or non-steroidal anti-inflammatory drugs.  Constipation 
indicative of bowel obstruction should be monitored and effectively 
managed. 
Management of cabozantinib associated non-GI fistula: 
Radiation therapy has been identified as a possible predisposing risk 
factor for non-GI fistula formation in subjects undergoing treatment 
with drugs that inhibit VEGF pathways.  In addition, subjects who 
have undergone extensive surgery may be at increased risk of 
developing a fistula of the involved organs Non GI fistula should be 
ruled out as appropriate in cases of onset of mucositis after start of 
therapy. Patients with tumor invading the respiratory tract are also 
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Management: Cabozantinib should be discontinued in subjects who 
have been diagnosed with GI or non GI perforation/fistula that is 
related to treatment. 
5.4.22 
Wound Healing and Surgery 
Management of cabozantinib-associated wound healing and 
surgery: Cabozantinib has the potential to cause wound healing 
complications and wound dehiscence which may even occur long 
after a wound has been considered healed. Therefore, surgical and 
traumatic wounds must not only be completely healed prior to starting 
cabozantinib treatment but must also be monitored for wound 
dehiscence, wound infection and other signs of impaired wound 
healing while the subject is being treated with cabozantinib. If 
dehiscence occurs, cabozantinib treatment should not be restarted 
until complete healing has taken place.  
Treatment with cabozantinib should be stopped at least 28 days prior 
to scheduled surgery. The decision to resume treatment with 
cabozantinib after surgery should be based on clinical judgment of 
adequate wound healing. 
The appropriate dose hold interval prior to elective surgery to reduce 
the risk for wound healing complications has not been determined. 
When possible, cabozantinib should be stopped at least 28 days prior 
to elective surgery. 
5.4.23 
Osteonecrosis of the Jaw 
Osteonecrosis has been reported in subjects treated with 
cabozantinib. Additional risk factors include use of bisphosphonates 
and denosumab, chemotherapy and anti-angiogenic drugs, use of 
corticosteroids, local radiotherapy, and dental or orofacial surgery 
procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, 
osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, 
toothache, gingival ulceration, or gingival erosion. Persistent pain or 
slow healing of the mouth or jaw after dental surgery may also be 
manifestations of osteonecrosis. 
Advise subjects regarding oral hygiene practice and to quickly report 
symptoms to investigator. Caution should be used in subjects 
receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental 
procedures are unavoidable, treatment with cabozantinib should be 
interrupted for at least 4 weeks prior to the procedure and resumed 
after complete wound healing has occurred. Bone healing may often 
require a protracted time. 
5.4.24 
QT (QTcF) Prolongation 
Management of cabozantinib-associated QT prolongation:  
Treatment with cabozantinib has been associated with a mild 
prolongation of the QTc interval.  Other factors which may contribute 
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· 
Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org). 
· 
Treatment with CyP 3A4 inhibitors (which may increase 
cabozantinib drug levels) 
· 
Electrolyte changes (hypokalemia, hypocalcemia, 
hypomagnesemia). 
· 
Medical conditions which can alter electrolyte status e.g., severe 
or prolonged diarrhea. 
Treatment with drugs that cause QTc prolongation as well as CyP 
3A4 inhibitors is discouraged on this study, but not prohibited. 
Subjects having any of these additional risk factors while on 
cabozantinib should have ECGs performed approximately one week 
after the onset of these factors. 
If at any time on study there is an increase in QTc interval to an 
absolute value > 500 msec, two additional ECGs should be performed 
within 30 minutes after the initial ECG with intervals not less than 3 
minutes apart.  If the average QTcF from the three ECGs is >500 
msec, study treatment must be withheld and the following actions 
should be taken: 
· 
Check electrolytes, especially potassium, magnesium and 
calcium.  Correct abnormalities as clinically indicated. 
· 
If possible, discontinue any QTc-prolonging concomitant 
medications. 
· 
 Repeat ECG triplets hourly until the average QTcF is ≤ 500 msec 
or otherwise determined by consultation with a cardiologist. 
The Sponsor should be notified immediately of any QTc prolongation 
event.  
Subjects with QTc prolongation and symptoms must be monitored 
closely until the QTc elevation has resolved.  Cardiology consultation 
is recommended for evaluation and subject management.  
Symptomatic subjects must be treated according to standard clinical 
practice. 
No additional cabozantinib is to be given to the subject until after the 
event has resolved, the subject has been thoroughly evaluated, and 
further treatment has been agreed to by the Study Chair. 
If any additional study treatment is given (e.g., after correction of 
electrolyte abnormalities and normalization of QTcF), it will be at a 
reduced dose as agreed to by the investigator and the Study Chair. 
5.4.25 
Guidelines for General Toxicities Commonly Associated with 
Cabozantinib 
As a general approach, it is suggested that all AEs be managed with 
supportive care when possible at the earliest signs of toxicity.  
Calcium, magnesium, potassium and phosphorus should be kept 
above the lower limits of the laboratory normal values. Additional 
information can be found in the Cabozantinib Investigator’s Brochure. 


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Once reduced, the dose of cabozantinib should not be re-
escalated. 
General Approach to the Management of Other Cabozantinib-
Related Non-Hematologic Adverse Events 
Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue 
cabozantinib treatment at the current dose level if AE 
is manageable and tolerable. 
Grade 2 AEs 
which are 
tolerable and are 
easily managed 
Grade 2 AEs 
which are 
intolerable and 
cannot be 
adequately 
managed  
Continue cabozantinib treatment at the current dose 
level with supportive care. 
At the discretion of the investigator, cabozantinib 
should be dose reduced or interrupted. 
Note: It is recommended that dose holds be as brief 
as possible.  
Grade 3 AEs 
(except clinically 
non-relevant 
laboratory 
abnormalities) 
Cabozantinib should be interrupted unless the 
toxicity can be easily managed with a dose reduction 
and optimal medical care.  
Note: It is recommended that dose holds be as brief 
as possible. 
Grade 4 AEs 
(except clinically 
non-relevant 
laboratory 
abnormalities) 
Subjects should have cabozantinib interrupted 
immediately.  
Discontinue cabozantinib unless the following criteria 
are met:  
· 
Subject is deriving clear clinical benefit as 
determined by the investigator 
· 
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care  
NOTE: 
A table referencing dose delay and modification criteria for 
specific medical conditions is provided in Section 5.4.3. 
Study treatment dose adjustment is only needed if the toxicity 
was deemed possibly, probably, or definitely related to 
cabozantinib treatment. 
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5.4.26 
Management of other Immune related events 
ALL OTHER EVENTS 
Management/Next Dose for Nivolumab and 
combination Nivolumab/Ipilimumab 
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1 OR baseline(exceptions 
as noted below)     
Grade 3 
 Off protocol therapy (exceptions as noted 
below)   
Grade 4 
Off protocol therapy 
Recommended management:  As clinically indicated  
Any grade 2 drug-related uveitis or eye pain or blurred vision that 
does not respond to topical therapy and does not improve to Grade 1 
severity within the re-treatment period OR requires systemic treatment 
should go off protocol treatment  
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.  
Any grade 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying 
organ pathology with electrolyte replacement, hormone replacement, 
insulin or that does not require treatment does not require 
discontinuation. 
5.5 
Supportive Care and Concomitant Treatments  
All supportive measures consistent with optimal patient care will be given 
throughout the study. There is no mandatory supportive care recommended for 
study therapy, but general guidelines and doses for specific symptoms are 
outlined above in the dose modification section.  
5.5.1 
Concomitant Systemic Treatments 
Chemotherapy: Participants are not allowed to receive other 
anticancer treatment such as chemotherapy while on this trial. 
Other Medications: See Appendix VII for a list of prohibited 
medications and medications which are permissible but should be 
used with caution with cabozantinib. 
5.5.1.1 
Cytochrome P450 substrates 
Please refer to the Flockhart drug interaction tables for lists 
of substrates, inducers, and inhibitors of selected CYP450 
isozyme pathways (Flockhart 2007) 
http://medicine.iupui.edu/clinpharm/ddis/ 
The FDA drug interaction tables are another source of lists 
of inducers and inhibitors. “Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers” 


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https://www.fda.gov/drugs/developmentapprovalprocess/d
evelopmentresources/druginteractionslabeling/ucm093664
.htm 
Potent CYP3A4 inducers (see Appendix VII) are not 
allowed due to interaction with the metabolism of 
cabozantinib. Dexamethasone can be used with caution 
but alternate medications should be considered.  
Potent CYP3A4 inhibitors should be avoided. Selection of 
alternate concomitant medications with no or minimal 
CYP3A4 enzyme inhibition potential is recommended. 
Consider dose reduction of cabozantinib in the event of 
drug interaction. 
NOTE: 
Grapefruit / grapefruit juice and Seville oranges 
are also strong CYP3A4 inhibitors and 
consumption should be avoided.  
Drugs Associated with QTcF Prolongation 
Treatment with cabozantinib has been associated with a 
mild prolongation of the QTcF interval. Caution should be 
used when treating subjects on cabozantinib with other 
drugs associated with QTcF prolongation. Additional QTcF 
monitoring is suggested for subjects who are treated 
concomitantly with QTcF prolonging drugs. 
5.5.1.2 
Other Drugs 
Concomitant medications that are highly protein bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol) 
should be used with caution.  Because warfarin is a highly 
protein bound drug with a low therapeutic index, 
administration of warfarin at therapeutic doses should be 
avoided in subjects receiving cabozantinib due to the 
potential for a protein binding displacement interaction. 
In vitro data suggest that cabozantinib is unlikely to be a 
substrate for P glycoprotein, but it does appear to have the 
potential to inhibit the P-glycoprotein transport activity. 
Therefore, cabozantinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-
glycoprotein. 
Cabozantinib was also shown to be a substrate of drug 
transporter MRP2 in an in vitro assay. Administration of 
MRP2 inhibitors to subjects may result in increases in 
cabozantinib plasma concentrations. 
Additional details regarding potential drug interactions with 
cabozantinib can be found in the investigator brochure. 
5.5.1.3 
Bone Resorption Inhibitors 
Bisphosphonates or denosumab should not be added 
while on study. Patients on these agents prior to 


