A Phase 2 Study of XL184 (Cabozantinib) in Combination With Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas
Phase: PHASE2
Conditions: Metastatic Large Cell Neuroendocrine Carcinoma, Metastatic Neuroendocrine Carcinoma, Metastatic Neuroendocrine Neoplasm, Metastatic Small Cell Neuroendocrine Carcinoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
i 
To:  
CTEP Protocol and Information Office 
   
From: 
 
Adel Mandl, MD 
 
Date:  
August 1, 2025 
 
Protocol:   
10315 A Phase 2 Study of XL184 (Cabozantinib) in Combination with Nivolumab 
and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine 
Carcinomas  
 
Re: 
Amendment #8 to address PIO’s comment from their review of amendment 7. 
 
SUMMARY OF CHANGES – Protocol 
 
I. Comments Requiring a Response – Major Issues: 
# 
Section 
Comments 
1. 
1.2.5, 
1.2.6, 
1.3, 5.8, 
5.9, 
9.4.5 
This amendment (A07) included edits to remove the biomarker-related objectives 
from the protocol.  Please remove the related language in the listed sections. 
Instead, it is suggested to report the following for each relevant objective to 
ClinicalTrials.gov: 
The number of patients with data collected for this outcome measure is zero: insert 
objective. Insert reason. Accordingly, no results will be reported.   
Example reason - This biomarker assay was not performed as there were 
insufficient samples available to interpret the planned correlative studies 
PI Response: Comments related to removing some of the correlative 
objectives have been removed. Corrected subsection numbering within 
section 5.9. 
 
 
SUMMARY OF CHANGES – Consent Form 
 
# 
Section 
Comments 
1. 
Header 
Updated Protocol Version Date. 
 
 
 
 
 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
ii 
To:  
CTEP Protocol and Information Office 
   
From: 
 
Adel Mandl, MD 
 
Date:  
June 3, 2025 
 
Protocol:   
10315 A Phase 2 Study of XL184 (Cabozantinib) in Combination with Nivolumab 
and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine 
Carcinomas  
 
Re: 
Amendment to address PIO’s recommendations from their review of 
amendment 6, replace the Study PI, and update the objectives and correlatives 
that the NCI has determined will not be performed. 
 
SUMMARY OF CHANGES – Protocol 
 
I. Recommendations from PIO’s review of Amendment 6: 
# 
Section 
Comments 
2. 
Cover Page 
Please revise the excerpt below as indicated. 
 
LAO-PA015 / UPMC Hillman University of Pittsburgh Cancer Center 
Institute LAO 
 
PI Response: This site has been updated. 
3. 
Page 2 of 
cover page 
Please delete IND #: 
 on page 2 of cover page and replace with IND 
#: 
 
PI Response: The IND number has been updated. 
4. 
8.1.1 
Please replace the Storage with the following: 
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 outside of 150 C and 300 C (590 F to 
860 F) 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 information has been updated. 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
iii 
# 
Section 
Comments 
5. 
8.1.1  
Please replace the Stability with the following: 
 
Stability:  Refer to the drug label for expiration date.  Dispense XL184 (Cabozantinib) 
in original bottles.  
 
However, if dispensing the exact quantity of cabozantinib tablets is an 
institutional guideline: 
 
• 
Removing the extra tablets from the original bottle is allowed, and it must be 
used within 30 days of the preparation date. Document the extra tablets as 
waste in Oral DARF. 
• 
Adding additional cabozantinib tablets into the original bottle in which the 
original bottle is exceeding its 30 Count bottle, is Not Allowed. 
 
Repackaging XL184 (Cabozantinib) for a short period of time is acceptable and 
limited to: 
 
• 
Up to 24 hours when dispensed in an open container such as a pill cup. 
• 
Up to 7 days when dispensed in a closed container (e.g., a pharmacy 
dispensing bottle).  
PI Response: This information has been updated. 
 
 
II. Requested changes by the PI 
 
# 
Section 
Comments 
6. 
Header,  
Title Page 
Update protocol version date. 
7. 
Title Page 
Removed Dr. Tesfaye as Study PI since he is no longer affiliated as a CTEP 
investigator.  
 
Adding Dr. Mandl as the Study PI. 
 