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registration are allowed to continue but caution is advised 
due to increased risk of osteonecrosis of the jaw.  
5.5.1.4 
Gastric Acid Inhibitors 
Administration of the PPI esomeprazole resulted in no 
clinically-relevant effect on cabozantinib plasma PK in 
healthy volunteers (Study XL184-018). Therefore, 
concomitant use of gastric pH modifying agents (ie, PPIs, 
H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib.  
Cimetidine should be avoided due to potential CYP 
interactions. 
5.5.1.5 
Anticoagulants 
Anticoagulation with LMWH and unfractionated heparin is 
permitted. Low-dose aspirin use is permitted (100mg daily 
or lower) 
No anticoagulation with warfarin or other coumarin-related 
agents, direct thrombin or direct FXa inhibitors, 
fodaparinux, antiplatelet agents such as clopidogrel, or 
aspirin above low dose levels. 
5.5.2 
Radiation Therapy 
Radiotherapy for symptomatic management of non-target areas is 
allowed for up to 10 total fractions of treatment while on trial. 
Cabozantinib should be held for at least 7 days prior to radiation 
starting, preferably up to 28 days if feasible. Cabozantinib should 
continue to be held on days of radiotherapy and for 14 days (2 weeks) 
after if the radiation is to bone, and for 28 days (4 weeks) for other 
sites of radiation. Immunotherapy may be continued except on days of 
radiation. 
5.5.3 
Invasive Procedures 
Minor procedures (not involving general anesthesia) are allowed on 
the study but are discouraged. These include chest tube placement 
and invasive dental procedures. For patients receiving cabozantinib, it 
is recommended that patients discontinue treatment 28 days prior and 
resume treatment after complete wound healing has occurred. 
Patients undergoing major surgical procedures may only resume 
treatment with the approval of the Study Chair. 
5.6 
Patient Reported Outcome Measures: Tobacco Use Assessment 
Assessments will be captured directly from the participants using the EASEE-
PRO portal. When patients consent to participate, they will be asked to provide a 
contact email address and that address along with their registration information 
will be sent directly from the parent trial’s registration system to EASEE-PRO, 
and the patient will be automatically registered into EASEE-PRO for participation. 
To activate their account for self-directed web entry of surveys, the system will 
send an activation message to the contact email address that will explain how to 
activate their account for self-directed web entry of surveys. After their account is 


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activated, the patient will be able to complete questionnaires using a secure 
browser interface from any web enabled computer, tablet, or mobile device. 
The Core and Extension C-TUQ items will be assessed, together with patient-
reported physical and psychological symptoms (See Table 2). Specifically, these 
items will be administered using the EASEE-PRO system described in the 
companion EA NCORP application. The advantage of our virtual electronic data 
capture system is that our proposed assessments will not be limited to, or 
dependent upon, patient trial visits.  Confidential and potentially stigmatizing 
information can be provided without requiring direct contact with the care team. 
The selected Core and Extension C-TUQ items (from categories of Basic 
Tobacco Use Information, Tobacco Use in Relation to Cancer Diagnosis and 
Treatment, Smoking Cessation/Cessation Products/Assistance Methods, Use of 
Other Products, and Second-Hand Smoke Exposure) will be assessed. The 4-
item Short Form PROMIS® for anxiety and depression, the Lung Cancer Stigma 
Scale, and six symptom items (general pain, fatigue, nausea, cough, sleep 
difficulties, shortness of breath) from FACIT (Functional Assessment of Chronic 
Illness Therapy) together with modifications of these same six questions to 
address the degree of bother associated with each symptom will be administered 
as well. Additionally, we will ask participants’ perceptions of how smoking 
improves or worsens each of the six symptom experience. All these items will be 
compiled into Survey of Tobacco Use (STU). Detailed information on various 
measures is outlined in Appendix VI. 
Contents and Corresponding Questions in Survey of Tobacco Use (STU) 
Dimension 
Source of Measures 
Baseline 
STU 
Follow-up 
STU 
Basic Tobacco Use 
Information 
C-TUQ 
Q1 – Q5 
Q1 – Q2 
Tobacco Use in Relation to 
Cancer Diagnosis and 
Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance 
Methods 
C-TUQ 
Q8 – Q13 
Q4 – Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke 
Exposure 
C-TUQ 
Q15 – Q16 
Q11 – Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma 
Scale 
Q17 – Q18 
Q13 – Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20 – 21 
 
NOTE: 
In order to minimize ambiguity and assure that patients are oriented to 
answer appropriately, the specific phrasing of items may vary 
depending specific cancer type and treatment. 
i. 
Assessment Schedule 
Survey of Tobacco Use will be administered at the following time points: 
Rev. Add2 


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1. at baseline (trial enrollment) 
2. at 3 month follow-up from study registration 
3. at 6 month follow-up from study registration 
5.7 
Duration of Therapy  
Patients will receive protocol therapy unless: 
· 
Patient declines further treatment to withdrawal of consent (Note that patients 
may decline further treatment without withdrawing consent for follow-up. The 
different levels of consent withdrawal should be documented in 
iMedidata/Rave 
· 
Disease progression by RECIST 1.1 criteria or clinically determined 
progression.  
NOTE: 
Patients with disease progression by RECIST 1.1 may be 
continued on treatment as long as they are believed to still have 
potential clinical benefit from the study therapy and are otherwise 
medically stable. Generally this is most appropriate for patients 
with mild asymptomatic radiographic progression. 
· 
Non-protocol anticancer therapies are administered (as outlined in Section 
5.5, above) 
· 
All study drugs have been held for more than 56 days, unless study chair 
approves resuming therapy after this point. 
· 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA5152 Forms Packet. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for radiographic response until progression, even if non-
protocol therapy is initiated, and for survival for 5 years following treatment 
discontinuation. All patients must also be followed through completion of all 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be re-evaluated for response 
approximately every 8 weeks.  
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009] with 
measurements performed at the imaging sites. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration.  
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers. 
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. It is sometimes permissible to 
not re-image all non-target lesions at every timepoint, for example, if 
there are non-clinically significant bone lesions outside of the normal 
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6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area may be considered measurable if they have grown 
subsequent to previous radiation. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be  
≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
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. 
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.   


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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 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
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used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (usually with IV contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
6.1.4 
Response Criteria 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. For Arm T patients, to be 
assigned a status of complete response, changes in tumor 
measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for 
response are first met.  Arm A, B, and C patients do not 
require confirmation scans for CR. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. For Arm T patients, to be assigned a status of 
partial response, changes in tumor measurements must be 


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confirmed by repeat assessments performed no less than 
four weeks after the criteria for response are first met.  Arm 
A, B, and C patients do not require confirmation scans for 
CR. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.2. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 7 weeks (as 
scans are ideally performed every 8 weeks).   
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 


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basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) it increases in size and there is new pathological 
confirmation that it is disease (regardless of size). 
A new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
criteria. 
For Arm T patients, to be assigned a status of complete or 
partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than 
four weeks after the criteria for response are first met. Arm 
A, B, and C patients do not require confirmation scans for 
complete or partial response. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 7 weeks. 


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For Arm A, B, C Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 7 wks. from study entry 
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. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
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For Arm T Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
Confirmation needed: ≥ 4 
weeks confirmation**** 
CR 
Non-CR/Non-PD*** 
No 
PR 
Confirmation needed: ≥ 4 
weeks confirmation**** 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 7 wks. from study entry 
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. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
**** It is recommended that the confirmation be obtained at the next scheduled evaluation 
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. 
6.1.4.5 
First Documentation of Response (for Arm T patients only) 
The time between initiation of therapy and first 
documentation of PR or CR. 
6.1.4.6 
Confirmation of Response (for Arm T patients only) 
To be assigned a status of complete or partial response, 
changes in tumor measurements must be confirmed by 
repeat assessments performed no less than four weeks 
after the criteria for response are first met. 
6.1.4.7 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease 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. 


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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. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after entry to that step at a minimum interval 7 weeks. 
6.2 
Exploratory imaging correlatives: 
Imaging correlatives performed for this study will be performed using the baseline 
study and 1st 3 follow-up time points, when available. All CT and FDG-PET/CT 
imaging data obtained for patients participating in this clinical trial at baseline and 
through the first 3 follow-up imaging time points will be de-identified and 
uploaded from the study site into Transmission of Imaging and Data (TRIAD®) 
database and delivered to the ACR Imaging Core Laboratory within 48 hrs. of 
completion. Using this submitted imaging data, the following measurements will 
be performed. 
6.2.1 
RECIST1.1 (central review) 
Measurements of RECIST1.1 response will be performed as 
described in Section 6.1 with time point and overall best response 
assessments categorized as complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD). 
These measurements will be performed by the central review and will 
only be used for analyses for the exploratory imaging correlatives. 
6.2.2 
Uni-dimensional immune related criteria (iRRC): (central review) 
Measurements of iRRC response will be performed as described by 
Nishino et al (Nishino ref) with time point and over all response 
assessments categorized as complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD). 
As per the iRRC, assessments of PD will be deferred to the following 
reimaging time point (performed at least 4 weeks later). Therefore, in 
patients with progressive disease, this criteria can only be performed 
on the patients that are maintained on therapy following evidence of 
progression on imaging with subsequent re-imaging acquired during 
the imaging window specified by the criteria. As such, this criteria will 
only be calculated on study patients with the available imaging. 
6.2.2.1 
Definitions 
Evaluable disease 
As detailed for RECIST1.1 in Section 6.1.1 
Measureable disease 
As detailed for RECIST1.1 in Section 6.1.2 with the 
following differences. Since iRRC is a metric of tumor 
burden, disease measured at each imaging time point 
includes up to 5 target lesions/organ (10 maximum visceral 
target lesions) and up to 5 new target lesions/organ 


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(maximum 10 new visceral lesions) to be included in the 
sum of disease measurement at each time point. 
Tumor Burden = SumIndex lesions + Sumnew lesions 
6.2.2.2 
Target lesion assessment by Unidimensional Immune 
related Response Criteria (irRC) 
Immune response Complete Response (irCR), partial 
response (irPR) and stable disease (irSD) 
As per RECIST1.1 (Section 6.1.4.1) noting that target 
lesion sums calculated at each imaging time point include 
baseline target and new target lesions. 
Progressive disease (irPD) 
At least a 20% increase in the sum of the diameters of the 
sums of target lesions and new 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. If a 
patient is classified as having irPD at a post-baseline tumor 
assessment, then confirmation of irPD by a second scan 
is required. Since imaging is being acquired for SOC, this 
will also be possible for patients that have the available 
imaging and are maintained on therapy beyond evidence 
of progression on imaging. 
NOTE: 
The appearance of one or more new lesions is 
NOT automatically considered progression with 
the uni-dimensional irRC. 
6.2.2.3 
Non Non-measureable disease assessment by uni-
dimensional irRC. 
Immune related Complete Response (irCR): 
Disappearance of all non-measurable lesions. All lymph 
nodes must be non-pathological in size (< 10 mm short 
axis) 
Immune related Non-CR/Non-PD: Persistence of one or 
more non-measureable lesion(s. 
Immune related Progressive Disease (irPD): Non-
measurable disease does not contribute to PD. 
6.2.2.4 
Best overall response by iRRC 
For iRRC the best overall response (iBOR) is the best 
timepoint response recorded from the start of the study 
treatment until the end of treatment, taking into account 
any requirement for confirmation. 


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6.2.3 
Immune Response Evaluation Criteria in Solid Tumors (iRECIST: 
central review only 
Measurements of iRECIST response will be performed as described 
by Seymour et al (Seymour ref) with time point and over all response 
assessments categorized as immune complete response (iCR), 
immune partial response (iPR), immune stable disease (iSD), immune 
unconfirmed progressive disease (iUPD) and confirmed progressive 
disease (iCPD). 
As per the iRECIST, all assessments of iUPD will be confirmed at 
subsequent reimaging (4-8 weeks later). Therefore, in patients with 
progressive disease, this criteria can only be performed on the 
patients that are maintained on therapy following evidence of 
progression on imaging with subsequent re-imaging acquired during 
the imaging window specified by the criteria. As such, this criteria will 
only be calculated on study patients with the available imaging. 
6.2.3.1 
Definitions 
Evaluable disease 
As detailed for RECIST1.1 in Section 6.1.1 
Measureable disease 
As detailed for RECIST1.1 in Section 6.1.2 with the 
following differences. New target lesions are tabulated 
separately, measured with unidimensional measurements 
and summed separately. New lesions should be 
considered measureable or non-measureable by 
RECIST1.1 criteria principles (see Section 6.1.2). Up to 2 
new target lesions/organ (maximum 5 new visceral lesions) 
to be included in the sum of new lesions which are 
tabulated and summed separately at each time point 
6.2.3.2 
Assessment of target lesions by Immune Response 
Evaluation Criteria in Solid Tumor Criteria (iRECIST) 
Immune Complete Response (iCR), partial response (iPR) 
and stable disease (iSD) 
iCR, iPR and iSD are calculated in a manner identical to 
RECIST1.1 
Unconfirmed Progressive Disease (iUPD) 
iRECIST defines iUPD using RECIST1.1 principles for 
progression namely a requirement for at least a 20% 
increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered to meet the criteria for iUPD, 
Measurements for new lesions are tabulated 
separately (not included in the sum of baseline 


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target lesions) and considered separately at 
subsequent re-imaging (4-8 weeks later). 
Confirmation of PD at subsequent re-imaging is necessary 
for iUPD to become iCPD. 
Confirmed Progressive Disease (iCPD) 
Assessment for possible iCPD occurs at re-imaging 4-8 
weeks following an assessment of iUPD which is done on 
the basis of observing either a further increase in size in 
the lesion category in which progression was first identified 
in (ie, target or non-target disease), or progression (defined 
by RECIST 1.1) in lesion categories that had not previously 
met RECIST 1.1 progression criteria. For the new lesion 
category, iUPD is considered confirmed if the sum of the 
new lesions increases by greater than 5 mm or new 
lesions appear. 
NOTE: 
If iUPD is not confirmed by further progression 
of the tumor (see iCPD), however tumor 
shrinkage occurs and meets the criteria for iCR, 
iPR, iSD, then the bar is reset so that iUPD 
needs to occur again (compared with nadir 
values) and then be confirmed (by further 
growth) at the next assessment for iCPD to be 
assigned. 
If no change in tumor size or extent from iUPD occurs, 
then the timepoint response would again be iUPD 
6.2.3.3 
Assessment of non-target lesions by iRECIST 
The iRECIST assessment of non-target lesions at each 
timepoint follows similar principles to evaluation of the 
iRECIST target lesions. iUPD (but not iCPD) can have 
been documented before iCR or when the criteria for 
neither CR nor PD have been met (referred to as non-
iCPD/non-iUPD) and can be assigned several times, as 
long as iCPD was not confirmed. iUPD is defined by 
RECIST 1.1 criteria; however, iUPD can be assigned 
multiple times as long as iCPD is not confirmed at the next 
assessment. Progressive disease in the non-target lesion 
category is confirmed if subsequent imaging, done 4–8 
weeks after iUPD, shows a further increase from iUPD. 
The criteria for iCPD are not judged to have been met if 
RECIST 1.1 criteria for complete response or non-iCR/non-
iUPD are met after a previous iUPD. The status is reset 
(unlike RECIST 1.1) and iCR, or non-iCR/non-iUPD is 
assigned; if no change is detected, the timepoint response 
is iUPD.) 
6.2.3.4 
Assessment of Best overall Response by iRECIST 
For iRECIST, the best overall response (iBOR) is the best 
timepoint response recorded from the start of the study 


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treatment until the end of treatment, taking into account 
any requirement for confirmation. iUPD will not override a 
subsequent best overall response of iSD, iPR, or iCR, 
meaning that iPR or iSD can be assigned (timepoint 
response or iBOR) even if new lesions have not regressed, 
or if unequivocal progression (non-target lesions) remains 
unchanged, providing that the criteria for iCPD are not met. 
6.2.4 
Image Acquisition 
6.2.4.1 
CT Exam Acquisition 
Recognizing that this protocol is collecting standard of care 
(SOC) imaging, the following imaging parameters have 
been chosen as a guide to accommodate a variety of Multi-
Detector CT Scanners. It is recommended that the imaging 
studies be acquired in full inspiration. 
Series 
Guideline 
Scout/Topogram 
· 100 kv 
· 10-40 mA 
· Aquire on inspiration 
Axial 
· Slice Thickness/Spacing: 
Standard of Care 
· mA: As Low As 
Reasonably Attainable 
· Dose Modulation: On – if 
available 
· Aquire on Inspiration 
Post Processing 
Reconstructions from 
Raw Data 
· Axial Plane (Optional) 
· Slice Thickness: 1mm 
· Slice Spacing: 1mm 
· Soft Tissue Algorithm 
(Kernel) 
· Bone/Lung Algorithm 
(Kernel) 
· Sagittal Plane (optional) 
· Slice Thickness: 1mm 
· Slice Spacing: 1mm 
· Soft Tissue Algorithm 
(Kernel) 
· Bone/Lung Algorithm 
(Kernel) 
· Coronal Plane (optional) 
· Slice Thickness: 1mm 
· Slice Spacing: 1mm 
· Soft Tissue Algorithm 
(Kernel) 
· Bone/Lung Algorithm 
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6.3 
Submission of Images for Central Review 
6.3.1 
Each participating site is required to submit all acquired diagnostic 
and follow-up images of study participants to the ACR Imaging Core 
Laboratory. Imaging should be submitted to the ACR Imaging Core 
Lab via TRIAD 4 and any associated data forms should be completed 
within 48 hours of acquisition. Prompt submission of all image data is 
essential to ensure adequate image quality assessment. 
6.3.2 
TRIAD® is ACR’s proprietary image exchange application that will be 
used as the sole method of data transfer to the ACR Clinical 
Research Center Core Laboratory for this trial. The TRIAD application 
can then be configured as a DICOM destination on either scanner(s) 
and/or PACS system for direct network transfer of study related 
images into the TRIAD directory. 
TRIAD Access Requirements: 
· 
Staff who will submit images through TRIAD will need to be 
registered with The Cancer Therapy Evaluation Program (CTEP) 
and have a valid and active CTEP Identity and Access 
Management (IAM) account. Please refer to the beginning of 
Section 4 for instructions on how to request a CTEP-IAM account. 
· 
To submit images, the user must be assigned the 'TRIAD site 
user' role on the relevant Group or CTSU roster. ECOG-ACRIN 
users should contact your site Lead RA to be added to your site 
roster. 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. Support and information on 
installation of TRIAD can be found at 
https://triadhelp.acr.org/clinicaltrials. The TRIAD helpdesk can be 
reached at TRIAD-Support@acr.org. This process can be done in 
parallel to obtaining your CTEP-IAM account username and 
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7. 
Therapeutic Parameters  
7.1 
Step 1: Therapeutic Parameters 
Treatment should start within seven working days after registration (see Section 5) 
 
Screening1 
Cycle 11,2 
(day 1) 
Cycle 1 mid2 
(day 15) 
Cycle 22  
(day 29) 
Cycle 2 mid2 
(day 43) 
Cycle 3+2 
(day 57) 
Post Treatment 
Follow Up3 
History and physical exam5 
X 
X 
X 
X 
X 
 X 
X 
Performance status, vital signs5 
X 
X 
X 
X 
X 
 X 
 
Complete blood count with 
differential6 
X 
 
X 
X 
X 
X 
 
Blood chemistry tests7 
X 
 
X 
X 
X 
X 
 
PT/INR and PTT 
X 
 
 
 
 
 
 
Thyroid tests (TSH and reflex free 
T4)4 
X 
 
 
X 
 
X 
 
Electrocardiogram (ECG)4 
X 
 
 
X 
 
X 
 
Echocardiogram/MUGA8 
X 
 
 
 
 
 
 
Urine protein assessment9 
X 
 
 
X 
 
X 
 
Serum or Urine Pregnancy Test10 
X 
 
 
 
 
 
 
Toxicity Assessment 
 
X 
X 
X 
X 
X 
X 
Tumor assessment imaging11,16 
X 
 
 
 
 
   X11 
 X3 
Brain Imaging12 
  X12 
 
 
 
 
   X12 
 
Nivolumab (Arms A, B, C, T) 
 
X 
 
X 
 
X 
 
Cabozantinib (Arms B, C, T)18 
 
X 
X 
X 
X 
X 
 
Ipilimumab (Arm C) 
 
X 
 
 
 
   X15 
 
MANDATORY: Tumor Tissue14 
X 
 
 
 
 
 
 
Tobacco Use Assessment PROs17 
See Section 5.6 
Cycle Length = 28 days 
1.  All baseline assessments must be done ≤ 2 weeks before registration with the exception of imaging studies that must be done ≤ 4 weeks before 
registration and brain imaging studies that must be done ≤ 12 weeks before registration in patients without known brain metastases. Patients 