Removed Dr. Chen as the Translational PI. Funds were not established for 
his work and then the study closed early for futility.  
8. 
1.2.5, 1.2.6, 
1.3, 5.8, 5.9.1, 
5.9.2, 5.10.1, 
5.10.2, 5.10.3, 
5.10.4, 9.4.5 
After discussion with the NCI in April 2025, it was agreed to remove WES 
and RNAseq as secondary objectives and all exploratory correlative 
analyses. The study closed early due to futility and as a result there are 
insufficient samples to provide meaningful interpretation of the data. 
9. 
3.3 
Per the Executive Order, the use of ‘gender’ has been removed. 
 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
iv 
SUMMARY OF CHANGES – Consent Form 
 
# 
Section 
Comments 
2. 
Header 
Updated Protocol Version Date. 
 
 
 
 
 
 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
1 
NCI Protocol #: 
P10315 
 
Local Protocol #: 
TBD 
 
 
ClinicalTrials.gov Identifier:  NCT04079712 
 
TITLE:  A Phase 2 Study of XL184 (Cabozantinib) in Combination with Nivolumab and 
Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas  
 
Corresponding Organization:  LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
 
Principal Investigator: 
 
 
  
Adel Mandl, MD 
Johns Hopkins University 
201 N. Broadway Street, Viragh, Box 7 
Baltimore, MD 21287 
410-955-8827 
amandl1@jhu.edu  
 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician: 
 
Ruizhe Chen, PhD 
 
Johns Hopkins University 
 
550 N. Broadway Street, Suite 1103 
 
Baltimore, MD 21205 
 
Phone: 410-955-4884 
 
Email: rzchen@jhu.edu 
 
Study Contact: 
 
 
Judy Murray, CCRC 
 
Johns Hopkins University 
 
201 N. Broadway Street, Viragh, Box 1 
 
Baltimore, MD 21287 
 
Phone: 443-927-3568 
 
Email: jmurra33@jhmi.edu 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
1 
 
 
NCI-Supplied Agents: XL184 (Cabozantinib) (NSC761968) 
 
Nivolumab (BMS-936558, MDX-1106) (NSC748726) 
 
Ipilimumab (BMS-734016, MDX-010) (NSC732442) 
 
 
IND #:  
 
IND Sponsor:  DCTD, NCI  
 
 
Protocol Type / Version # / Version Date: 
 
Original / May 1, 2019 
Revision 1 / July 22, 2019 
Revision 2 / August 15, 2019 
Revision 3a / September 30, 2019 
Revision 4 / October 18, 2019 
Revision 5 / September 4, 2020 
Revision 6 / September 18, 2020 
Revision 7 / October 20, 2020 (CIRB Approved, CTEP Disapproved) 
Revision 8 / February 22, 2021 
Amendment 4 / August 23, 2024 
Amendment 5 / November 5, 2024 RRA 
Amendment 6 / November 25, 2024 
Amendment 7 / June 3, 2025 Disapproved 
Amendment 8 / August 1, 2025 
 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
2 
SCHEMA 
 
This study is a multicenter phase 2 study of XL184 (cabozantinib) in combination with 
nivolumab and ipilimumab in patients with advanced/metastatic poorly differentiated 
neuroendocrine neoplasms after the failure of at least one line of systemic cancer treatment. 
 
Regimen Description 
Cycles 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
1-4 
XL184 
(cabozantinib) 
XL184 (cabozantinib) 
should be taken on an 
empty stomach.  Patients 
should not eat for at least 
2 hours before, and 1 hour 
after each dose. 
40 mg 
PO 
Days 1-21 
21 days  
(3 weeks) 
Nivolumab 
N/A 
3 mg/kg 
IV 
Day 1 of Cycles 
1-4 
(4 total doses)  
Ipilimumab 
N/A 
1 mg/kg 
IV 
Day 1 of Cycles 
1-4 
(4 total doses) 
5+ 
XL184 
(cabozantinib) 
XL184 (cabozantinib) 
should be taken on an 
empty stomach.  Patients 
should not eat for at least 
2 hours before, and 1 hour 
after each dose. 
40 mg 
PO 
Days 1-28 
28 days 
(4 weeks) 
Nivolumab 
N/A 
480 mg 
IV 
Day 1of Cycles 
5+ 
PO = Oral; IV = Intravenous 
Treatment will be continued until criteria for removal from the study are met (See Section 6.5 
Duration of Therapy) 
 
Treatment will be given on an outpatient basis and includes continuous daily administration of 
XL184 (cabozantinib) 40 mg by mouth (PO).  Nivolumab will be given at a dose of 3 mg/kg on 
Day 1 (±3 days) of each 3-week cycle for the first 4 cycles (12 weeks).  Ipilimumab is to be 
administered at a dose of 1 mg/kg immediately following nivolumab administration on Day 1 of 
each 3-week cycle for the first 4 cycles.  No more than four doses of ipilimumab should be 
administered. 
 