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with known brain metastases at baseline must have a brain MRI or head CT with contrast ≤ 4 weeks prior to registration. All baseline laboratory 
tests can be used for Cycle 1 Day 1 treatment purposes. 
2. Window for study visits and drug administration is ± 3 days. Mid-cycle 1 and 2 visits are required for all arms. Starting with cycle 3, in-person visit 
by investigator is only required once per cycle. 
NOTE: 
All hematology and chemistry assessments must be done ≤ 72 hours prior to day 1 of the treatment cycle except for Cycle 1 Day 1 
(see footnote 1). 
3. Every 3 months until patient is 5 years from registration. Physical exam not required. If in person visit is not possible, patient should be contacted 
for follow up of vital status and assessment of any study-related toxicities until resolution. For patients that discontinued study therapy prior to 
radiographic progressive disease, tumor assessments should be performed at least every 3 months during long term follow up until progressive 
disease is documented. 
4. Screening TSH and reflex free T4 to be done only if clinically indicated. Every cycle (4 weeks) for these tests. ECG, TSH and reflex free T4 for 
all arms. ECG required to monitor patients on cabozantinib containing arms for QTcF ≤ 500 msec, and monitor for evidence of myocarditis on all 
arms. 
5. Smoking status and height are to be collected once prior to treatment. ECOG performance status. Vital signs include heart rate, blood pressure, 
O2 saturation, respiratory rate, and weight. 
6. CBCs (with differential and platelet count) includes WBC, ANC, Platelets, Hgb, and Hct and must be done ≤ 72hours prior to day 1 of the 
treatment cycle, except for Cycle 1 Day 1 they may be performed within 2 weeks of registration. 
7. Blood chemistry tests include measurement of magnesium and phosphorus plus comprehensive metabolic panel (ALT, AST, alkaline 
phosphatase, bilirubin, creatinine, blood urea nitrogen, calcium, sodium, potassium, albumin, chloride, and bicarbonate (or CO2). All blood 
chemistries must be done ≤ 72 hours prior to day 1 of the treatment cycle, except for Cycle 1 Day 1 they may be performed within 2 weeks of 
registration. 
8. Baseline Echocardiogram OR MUGA to evaluate ejection fraction to be performed during screening ONLY as clinically indicated - in patients 
with a history of CHF or at risk because of underlying cardiovascular disease or prior exposure to cardiotoxic drugs. 
9. Urine protein analysis required at screening, then only for patients receiving cabozantinib (Arms B, C, T). Urine dipstick at baseline must be < 1 
+ (0 or “trace”) or Urine Protein Creatinine (UPC) must have been performed  If urine dipstick results are ≥ 1+, UPC ratio is clinically indicated 
and Section 5 should be referred to for management. 
10. Women of childbearing potential only. All women of childbearing potential must have a negative pregnancy test ≤ 2 weeks before registration.  
11. All efforts must be made to assess tumor from the same type of scan that was performed at baseline. A CT scan with contrast involving known 
systemic areas of disease is recommended.  Imagine studies should be done within 4 weeks prior to registration and every 8 weeks (based on 
Cycle 1 Day 1) during treatment until PD. The imaging should be done within 7 days prior to cycle 3, 5, 7, 9 etc. but may be performed after the 
treatment for unusual circumstances such as holidays. If drugs are held, the imaging should still be performed every 8 weeks counting from 
Cycle 1 Day 1. 
12. Patients must have a brain MRI or head CT with contrast at baseline within 12 weeks prior to registration.  Patients with known brain metastases 
at baseline must have a brain MRI or head CT within 4 weeks prior to registration.  Patients with known brain metastases should have repeat 
imaging at least every 16 weeks (4 cycles). Repeat brain imaging is not required for patients without known brain metastases at baseline. 
13. Tumor tissue specimens are required to be submitted for defined laboratory research studies as outlined in Section 10.  
14. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
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15. Ipilimumab administration every 8 weeks (cycle 1, 3, 5, 7, etc.) 
16. For Arm T patients, to be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for response are first met. Arm A, B, and C patients do not require confirmation 
scans for complete or partial response. 
17. Tobacco use assessment PROs will be collected using EASEE-PRO. 
18. Oral daily dosing 