Starting Cycle 5, patients will continue to take cabozantinib 40 mg PO daily and receive IV 
infusion of nivolumab 480 mg every 4 weeks.  Treatment will be continued until criteria for 
removal from the study is met. 
 
 

NCI Protocol #:  10315 
Version Date:   August 1, 2025 
 
3 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease ...........................................................................................................7 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Rationale ................................................................................................................23 
2.4 
Correlative Studies Background ............................................................................24 
3. 
PATIENT SELECTION ....................................................................................................27 
3.1 
Eligibility Criteria ..................................................................................................27 
3.2 
Exclusion Criteria ..................................................................................................29 
3.3 
Inclusion of Women and Minorities ......................................................................33 
4. 
REGISTRATION PROCEDURES ...................................................................................34 
4.1 
Investigator and Research Associate Registration with CTEP ..............................34 
4.2 
Site Registration .....................................................................................................35 
4.3 
Patient Registration ................................................................................................37 
4.4 
General Guidelines .................................................................................................39 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................40 
5.1 
Summary Table for Specimen Collection. .............................................................40 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies .............40 
5.3 
Specimen Procurement Kits and Scheduling .........................................................41 
5.4 
Specimen Tracking System Instructions ................................................................42 
5.5 
Specimen Collection ..............................................................................................46 
5.6 
Shipping Specimens from Clinical Site to the ETCTN Biorepository ..................46 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories .........................48 
5.8 
Biomarker Plan ......................................................................................................48 
5.9 
Integrated Correlative Studies ................................................................................51 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................52 
6. 
TREATMENT PLAN ........................................................................................................55 
6.1 
Agent Administration .............................................................................................55 
6.2 
General Concomitant Medication and Supportive Care Guidelines ......................57 
6.3 
Duration of Therapy ...............................................................................................60 
6.4 
Duration of Follow-Up ..........................................................................................60 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................61 
7.1 
XL184 (Cabozantinib) ...........................................................................................61 

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7.2 
Nivolumab and Ipilimumab ...................................................................................79 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................93 
8.1 
CTEP IND Agents .................................................................................................93 
9. 
STATISTICAL CONSIDERATIONS.............................................................................102 
9.1 
Study Design/Endpoints.......................................................................................102 
9.2 
Sample Size/Accrual Rate ....................................................................................102 
9.3 
Stratification Factors ............................................................................................104 
9.4 
Analysis of Secondary Endpoints ........................................................................104 
9.5 
Reporting and Exclusions ....................................................................................106 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........................107 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ...............107 
10.2 
Adverse Event Characteristics .............................................................................123 
10.3 
Expedited Adverse Event Reporting ....................................................................123 
10.4 
Routine Adverse Event Reporting .......................................................................126 
10.5 
Pregnancy .............................................................................................................126 
10.6 
Secondary Malignancy .........................................................................................127 
10.7 
Second Malignancy ..............................................................................................127 
11. 
STUDY CALENDAR .....................................................................................................128 
12. 
MEASUREMENT OF EFFECT......................................................................................131 
12.1 
Antitumor Effect – Solid Tumors ........................................................................131 
12.2 
Other Response Parameters .................................................................................137 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................138 
13.1 
Study Oversight ...................................................................................................138 
13.2 
Data Reporting .....................................................................................................138 
13.3 
Data Quality Portal ..............................................................................................141 
13.4 
CTEP Multicenter Guidelines ..............................................................................141 
13.5 
Collaborative Agreements Language ...................................................................142 
13.6 
Genomic Data Sharing Plan ................................... Error! Bookmark not defined. 
13.7 
Incidental/Secondary Findings Disclosure Procedure ......... Error! Bookmark not 
defined. 
14. 
REFERENCES ................................................................................................................144 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................151 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE ...................................................................................................152 
APPENDIX C 
PATIENT CLINICAL TRIAL WALLET CARD ...................................153 
APPENDIX D 
PRE-BIOPSY ASSESSMENT ................................................................154 

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APPENDIX E 
PATIENT MEDICATION DIARY .........................................................155 
APPENDIX F: 
NIVOLUMAB AND IPILIMUMAB MANAGEMENT 
ALGORITHMS FOR ENDOCRINOPATHY, GASTROINTESTINAL, 
HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND SKIN 
ADVERSE EVENts.........................................................................................................158 
 
 
 

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6 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To evaluate the overall response rate (ORR) associated with the combination of XL184 
(cabozantinib), nivolumab, and ipilimumab in patients with advanced poorly-
differentiated neuroendocrine carcinomas (NECs), after the failure of at least one line of 
prior therapy. 
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate progression-free survival (PFS). 
 
1.2.2 To measure the safety and tolerability of the combination of XL184 (cabozantinib), 
nivolumab, and ipilimumab in patients with advanced, poorly-differentiated NECs. 
 
1.2.3 To evaluate disease control rate (DCR).  
 
1.2.4 To measure duration of response (DOR). 
 
 
1.2.5 To describe the tumor molecular profile using whole exome sequencing (WES) and 
correlate it with treatment outcome. 
 
1.2.6 To describe the tumor molecular profile using RNA sequencing (RNAseq) and correlate 
it with treatment outcome. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment 
biopsies. 
 
1.3.2 To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and on-
treatment biopsies. 
 
1.3.3 To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and on-
treatment biopsies. 
 
1.3.4 To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and 
infiltrating immune cells. 
 
 
 
 

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2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Neuroendocrine neoplasms (NENs) are rare cancers contributing to 1-2% of cancers diagnosed 
in the western hemisphere (Taal et al., 2004; Basu et al., 2010; Dasari et al., 2017).  Studies 
show a rise in their incidence in the United States (US), from 1.09/100,000 population in 1973 to 
6.98/100,000 in 2012 (Dasari et al., 2017).  This is mostly attributed to increased use of better 
diagnostic imaging.  There are regional reports indicating an incidence of 10.3 per 100,000 
population (Chauhan et al., 2018).  Given the mostly indolent nature of the disease, the 
prevalence is much higher than its incidence.  The gastrointestinal tract is the most common site 
of origin (55-60%), followed by the bronchopulmonary tract (20-30%).  Other sites include 
genitourinary, biliary, soft tissue, and head and neck (Taal et al., 2004; Maggard et al., 2004). 
 
The 2018 WHO classification system reclassified NENs into well differentiated NETs and 
poorly differentiated neuroendocrine carcinomas (NECs) on a morphologic basis (Rindi et al., 
2018).  Based on Ki-67 index or mitotic index, well-differentiated NETs are further classified 
into low-grade (G1, Ki-67 index <3%, mitotic index <2 per 2 mm2); intermediate-grade (G2, Ki-
67 index 3-20%, mitotic index 2-20 per 2 mm2); and high-grade (G3, Ki-67 index >20%, mitotic 
index >20 per 2 mm2).  This reclassification highlights the better understanding of the 
histological subtypes and their importance in the prognosis and treatment of these patients 
(Bosman et al., 2010; Kim et al., 2017).  Tumor grade corresponds to disease virulence in the 
well differentiated NETs.  Median overall survival (OS) is reported to be 16.2 years, 8.3 years, 
and 10 months in low-, intermediate-, and high-grade disease, respectively (Dasari et al., 2017). 
 
Poorly-differentiated NECs can have small cell, large cell, or mixed phenotypes.  It is estimated 
that poorly-differentiated NECs contribute to about 10-20% of all the cases of NENs (Dasari et 
al., 2017; Kang et al., 2017; Yao et al., 2008).  Poorly-differentiated NECs have an aggressive 
clinical course, marked by presentation at a late stage and dismal median overall survival.  A 
report from the Nordic NEC study showed the median OS of patients with gastrointestinal NEC 
to be 11 months with palliative chemotherapy and only 1 month with best supportive care alone 
(Sorbye et al., 2013). 
 