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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
Drug Ordering: Bristol-Myers Squibb and Exelixis are supplying Nivolumab, Ipilimumab, 
and Cabozantinib, through the Division of Cancer Treatment and Diagnosis, NCI, for this 
protocol. Maintenance of NCI drug accountability records is required. Drugs may be 
requested by the Principal Investigator (or their authorized designees) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
drug be shipped directly to the institution where the patient is to be treated. PMB does 
not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained – see general information). 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 investigator at that institution. 
No starter supplies will be provided. Study agents must be ordered after the patient is 
enrolled on the assigned treatment arm. If expedited shipment is required, sites should 
provide an express courier account through the Online Agent Order Processing (OAOP) 
application. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status 
and a “current” password. For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time. Refer to the PMB’s website for specific 
policies and guidelines related to agent management. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available on the NCI 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  
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.  
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Investigator Brochure Availability: The current versions of the IBs for the agents will 
be accessible to site investigators and research staff through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password.  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) 
8.1 
Cabozantinib (NSC 761968 
8.1.1 
Other Names 
XL-184, Cabozantinib s-malate, EXEL-7184, EXEL-02977184, 
Cabometyx® 
8.1.2 
Classification 
Receptor Tyrosine Kinases Inhibitor (RTK) 
8.1.3 
Mode of Action 
XL184 inhibits multiple RTKs implicated in tumor growth, metastasis, 
and angiogenesis, and targets primarily MET and VEGFR2.  Other 
targets are VEGFR3, RET, AXL, KIT, TIE-2, FLT-3, ROS1, and RON. 
8.1.4 
How Supplied  
XL184 is supplied by Exelixis and distributed by the DCTD.  XL184 
will be provided in 20 mg tablets.  The tablets are yellow film coated 
containing cabozantinib malate equivalent to 20 mg and 60 mg of 
cabozantinib.  The 20 mg tablets have a round shape and they are 
packaged as 30 tablets per bottle. 
XL184 should be dispensed in its original container; however, XL184 
tablets can be dispensed in a pill cup with an expiration date not to 
exceed 24 hours.  It can also be repackaged in a pharmacy 
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XL184 Tablet Components and Composition 
Ingredient 
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
8.1.5 
Storage and Stability  
Store intact bottles at controlled room temperature, 20° to 25°C (68°F 
to 77°F); temperature excursions are permitted between 15°C and 
30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 
If a storage temperature excursion is identified, promptly return XL 
184 (Cabozantinib) to 20° to 25°C (68° to 77°F) and quarantine the 
supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
Stability testing of the intact bottles is on-going.  XL184 is stable up to 
24 hours when dispensed in an open container such as a pill cup, and 
up to 7 days when dispensed in a closed container such as a 
pharmacy bottle other than the original container. 
8.1.6 
Dose Specifics  
See Section 5 for dosing guidelines.  
8.1.7 
Route of Administration 
Oral  
8.1.8 
Method of Administration  
Take XL184 on an empty stomach; i.e., do not eat 2 hours before or 1 
hour after each dose of XL184.  Do not crush or chew.  Do not take 
missed dose within 12 hours of the next dose. 
8.1.9 
Incompatibilities 
CYP450 isozymes: 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of 
CYP2C9.  In healthy volunteers, XL184 AUC increased 38% with co-
administration of ketoconazole, a strong inhibitor of CYP3A4, and 
decreased by 77% with a strong CYP3A4 inducer rifampin.  
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Therefore, avoid chronic use of strong CYP3A4 inducers such as 
rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifampentin, phenobarbital, and St. John’s Wort while taking XL184. 
Avoid chronic use of strong CYP3A4 inhibitors such as ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir. Use alternative medications.  
NOTE: 
Use caution when discontinuing medication that is a strong 
inducer of CYP3A4 in patients who has been on a stable 
dose of XL184, as this could significantly increase the 
exposure to XL184. 
XL184 is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 µM), a 
mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 µM) and 
CYP2C19 (Kiapp = 28.8 µM), and a weak competitive inhibitor of 
CYP3A4 (estimated Kiapp = 282 µM) in human liver microsomal 
(HLM).  IC50 values >20 µM were observed for CYP1A2, CYP2D6, 
and CYP3A4 isozymes.  XL184 is an inducer of CYP1A1 mRNA in 
human hepatocyte incubations, 
Avoid grapefruit/ grapefruit juice and Seville oranges while 
participating in this trial. 
P-glycoprotein/ MRP2: 
In vitro data indicate that XL184 is an inhibitor of P-glycoprotein 
transport activity (IC50 = 7.0 µM). Co-administration of XL184 with a 
P-gp substrate may result in an increase in P-gp substrate plasma 
concentration.  Therefore, use caution when administering XL-184 
with drugs known to be P-gp substrates (e.g., fexofenadine, aliskiren, 
ambrisentan, digoxin, colchicine, maraviroc, posaconazole, tolvaptan, 
etc.). 
XL184 is also a substrate of drug transporter MRP2, which may result 
in an increase plasma concentration of XL184 when administered with 
an inhibitor of MRP2.  Use caution and monitor adverse events when 
administering XL184 with MRP2 inhibitors such as cyclosporine, 
delavirine, efavirenz, emtricitabine. 
Protein bound: 
XL184 is highly protein bound (≥ 99.9%).  Use caution when 
coadministering XL184 with medications that are highly protein-bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol).  Avoid 
administration of warfarin with XL184 as warfarin is highly protein-
bound and has a very narrow therapeutic index. 
Antacids, H2-blockers, PPIs: 
Co-administration of gastric pH modifying drugs such as PPI, H2-
blockers or antacids has no clinically-relevant effect on XL184 plasma 
PK in healthy volunteers; thus, concomitant use of these drugs with 
XL184 is allowed. 
QTc prolongation: 
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receiving antiarrhythmic drugs.  Concomitant use of strong CYP3A4 
inhibitors should be avoided as it may increase XL184 plasma 
concentrations.  Refer to the protocol for QTcF criteria.  
Potential Food Effect 
A high fat meal increased both XL184 Cmax and AUC values by 41% 
and 57%, respectively relative to fasted conditions; therefore, XL184 
should be taken on an empty stomach (fasting is required 2 hours 
before and 1 hour after each XL184 dose). 
8.1.10 
Side Effects 
See Section 5.3 for side effects.  
8.1.11 
Nursing/Patient Implications  
Do not take grapefruit/ grapefruit juice or Seville oranges while 
participating in this trial.  Inform physician and study healthcare team 
about current medications including over the counter drugs, herbals, 
or natural medicines.  Refer to the protocol for management of 
adverse events. 
8.2 
Nivolumab (NSC 748726) 
8.2.1 
Other Names  
BMS-936558, MDX1106 
8.2.2 
Classification  
Anti-PD-1MAb 
8.2.3 
Mode of Action 
Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is 
a negative regulatory receptor expressed by activated T and B 
lymphocytes. Binding of PD-1 to its ligands, programmed death–
ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-
L1 and PD-L2.  Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell 
responses to both foreign antigens as well as self-antigens. 
8.2.4 
Description 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow 
liquid; light (few) particulates may be present. The drug product is a 
sterile, nonpyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 
(Tween® 80), and water for injection. Dilute solutions of hydrochloric 
acid and/or sodium hydroxide may be used for pH adjustment (pH 
5.5-6.5). 
8.2.5 
Storage and Stability  
Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and 
protected from light and freezing. The unopened vials can be stored at 
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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. 
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 (20°-25°C, 68°-77°F) and 
room light.  The maximum 8-hour period under room temperature and 
room light conditions includes the product administration period. 
CAUTION:  The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent.  Therefore, it is advised that the 
product be discarded 8 hours after initial entry. 
8.2.6 
Dose Specifics  
See Section 5 for dosing guidelines.   
8.2.7 
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 (eg, 240 mg, 360 mg, or 480 mg 
flat dose), nivolumab injection can be infused undiluted or diluted so 
as not to exceed a total 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. 
8.2.8 
Route of Administration 
Intravenous infusion over 30 minutes.  Do not administer as an IV 
push or bolus injection. Administer through a 0.2 micron to 1.2 micron 
pore size, low-protein binding (polyethersulfone membrane) in-line 
filter. 
8.2.9 
Incompatibilities  
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 nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug 
interaction. 
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8.2.10 
Availability  
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg 
vials (10 mg/mL) with a 0.7mL overfill.  It is supplied in 10 mL type I 
flint glass vials, with fluoropolymer film-laminated rubber stoppers and 
aluminum seals. 
8.2.11 
Side Effects  
See Section 5.3 for side effects 
8.2.12 
Nursing/Patient Implications  
Women of childbearing potential (WOCBP) receiving nivolumab must 
continue contraception for a period of 5 months after the last dose of 
nivolumab. Men receiving nivolumab and who are sexually active with 
WOCBP must continue contraception for a period of 7 months after 
the last dose of nivolumab. 
8.3 
Ipilimumab (NSC 732442) 
8.3.1 
Other Names  
Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
8.3.2 
Classification 
Human monoclonal antibody 
8.3.3 
Mode of Action  
Ipilimumab is specific for the CTLA4 antigen expressed on a subset of 
activated T-cells. CTLA4 interaction with the B7 molecule, one of its 
ligands expressed on professional antigen presenting cells, can down-
regulate T-cell response. Ipilimumab is, thought to act by blocking the 
interaction of CTLA4 with the B7 ligand, resulting in a blockade of the 
inhibitory effect of T-cell activation.  The CTLA4/B7 creates the 
interaction. 
8.3.4 
Description 
Ipilimumab is a fully human immunoglobulin (IgG1κ) with two 
manufacturing processes – ongoing trials have been using 
substances manufactured using Process B. New clinical trials will be 
using ipilimumab that is manufactured by Process C. The Process C 
has been developed using a higher producing sub-clone of the current 
Master Cell Bank, and modified cell culture and purification steps. 
8.3.5 
Storage and Stability 
Store intact vials refrigerated at (2° to 8° C), protected from light.  Do 
not freeze. 
Shelf-life surveillance of the intact vials is ongoing. 
 Solution as described above is stable up to 24 hours refrigerated at 
(2° to 8° C) or at room temperature/ room light.  
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  
Use prepared IV solution immediately. Discard partially used vials. 
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8.3.6 
Dose Specifics  
Dose adjustments do not need to be made every cycle for weight 
changes < 10% (but may if that is usual local practice). Dose must be 
adjusted if weight changes by 10% or more from the dosing weight.  
See Section 5.1. 
8.3.7 
Preparation 
Do not shake. Allow the vials to stand at room temperature for 
approximately 5 minutes prior to preparation of infusion. Ipilimumab is 
given undiluted or further diluted in 0.9% NaCl Injection, USP or 5% 
Dextrose Injection, USP in concentrations between 1 mg/mL and 4 
mg/mL.  Ipilimumab is stable in a polyvinyl chloride (PVC), non-
PVC/non DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass container 
up to 24 hours refrigerated at (2° to 8° C) or at room temperature/ 
room light. 
Recommended safety measures for preparation and handling include 
protective clothing, gloves, and safety cabinets. 
8.3.8 
Route and Method of Administration 
Intravenous infusion over 90 minutes. Do not administer ipilimumab 
as an IV push or bolus injection.  
Can use a volumetric pump to infuse ipilimumab at the protocol-
specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, 
sterile, non-pyrogenic, low-protein-binding filter (0.2 micron to 1.2 
micron). 
8.3.9 
Availability 
Bristol-Myers-Squibb (BMS) supplies ipilimumab to the DCTD/NCI. 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a 
clear to slightly opalescent, colorless to pale yellow, sterile, 
nonpyrogenic, single-use, isotonic aqueous solution that may contain 
particles. 
Each vial is a Type I flint glass vial with gray butyl stoppers and 
sealed with aluminum seals. 
8.3.10 
Side Effects 
See Section 5.3 for details. 
8.3.11 
Nursing/Patient Implications 
Monitor patients for immune-related adverse events, e.g., rash/vitiligo, 
diarrhea/colitis, uveitis/episcleritis, hepatitis and hypothyroidism.  If 
you suspect toxicity, refer to the protocol guidelines for ruling out other 
causes. 
Women of childbearing potential should be advised to continue 
contraception for 3 months following the last dose of ipilimumab 
Post-marketing surveillance identified a fatal toxic epidermal 
necrolysis (TEN) event in a patient who received ipilimumab after 
experiencing a severe or life-threatening skin adverse reaction on a 
prior cancer immune stimulating therapy. Caution should be used 
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when considering the use of ipilimumab in a patient who has 
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9. 
Statistical Considerations 
9.1 
Study Design and Objectives 
Main study: This is a randomized phase II study comparing nivolumab (N) to the 
combination of nivolumab with cabozantinib (NC) and to the combination of 
nivolumab with cabozantinib and ipilimumab (NCI) in patients with 2nd line 
metastatic non-squamous non-small cell lung cancer. Prior therapy must have 
included one line of platinum-based chemotherapy, and must not have included 
any prior MET/PD-L1/PD-1 inhibitors. Patients must also not have any known 
activating mutations in EGFR, ALK, ROS1, RET or MET amplification/MET 
mutations, except for the targeted sub-arm below. 
The primary objective of the trial is to determine whether combination therapy 
including nivolumab and cabozantinib or nivolumab and cabozantinib and 
ipilimumab extends progression-free survival (PFS) for this patient population as 
compared to nivolumab alone. Secondary objectives include estimation of overall 
survival, best objective response, and toxicity. 
Targeted cohort sub-study: A separate arm (Arm T) will evaluate the efficacy of 
the combination of nivolumab and cabozantinib in patients with NSCLC tumor 
subtypes predicted to be sensitive to targeted agent cabozantinib (MET exon 14 
mutations, MET amplification/other mutations, ROS1 rearrangement, RET 
rearrangement). 
9.2 
Study Endpoints 
Main study: Progression-free survival (PFS) is defined as the time from 
randomization to documented disease progression (site review of imaging) or 
death from any cause, whichever occurs first. Patients who have not experienced 
an event of interest by the time of analysis will be censored at the date they are 
last known to be alive and progression-free. Overall survival is defined as the 
time from randomization to death from any cause, and patients who are thought 
to be alive at the time of final analysis will be censored at the last date of contact. 
Best objective response will be evaluated via RECIST1.1 criteria, as described in 
Section 6 of this protocol document. Toxicity will be determined using the CTCAE 
criteria. 
Targeted therapy sub-study: This group will be evaluated by PFS, overall 
survival, best objective response rate, and toxicity as above. 
Exploratory Imaging Correlative Study: For RECIST1.1 (central review) and irRC 
PFS is defined as the time from randomization to documented disease 
progression or death from any cause, whichever occurs first. For iRECIST, PFS 
is defined as the date of the time from randomization to documented disease 
progression (date of the documented iUPD that is followed by subsequent iCPD) 
or death from any cause, whichever occurs first. 
For the imaging correlatives, overall survival is defined as the time from 
randomization to death from any cause, and patients who are thought to be alive 
at the time of final analysis will be censored at the last date of contact. Best 
objective response will be evaluated for all three criteria performed by central 
review as defined in Section 6 of this protocol document. 
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9.3 
Statistical Analysis Plan 
The primary and some secondary analyses will include all eligible and treated 
patients. Exceptions to this include: analysis of toxicity data, which will include all 
patients who received study drug regardless of eligibility, and analyses of 
response, which will include eligible and treated patients with measurable and 
evaluable disease.  
Time-to-event data, such as PFS and OS, will be estimated using the Kaplan-
Meier method, and Cox proportional hazards models will be used to estimate the 
treatment hazard ratios. The primary comparison of PFS will use a logrank test 
stratified on the randomization stratification factors with a one-sided type I error 
rate of 10%. Other comparisons of groups will be made using the logrank test 
and Cox modeling. 
Categorical data, such as response rates (CR+PR) and toxicity, will be compared 
using Fisher’s exact tests with a one-sided type I error rate of 10%; multivariable 
logistic regression modeling will be used to adjust for the effect of any covariates 
that are associated with these categorical outcomes. Though none are currently 
planned, any continuous outcomes will be analyzed using Wilcoxon rank sum 
test, and multivariable linear regression models may be used to adjust for 
multiple associations with outcome.  
Modeling procedures will implement backward selection; variables significant at 
the 0.10 level in the univariate setting will be chosen for inclusion in an initial full 
model, and at each step the least significant variable will be removed from the 
model. Only those covariates with p<0.05 will remain in any final models, unless 
there are factors identified by the study team as crucial to model interpretation.  
Point estimates of all endpoints will be accompanied by the corresponding two-
sided 80% confidence intervals. 
In the event that there are missing data, no imputation of the missing data will be 
conducted. We will assume that data are missing at random and will conduct all 
analyses as originally planned because we do not anticipate an excess of 
missing data.  
Subset analyses are planned for all stratification factors and all known prognostic 
factors, such as performance status, age, sites of metastases, gender, etc. 
Subset analyses of all variables, including correlatives, are considered to be 
exploratory in nature. 
9.4 
Sample Size Considerations 
The overall sample size for the trial is 169 patients.  
Main study: The primary comparison will include all eligible and treated patients, 
of whom 129 will be accrued and randomized equally, for a total accrual of 43 
patients per arm. After adjusting for an ineligibility rate of 10%, the total required 
sample size for randomization is 144 patients. Using an overall one-sided 0.10 
level log rank test for each comparison, this study will have 89% power to detect 
a 44% reduction in the PFS hazard rate of 0.173 to 0.096 based on the estimated 
accrual and follow-up period. Assuming exponential survival, this corresponds to 
an 80% improvement in the median PFS of 4 months on nivolumab alone to 7.2 
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ipilimumab. The number of PFS events needed to achieve this power is 74 
events under the alternative hypothesis for each of the two primary comparisons. 
Targeted therapy sub-study: Up to 25 additional patients may be enrolled in Arm 
T. The best objective response rate and PFS will be described for this group of 
patients. Accrual to the study will stop when the total accrual goal for the 
randomized study is reached, even if 25 patients have not been enrolled to Arm 
T. If 25 patients enroll to Arm T before accrual to the randomized part of the 
study is reached, then Arm T only will be closed. With 25 patients enrolled, the 
maximum width of the 2-sided 90% exact binomial confidence interval for the 
best objective response rate will be 35%; with as few as 10 patients enrolled, it 
will be 56%. 
9.5 
Projected Accrual 
As reflected by our prior E1512 study, it is estimated that patient accrual will be 
approximately 10 patients per month. It is estimated that the accrual goal will be 
reached within approximately 15 months with a follow up period of approximately 
9-10 months, for a total study duration of 25 months. 
9.6 
Gender and Ethnicity 
Based on previous data from E1512 the anticipated accrual in subgroups defined 
by gender and race is: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
4 
1 
0 
0 
5 
Asian  
1 
1 
0 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
1 
1 
0 
0 
2 
Black or African American 
6 
7 
0 
0 
13 
White 
78 
65 
1 
1 
145 
More Than One Race 
1 
1 
0 
0 
2 
Total 
91 
76 
1 
1 
169 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses.  Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
9.7 
Randomization Scheme 
Main study: Randomization to treatment will be determined using permuted 
blocks within strata with dynamic balancing on main ECOG-ACRIN institutions 
plus affiliates. The randomization will be stratified by known PD-L1 status 
(negative vs. positive (≥ 1%) vs. unknown/not tested). It will be a 1:1:1 between 
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9.8 
Monitoring Plan 
9.8.1 
Interim Analysis: Efficacy 
Main study: This study will also be monitored for futility and one 
interim analysis at roughly 50% information is planned for each 
comparison. At that time, if the point estimate of the PFS hazard ratio 
is consistent with detriment (HR > 1.0) on either of the two 
combination arms, then the data monitoring committee may consider 
terminating an arm early for overall lack of treatment difference. 
9.8.2 
Interim Analysis: Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-
ACRIN studies. Reports of these analyses are sent to the ECOG-
ACRIN Principal Investigator or Senior Investigator at the participating 
institutions. Expedited reporting of certain adverse events is required, 
as described in Section 5.2. 
Because this is the first time that ipilimumab is being combined with 
nivolumab and cabozantinib in this population, close monitoring of 
toxicity is an important endpoint of the trial. We will collect data and 
conduct an interim safety analysis among the first 15 patients who 
have completed the first two cycles of treatment on each arm. This will 
be done without a planned suspension to accrual. The safety analysis 
will be done based on the case report form database and the CTEP-
AERS database, although the focus will largely be placed on the 
CTEP-AERS data. The safety data will be reviewed with the sponsor 
(CTEP) to rule out the incidence of excessive toxicities. This 
preliminary toxicity analysis will occur in addition to the twice yearly 
monitoring for toxicity for the purposes of interim reporting.  
In particular, there is concern for excessive rates of pneumonitis or 
colitis on the 3-drug regimen. With respect to colitis, prior studies have 
demonstrated that grade 3-5 colitis occurs in approximately 11% of 
patients with nivolumab and ipilimumab therapy. As such, if we 
observe 5 or more patients with grade 3-5 treatment-related colitis 
among 15 patients analyzed per arm, the lower bound of the two-
sided 90% exact binomial confidence interval will have exceeded 11% 
and consideration may be given to terminating the arm associated 
with the higher rate of colitis.  
With respect to pneumonitis, a similar approach will be used. Prior 
studies have demonstrated that grade 3-5 pneumonitis occurs in 
approximately 3% of patients treated with nivolumab and ipilimumab. 
Therefore, if we observe 3 or more grade 3-5 incidents of treatment-
related pneumonitis in a cohort of 15 patients, then the lower bound of 
the two-sided 90% exact binomial confidence interval will have 
exceeded 3% and consideration may be given to terminating the arm 
associated with the higher rate of pneumonitis. 
9.9 
Tobacco Use Assessment 
Detailed statistical considerations are outlined in Appendix VIII 
 
Rev. Add2 


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10. 
Specimen Submissions 
Tumor tissue specimens must be submitted for defined laboratory research studies 
described in Section 11. 
It is required that all specimens submitted on this trial be entered and tracked using the 
ECOG-ACRIN Sample Tracking System (see Section 10.2). An STS shipping manifest 
form is to be included with every submission. 
All specimens must be labeled clearly with the ECOG-ACRIN protocol number 
(EA5152), ECOG-ACRIN patient sequence number, patient’s initials, collection date, and 
specimen type.  
10.1 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
If you have any questions concerning tumor tissue submission please contact the 
ECOG-ACRIN CBPF at (844) 744-2420 or eacbpf@mdanderson.org 
10.1.1 
Pathological Material Submission 
Representative tumor tissue specimens are to be submitted for 
defined laboratory research studies within one month of 
randomization. 
Submitting pathologist and clinical research associate may refer to 
Appendix I which outlines the Pathology Submission Guidelines. 
The tumor tissue specimens are to be labeled with the institution’s 
assigned pathology ID# as well as the information above. 
10.1.1.1 
Required Materials 
Forms: Must be submitted with all pathology submissions. 
· 
STS generated shipping manifest form 
· 
Copy of the institutional pathology report 
· 
Immunological study reports, if available 
Tumor Tissue Submission: 
· 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block 
NOTE: 
If blocks are unavailable for submission, cores 
and slides are to be submitted. All cores and 
slides must be adequately labeled, with slides 
numbered sequentially in the order cut. 
Alternative submission requirements: 
· 
One (1) H&E slide  
· 
Twenty (20) 5 µm unstained, uncharged, 
air-dried plus slides from the thickest part of 
the tumor 
· 
One (1) or more core punches (minimum of 
4mm diameter). If core punch tool is 
unavailable, request core punch kit from the 
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Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the ECOG-
ACRIN CBPF (eacbpf@mdanderson.org) to obtain 
alternative submission requirements. 
10.1.2 
Shipping Procedures 
Pathology materials are to be shipped at ambient temperature within 
one month following randomization. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all specimen submissions.  
10.2 
ECOG-ACRIN Sample Tracking System  
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 


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An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.3 
Use of Specimens in Research 
Digitally scanned H&E slides will be distributed to NeoGenomics Laboratories for 
PD-L1 Immunohistochemistry. See Section 11 for the description of the 
laboratory research studies to be performed. 
Specimens from patients who consented to allow their specimens to be used for 
future undefined research studies will be retained in an ECOG-ACRIN 
designated central repository.  
NOTE: Specimens will not be used for future research studies that are not 
defined in this protocol until an amendment to this treatment protocol or 
a separate correlative science protocol is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). 
Any residual blocks will be available for purposes of individual patient 
management on specific written request. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the 
institution.  All other specimens will be destroyed per guidelines of the respective 
repository. 
10.4 
Sample Inventory Submission Guidelines  
Inventories of all specimens submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of specimens forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 
 


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11. 
Laboratory Research Studies 
11.1 
Reference PD-L1 Testing and Correlation with Outcome.  
Reason for study: We propose to do PD-L1 testing on tumor tissue obtained for 
this study. In the CheckMate 057 nivolumab trial, improvements in overall 
survival and progression-free survival were predicted by PD-L1 expression on 
tumors. [8] However, some patients that responded did not have tumor PD-L1 
expression. This biomarker was approved as a complementary diagnostic test to 
help predict the probability of response in patients who receive this therapy. It 
may not be done routinely under standard of care on patients enrolled in this 
study.  
Since patients on both arms will be receiving nivolumab, we are integrating this 
test primarily to identify potential imbalances with regard to PD-L1 status.  We 
are not proposing real-time testing because this would likely result in delays of 
treatment. Thus, we will batch test retrospectively and use this test to adjust the 
outcome results for the impact of PD-L1 expression status in multivariable 
models. We expect PD-L1 positive patients to have a PFS approximately double 
that of PD-L1 negative patients (PFS HR = 0.5) and will use this to adjust our 
outcome models.  
Test details:  
Test: PD-L1 IHC 28-8 pharmDx test  
Formalin-fixed paraffin embedded tumor tissue (blocks or slides) will be collected 
at baseline. Archival specimens from prior biopsies are allowed. Cytologic 
specimens are allowed as long as they contain sufficient material for routine 
immunohistochemical testing. 
This study is FDA approved and used for clinical care. Results from this testing 
will be used to retrospectively determine PD-L1 positivity in tumor specimens 
from this trial to evaluate its association with progression-free and overall 
survival, as well as RECIST response. 
Specimens will be batched and analyzed at one central laboratory. This will be 
performed by the CLIA certified laboratory, NeoGenomics. This test will be 
performed by standard immunohistochemical methods as per the FDA approved 
criteria. More information is available here:  
http://www.neogenomics.com/t_test/pd-l1/ 
Results will be reported as a percentage of tumor positivity ranging from 0-100%. 
Categories will be determined at the time of analysis, which may include any of 
the following or other cutpoints not listed below: 
< 1% (zero) expression 
≥ 1% expression 
≥ 5% expression 
≥ 10% expression 


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11.2 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off 
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12. 
Electronic Data Capture 
Please refer to the EA5152 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed in Medidata Rave and EASEE-PRO (for 
tobacco use assessment). 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP bust of data. Reports are due January 31, April 30, 
July 31, and October 31. Instructions for submitting data using the CDUS can be found 
on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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ipilimumab in advanced melanoma.  N Engl J Med.  369:122-133. 
69. 
Woo, S.R., M.E. Turnis, M.V. Goldberg, et al.  (2012).  Immune inhibitory 
molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote 
tumoral immune escape.  Cancer Res.  72:917-927. 
70. 
Wu, C., Y. Zhu, J. Jiang, et al.  (2006).  Immunohistochemical localization of 
programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical 
significance.  Acta Histochem.  108:19-24. 
71. 
Zitvogel, L., A. Tesniere, and G. Kroemer.  (2006).  Cancer despite 
immunosurveillance: immunoselection and immunosubversion.  Nat Rev 
Immunol.  6:715-727. 
72. 
Benson, A.B. 3rd, J.A. Ajani, R.B. Catalano, et al.  (2004).  Recommended 
guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol.  
22:2918-2926.  
73. 
Birchmeier, C., W. Birchmeier, E. Gherardi, and G.F. Vande Woude.  (2003).  
Met, metastasis, motility and more.  Nat Rev Mol Cell Biol.  4:915-925. 
74. 
Boccaccio, C., and P.M. Comoglio.  (2006).  Invasive growth: a MET-driven 
genetic programme for cancer and stem cells.  Nat Rev Cancer.  6:637-645. 


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Christensen, J.G., J. Burrows, and R. Salgia.  (2005).  c-Met as a target for 
human cancer and characterization of inhibitors for therapeutic intervention.  
Cancer Lett.  225:1-26. 
76. 
Comoglio, P.M., S. Giordano, and L. Trusolino.  (2008).  Drug development of 
MET inhibitors: targeting oncogene addiction and expedience.  Nat Rev Drug 
Discov.  7:504-516. 
77. 
Investigator's Brochure.  (2016).  Investigator's Brochure for XL184.  Exelixis, 
Inc., South San Francisco, CA. 
78. 
Investigator's Brochure.  (2016).  Investigator's Brochure for Cabozantinib 
(XL184).  Exelixis, Inc., South San Francisco, CA. 
79. 
Jeffers, M., L. Schmidt, N. Nakaigawa, et al.  (1997).  Activating mutations for the 
met tyrosine kinase receptor in human cancer.  Proc Natl Acad Sci U S A.  
94:11445-11450. 
80. 
Kurzrock, R., S.I. Sherman, D.W. Ball, et al.  (2011).  Activity of XL184 
(Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid 
cancer.  J Clin Oncol.  29:2660-2666. 
81. 
Liu, X., R.C. Newton, and P.A. Scherle.  (2010).  Developing c-MET pathway 
inhibitors for cancer therapy: progress and challenges.  Trends Mol Med.  16:37-
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82. 
Paez-Ribes M., E. Allen, J. Hudock, et al. (2009).  Antiangiogenic therapy elicits 
malignant progression of tumors to increased local invasion and distant 
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83. 
Roskoski, R., Jr.  (2008).  VEGF receptor protein-tyrosine kinases: structure and 
regulation.  Biochem Biophys Res Commun.  375:287-291. 
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Schmidt, L., F.M. Duh, F. Chen, et al.  (1997).  Germline and somatic mutations 
in the tyrosine kinase domain of the MET proto-oncogene in papillary renal 
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85. 
Sennino, B., R.M. Naylor, S.P. Tabruyn, et al.  (2009).  Abstract A13:  Reduction 
of tumor invasiveness and metastasis and prolongation of survival of RIP-Tag2 
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Tugues, S., S. Koch, L. Gualandi, et al.  (2011).  Vascular endothelial growth 
factors and receptors: anti-angiogenic therapy in the treatment of cancer.  Mol 
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87. 
Yakes, F.M., J. Chen, J. Tan, et al.  (2011).  Cabozantinib (XL184), a novel MET 
and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, 
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You, W.K., B. Sennino, C.W. Williamson, et al.  (2011). VEGF and c-Met 
blockade amplify angiogenesis inhibition in pancreatic islet cancer.  Cancer Res.  
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Zhang, S., H. Zhau, A. Osunkoya, et al.  (2010).  Vascular endothelial growth 
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Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
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Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer 
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Squamous NSCLC 
 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 


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Guidelines for Submission of Pathology Materials 
 
The following pathology materials are to be submitted within one (1) month of randomization:  
1. Pathology Submissions: 
· 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue block 
NOTE: If blocks are unavailable for submission, cores and slides are to be submitted. All 
cores and slides must be adequately labeled, with slides numbered sequentially 
in the order cut. Alternative submission requirements: 
· 
One (1) H&E slide  
· 
Twenty (20) 5 µm unstained, uncharged air-dried plus slides from the thickest 
part of the tumor 
· 
One (1) or more core punches (minimum of 4mm diameter). If core punch 
tool is unavailable, request core punch kit from the ECOG-ACRIN CBPF 
(844) 744-2420 
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
2. Forms and Reports: 
NOTE: Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 
will be used only to identify patient materials, and will help to expedite any 
required communications with the institution (including pathologists). 
The following items are to be included with the pathology materials: 
· 
Institutional Pathology Report 
· 
ECOG-ACRIN Generic Specimen Submission Form (#2981) [if STS is unavailable] 
· 
Sample Tracking System (STS) Shipping Manifest Form  
· 
Immunological study reports, if available 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility by telephone: (844) 744-2420 or email: eacbpf@mdanderson.org 


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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA5152: A Randomized Phase 
II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and Cabozantinib 
Plus Nivolumab Plus Ipilimumab in Patients with Previously Treated 
Non-Squamous NSCLC 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for defined laboratory research 
studies.  
Keep a copy of the submission for your records and return any relevant completed 
forms, the surgical pathology report(s), the slides and/or blocks and any other required 
material to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology materials to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF). 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future research studies per patient consent.  Paraffin blocks will be 
returned upon written request for purposes of patient management. 
Please note: Since blocks are being used for laboratory research studies, in some cases 
the material may be depleted, and, therefore, the block may not be returned.  
If you have any questions regarding this request, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility at (1-844-744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 


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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 


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Appendix III 
 
Patient Pill Calendar 
 
Cabozantinib Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. Do not eat 2 hours before or 1 hour after each dose of cabozantinib. Do not crush or 
chew pills. 
3. If you forget, the missed pills will not be taken later. 
4. Please bring the empty bottle or any leftover tablets and your  
pill calendar to your next clinic visit. 
 


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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take each day.  
You should take your scheduled dose of each pill. Note the times and the number of tablets 
that you take each day. If you develop any side effects, please record them and anything you 
would like to tell the doctor in the space provided. Bring any unused tablets and your completed 
pill calendar to your doctor’s visits. 
DAY 
Date 
 
 
Month   Day   
Year 
Time pills 
taken 
 
 
(AM   or   PM) 
Number of 
pills taken 
 
 
(AM  or  PM) 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 


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Appendix IV 
 
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) 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 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 


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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: 
ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 


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


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Appendix VI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on Nivolumab, 
Cabozantinib, or Ipilimumab, or within 28 days of the female patient’s last dose of 
Nivolumab, Cabozantinib, or Ipilimumab must be reported in an expeditious manner. The 
outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
For this study, a pregnancy, suspected pregnancy (including a positive or inconclusive 
pregnancy test) must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave.  
Once the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the pregnancy requires expedited reporting.  
The CTEP-AERS report must then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website. 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report, accessed via Medidata Rave report 
within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
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.  
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status in CTEP-AERs accessed 
via Medidata Rave. 
· 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Rev. Add1 
Rev. Add3 
Rev. Add4 


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Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.   
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself. 
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new and 
separate CTEP-AERs report should be initiated (via Medidata Rave) reporting the outcome 
of the pregnancy. To do this, report the pregnancy on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle/Post Registration folder in Medidata 
Rave. The CTEP-AERS report must then be initiated directly from the Adverse Event/Late 
Adverse Event Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
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.  For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
For this study, it must initially be reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the adverse event requires expedited reporting. 
The CTEP-AERS report must then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website. The pregnancy loss must be reported as a Grade 4 “Pregnancy Loss” under 
the System Organ Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention.  However, for this protocol, any neonatal death that 
occurs within 28 days of birth, without regard to causality, AND any infant death after 28 
days that is suspected of being related to the in utero exposure to Nivolumab, Cabozantinib, 
or Ipilimumab, must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the event is entered into Rave, the Rules engine on the Expedited Reporting Evaluation 
Form will confirm whether or not the event requires expedited reporting. The CTEP-AERS 
report must then be initiated directly from the Expedited Reporting Evaluation Form in 
Medidata Rave.  Do not initiate the CTEP-AERS report via the CTEP-AERS website.  The 
neonatal death must be reported as a Grade 4 “Death neonatal” under the System Organ 
Class (SOC) “General disorder and administration site conditions”. 


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A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.pdf) 


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A Randomized Phase II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and 
Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients with Previously Treated Non-
Squamous NSCLC 
 
Appendix VII 
 
Prohibited Medications and Medications to Use with Caution 
NOTE: This is not an exhaustive list. More information and references may be found in 
the protocol, Section 5.5.1. 
Prohibited Medications 
Strong CYP3A4 inducers  
Carbamazepine 
Modafinil 
Phenobarbital 
Phenytoin 
Rifampin, rifabutin, rifapentin 
St. John’s Wort 
CYP3A4 inhibitors  
Cimetidine  
Grapefruit / grapefruit juice and Seville oranges 
Warfarin (May result in increased INR) 
Medications to use with caution 
Warfarin  
Strong CYP3A4 inducers:  
Dexamethasone 
Strong CYP3A4 inhibitors:  
Clarithromycin, ketoconazole, itraconazole, indinavir, nefazodone, nelfinavir, and 
ritonavir 
Protein bound drugs 
Diazepam, furosemide, dicloxacillin, and propranolol 
Bone resorption inhibitors: 
Bisphosphonates, denosumab 
Gastric Acid Inhibitors 
Proton pump inhibitors - omeprazole, lansoprazole, rabeprazole, pantoprazole, and 
esomeprazole 
H2 blockers (cimetidine which is prohibited) - ranitidine, famotidine, and nizatidine 
Drugs associated with QTcF prolongation including the following (for full list see 
http://www.qtdrugs.org/) 


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High Risk of Torsades:  
Amiodarone, Azithromycin, Bepridil, Chloroquine, Chlorpromazine, Cisapride, 
Citalopram, Clarithromycin, Dofetilide, Erythromycin, Flecainide, Haloperidol, Ibutilide, 
Methadone, Moxifloxacin, Pentamidine, Procainamide, Quinidine, Sotalol, Terfenadine, 
Thioridazine  
Possible Risk of Torsades:  
Amantadine, Atazanavir, Clozapine, Dolasetron, Escitalopram, Famotidine, Felbamate, 
Foscarnet, Fosphenytoin, Gatifloxacin, Granisetron, Levofloxacin, Lithium, Moexipril, 
Nicardipine, Octreotide, Ofloxacin, Ondansetron, Paliperidone, Quetiapine, Risperidone, 
Tacrolimus, Tamoxifen, Telithromycin, Tizanidine, Vardenafil, Venlafaxine, Voriconazole, 
Ziprasidone 
Conditional Risk of Torsades:  
Amitriptyline, Ciprofloxacin, Clomipramine, Desipramine, Diphenhydramine, Doxepin, 
Fluconazole, Fluoxetine, Imipramine, Itraconazole, Ketoconazole, Nortriptyline, 
Paroxetine, Protriptyline, Ritonavir, Sertraline, Trazodone, Trimethoprim-Sulfa, 
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Appendix VIII 
 
Ancillary for Tobacco Use Assessment: EAQ16T 
Study Co-Chairs:  Elyse Park, Ilana Gareen, Lynne Wagner, Jamie Ostroff, Ben Herman 
Patients registered to selected ECOG-ACRIN trials are eligible to participate in this ancillary 
study, once the appropriate amendment incorporating the study is activated. 
The Ancillary for Tobacco Use Assessment is a project that seeks to address questions about 
patient-reported tobacco use and smoking behaviors that may span several studies and/or 
diseases. The tobacco use ancillary is embedded into parent protocols, with participation in the 
ancillary informed in the parent consent form and participation determined via providing email 
address to the sites. The general objectives of the tobacco use ancillary are not specific to any 
single parent protocol; however, specific objectives may be included in the parent or related 
parent protocols. 
A significant proportion of cancer patients are current smokers at the time of cancer diagnosis,1–
5 and there are known risks associated with continued smoking following cancer diagnosis. 
These include decreased survival time; increased complications from surgery, radiation, and 
chemotherapy; and increased risk of second primary tumors.6–11 As such, the National 
Comprehensive Cancer Network (NCCN), the American Association of Cancer Research 
(AACR) and the American Society of Clinical Oncology (ASCO) have identified persistent 
smoking as a modifiable risk factor and recommend cessation counseling for cancer patients 
who smoke. Although evidence-based guidelines for treating tobacco dependence exist,12 they 
have not yet been well-integrated into cancer care settings. Moreover, knowledge regarding the 
scope and patterns of tobacco use among cancer patients is limited.  As a critical step in closing 
this knowledge gap, the NCI-AACR Cancer Patient Tobacco Use Asssessment Task Force 
developed the Cancer Patient Tobacco Use 1–4,13,14 Questionnaire (C-TUQ). Through this 
ancillary, the modified C-TUQ measures will be administered to participants enrolling in selected 
Phase II and Phase III ECOG ACRIN (EA) therapeutic trials. 
The major questions may be summarized: 
1. What is the smoking status of cancer patients enrolled on EA clinical trials? 
2. Do patients quit smoking or try to quit smoking after receiving a cancer diagnosis? 
3. What forms of tobacco use do patients engage in? 
4. What assistance do patients use or receive to try to quit? 
5. How does tobacco use, other forms of tobacco use, and/or environmental tobacco exposure 
affect patient’s treatment toxicity, patient-reported physical and psychological symptoms, 
trial adherence, and therapeutic outcomes? 
When patients consent to participate, they will be asked to provide a contact email address and 
that address along with their registration information will be sent directly from the parent trial’s 
registration system to ECOG-ACRIN Systems for Easy Entry of Patient Reported Outcomes 
(EASEE-PRO), and the patient will be automatically registered into EASEE-PRO for 
participation.  To activate their account for self-directed web entry of surveys, the system will 
send an activation message to the contact email address that will explain how to activate their 
account for self-directed web entry of surveys.  After their account is activated, the patient will 


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be able to complete questionnaires using a secure browser interface from any web enabled 
computer, tablet, or mobile device. 
Measures 
The selected Core and Extension C-TUQ items will be assessed. The 4-item Short Form 
PROMIS® for anxiety and depression, the Lung Cancer Stigma Scale, and six symptom items 
(general pain, fatigue, nausea, cough, insomnia, shortness of breath) from FACIT (Functional 
Assessment of Chronic Illness Therapy)) together with modifications of these same six 
questions to address the degree of bother associated with each symptom will be administered 
as well. Additionally, we will ask participants’ perceptions of how smoking improves or worsens 
each of the six symptom experience. All these items will be compiled into Survey of Tobacco 
Use (STU) (baseline and follow-up). 
Contents and Corresponding Questions in Survey of Tobacco Use (STU) 
Dimension 
Source of Measures 
Baseline STU 
Follow-up STU 
Basic Tobacco Use Information 
C-TUQ 
Q1 – Q5 
Q1 – Q2 
Tobacco Use in Relation to Cancer 
Diagnosis and Treatment 
C-TUQ 
Q6 – Q7 
Q3 
Smoking Cessation, Cessation 
Products, and Assistance Methods 
C-TUQ 
Q8 – Q13 
Q4 – Q9 
Use of Other Products  
C-TUQ 
Q14 
Q10 
Second-Hand Smoke Exposure 
C-TUQ 
Q15 – Q16 
Q11 – Q12 
Psychological Symptoms 
PROMIS  
Lung Cancer Stigma 
Scale 
Q17 – Q18 
Q13 – Q14 
Physical Symptoms 
FACIT 
Q19 
Q15 
Sociodemographics 
 
Q20 – 21 
 
NOTE: 
In order to minimize ambiguity and assure that patients are oriented to answer 
appropriately, the specific phrasing of items may vary depending specific cancer type 
and treatment. 
Tobacco Use. The selected Core and Extension C-TUQ items (from categories of Basic 
Tobacco Use Information, Tobacco Use in Relation to Cancer Diagnosis and Treatment, 
Smoking Cessation/Cessation Products/Assistance Methods, Use of Other Products, and 
Second-Hand Smoke Exposure) will be assessed in the baseline and follow-up Survey of 
Tobacco Use. 
Oncology Provider Assistance. C-TUQ Question 13 assesses “cancer doctors” Advise. We 
will add 4 As to assess participants’ reported 5As (Ask (Q12a), Advise (Q12b), Assess (Q12c), 
Assist (Q12d-Q12f), and Arrange follow-up (Q12g), as in Baseline STU).80 
Psychological Symptom Assessment. Anxiety & Depression: (The Patient Reported 
Outcomes Measurement Information System (PROMIS®)). We will administer the 4-item Short 
Form PROMIS® for anxiety and depression (Q17 in Baseline STU).  Stigma: The Lung Cancer 
Stigma scale measures the extent to which shame is internalized (Q18 in Baseline STU).81 
Physical Symptom Assessment Physical Symptom Assessment (Functional Assessment of 
Chronic Illness Therapy (FACIT)). FACIT, a measurement system with a collection of quality-of-
life questionnaires, expands the more familiar FACT (Functional Assessment of Cancer 
Therapy) questionnaires into other chronic illness and conditions. FACIT consists of many 


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individual questions to assess various symptoms from the patient perspective. We will use 6 
FACIT items, selected based on the therapeutic regimens, expected toxicity, and malignancy 
type of the parent trials. In addition, we have created modifications of these same six questions 
to address the degree of bother associated with each symptom” The symptoms of general pain, 
fatigue, nausea, cough, sleep difficulty, and shortness of breath will be assessed, first using the 
standard and validated FACT item, and then asking the degree of “bother” imposed by each 
symptom, on the same 5-point scale. These clusters of symptoms were specifically chosen 
based on potential interactions between tobacco use and longitudinal symptoms. 
Sociodemographic Variables. Sociodemographic variables, including age, sex, zip code, and 
race/ethnicity are collected for all NCTN trial participants at registration.  At baseline, 
participants will provide information on marital status (Q20 in Baseline STU) and education level 
(Q21 in Baseline STU) as part of the tobacco supplemental assessment. 
Cancer Treatment Variables. Clinical variables including date of diagnosis, malignancy type 
(smoking related vs. non-smoking related, cancer stage), and treatment details (i.e. types and 
dates of surgery, chemotherapy, and/or radiation received), along with disease status and 
survival, will be captured in Medidata Rave via the parent protocol and will be available for 
analysis of the ancillary. Provider-assessed adverse events will also be captured via the parent 
protocol in Medidata Rave, using case report forms commonly used across the NCTN and using 
standard data elements. 
Assessments 
All items in Survey of Tobacco Use will be administered using the EASEE-PRO system. The 
advantage of our virtual electronic data capture system is that our proposed assessments will 
not be limited to, or dependent upon, patient trial visits.  Confidential and potentially stigmatizing 
information can be provided without requiring direct contact with the care team. 
Timing of Assessments 
Given the critical questions that remain13 about the timing of conducting tobacco use 
assessments, we have carefully chosen to collect tobacco assessment data at trial enrollment, 3 
and 6 month follow-up.  For tobacco treatment trials, 6 month follow-up is the recommended 
primary outcome time point. By 6 month follow-up, most cancer treatment-related quitting 
activity62, cancer treatment initiation of therapy, and FDA-approved smoking cessation 
medication regimens will be completed. Adverse events during treatment will have been 
observed. 
Statistical Considerations and Analysis Plans 
The analysis plans described below are planned for a combined analysis of the data from the 8 
selected ECOG-ACRIN trials. Consistency in the effects over the studies would be examined in 
this analysis. 
1. CHANGES IN SMOKING STATUS AND EXPOSURE. At baseline, combustible tobacco use 
(1a) will be characterized by smoking status (never smoker, former smoker, and current 
smoker based on Baseline STU Qs 1 and 5), other forms of tobacco use (1b) will be a 
composite variable determined by non-cigarette items (based on Baseline STU Q7 and 
Q14), and environmental tobacco smoke (ETS) level (1c) will be determined by current 
household and work exposure (Baseline STU Qs 15-16). At follow-up, combustible tobacco 
use (1a) will be examined by smoking status (Follow-up STU Qs 1 and 2), other forms of 
tobacco use (1b) will be determined by Follow-up STU Q10, and ETS level (1c) will be 
determined by 30 day household and work exposure (Follow-up STU Qs 11-12). We will 
examine tobacco use at baseline, 3 and 6 month follow-up, and change in status 
(abstinence in combustible tobacco, abstinence of other forms of tobacco use, and change 


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in exposure to smoke-free home and work) using summary statistics (frequency and 
proportion). We will explore the effects of sociodemographic and cancer treatment factors 
on smoking status using logistic regression (comparing smokers and non-smokers). We will 
also evaluate factors associated with changes in smoking status. 
2. TREATMENT TOXICITY. The selected trials capture information about adverse events 
during treatment using NCI’s Common Terminology Criteria for Adverse Events. Toxicities 
are measured at each treatment visit and graded according to severity, with grade 1 
corresponding to mild toxicity and grade 5 signifying a lethal adverse event.  We will 
determine each patient’s worst degree toxicity across all event types and treatment visits 
and will compare the distribution of worst degree grades between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure using exact tests. We will also examine the distribution of worst degree grades 
between users with different form of tobacco use. In addition, we will explore the effects of 
tobacco use on dose modifications (yes vs. no) using logistic regression, with each patient’s 
dose modification status determined across all treatment visits. 
3. SYMPTOM BURDEN. Tobacco variables will be conceptualized as described in the section 
of CHANGES IN SMOKING STATUS AND EXPOSURE. Tobacco use status (as measured 
at baseline, 3 and 6 month follow-up) will be compared to physical and psychological 
symptom burden (as measured at each corresponding time points). At 3 and 6 month follow-
up, we will also examine the association between tobacco use changes and changes in 
symptom burden. We will explore the effects of sociodemographic and cancer treatment 
factors on symptom burden using repeated measures mixed effects models. As an example 
of statistical power, we consider the PROMIS SF-4 depression measure. We assume that 
1500 patients will be enrolled across the 8 parent studies over 13 months, and that 20% are 
smokers. We assume that 85% of patients will have assessments at 6 months. Given 
groups of these sizes (26 quitters and 230 still-smokers) and standard deviation of 4.08 for 
the PROMIS SF-4 depression scale, there will be 83% power to detect a difference in 
change scores of 2.5 between groups using a two-sample t-test with Type I error of 5%.  
The minimally important difference for this instrument is 2.2.79 
4. CESSATION PATTERNS AND TREATMENT. At baseline we will explore pre-treatment 
combustible tobacco use patterns (STU Q6a and Q6b), quitting behaviors (STU Q13), 
behavioral program utilization (STU Q11) and oncology provider support (5As, STU Q12), 
and smoking cessation medication use (STU Q10). At follow-up we will explore post-
treatment combustible tobacco use patterns (STU Q3a-Q3e), quitting behaviors (STU Q9), 
behavioral program utilization (STU, Q7) and oncology provider support (5As, STU Q8), and 
smoking cessation medication use (STU Q6). We will explore the effects of 
sociodemographic and cancer treatment factors on these variables. We will examine 
associations of quitting behaviors and behavioral and medication utilization with tobacco use 
status (as outlined in the section of CHANGES IN SMOKING STATUS AND EXPOSURE) at 
baseline and on respective 3 and 6 month tobacco outcomes. These analyses will be 
descriptive in nature. Summary statistics (frequency, proportions, and 95% confidence 
intervals) will be used. 
5. TRIAL OUTCOMES. We will compare treatment duration between smokers and non-
smokers and between patients with environmental tobacco exposure and those without 
exposure. Cumulative incidence/competing risk methods will be used to estimate time to 
treatment discontinuation for adverse events, disease progression, completion per protocol, 
or other causes. Gray’s test will be used to test for differences in the cumulative incidence 
distributions.78 Differences in the distribution of reasons for discontinuation of treatment will 
be examined using exact tests. Relative dose intensity is defined as the ratio of actually 
delivered dose intensity to the planned dose intensity. The effects of tobacco use and 
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exposure on relative dose intensity (≥ 90% vs. < 90%) will be explored using logistic 
regression. Differences in the primary endpoint and important secondary endpoints will be 
examined using log rank test and exact test (as appropriate). 
Data collected in the tobacco use project will support a range of analyses. Precise estimates of 
power will depend on the prevalence of smoking at baseline among study participants, the 
proportion whose smoking status changes, and the duration and adequacy of follow-up. 
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