2.1.1 Currently accepted treatment strategies for poorly-differentiated NECs 
 
Poorly-differentiated NECs with small cell phenotype outside of the thorax are generally labelled 
as extra pulmonary small cell carcinomas.  Other phenotypes, large cell, or mixed NECs are also 
seen.  Regardless of the heterogeneity in origin, poorly-differentiated NECs are uniformly fatal 
and are traditionally treated with a platinum and etoposide combination, a regimen used to treat 
small cell carcinoma of the lungs, the efficacy of which was shown in small single-arm studies 
(Mitry et al., 1999; Moertel et al., 1991). 
 
Smaller studies have shown response rates to platinum etoposide combination chemotherapy 
ranging from 40-67% and median OS ranging from 15 to 19 months (Mitry et al., 1999; Moertel 
et al., 1991; Imai et al., 2016; Iwasa et al., 2010; Patta et al., 2011).  Second line treatment 
options reported include reintroduction of platinum-etoposide, temozolomide-based regimens, 

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8 
topotecan, FOLFOX, and FOLFIRI.  Response rates with these regimens in the second line 
varies from 0-40%, with a median OS ranging from 3.2 to 18 months (Sorbye et al., 2013; Olsen 
et al., 201; Hentic et al., 2012;  Hadoux et al., 2015).  Overall, there is a paucity of effective 
treatment options for patients with high-grade NENs, which follow a very aggressive clinical 
course, beyond these traditional chemotherapy regimens tried based on pure empiricism. 
 
2.1.2 Immunotherapy and NENs  
 
Immunotherapy has been explored for the treatment of NENs in the era of interferon (IFN)-based 
therapy.  Although there was clinical benefit shown from IFN-based therapy, because of 
difficulty of administration and resulting increased toxicity, such treatment has not been adopted 
into a routine clinical practice (Oberg et al., 1991; Oberg et al., 1986).  Findings from small 
studies have shown that NENs are responsive to immune modulation.  In metastatic pancreatic 
NETs, the efficacy of IFN was demonstrated after failure to first-line chemotherapy showing a 
biochemical response of 63% (20/32) with a median DOR of 20.5 months (Eriksson et al., 1990).  
Oberg et al. treated 9 NET patients, including six with carcinoid syndrome, with daily 
intramuscular IFN for three months (Oberg et al., 1983).  All six syndromic patients experienced 
temporary relief in carcinoid syndrome symptoms and concomitant decline in urinary 5-
hydroxyindoleacetic acid (5-HIAA) levels.  
 
The role of IFNα-2b in combination with continuous fluorouracil infusion was studied in 24 
patients with rapidly progressive NETs, 9 of which were confirmed high-grade NECs (Andreyev 
et al., 1995).  An ORR of 41.6% and a median DOR of 20 months were seen in all patients, with 
a response rate of 33% and median DOR of 6 months.  The median OS of patients with the high-
grade NECs was 8 months.  Moertel et al. treated 27 of their NET patients with IFN, twenty-four 
of whom had carcinoid syndrome (Moertel et al., 1989).  Objective response (OR) was seen in 
20% of the patients, while 39% of functional NET patients experienced reduction in urinary 5-
HIAA (>50%) levels.  In a prospective randomized clinical trial of octreotide (n=35) versus 
octreotide with IFN (n=33) for metastatic midgut carcinoid tumor patients, a superior PFS was 
evident for the combination arm (Kolby et al., 2003). 
 
2.1.2.1 
Immune-Checkpoint inhibitors and high-grade NECs 
 
On analysis of 37 cases of poorly differentiated NEC of the digestive tract, programmed cell 
death protein-1 (PD-1) expression on tumor cells and tumor-associated immune cells was seen in 
16% and 63%, respectively  (Roberts et al., 2017).  The expression of PD-L1 was seen on tumor 
cells and tumor associated immune cells in 14% and 27% respectively. There was no difference 
in PD-1 and PD-L1 expression between small cell and large cell NECs.  The expression of PD-1 
and PD-L1 in small cell NECs was studied in 94 patient-derived samples (61 pulmonary, 33 
extrapulmonary) (Schultheis et al., 2015).  PD-L1 and PD-1 expression was seen in the stroma 
and not on the carcinoma cells themselves.  On immunohistochemistry, 18.5% of the samples 
had expression of PD-L1 on their tumor-infiltrating macrophages, while 48% showed PD-1 
expression on tumor-infiltrating lymphocytes.  On RNA sequencing, there was moderate PD-L1 
gene expression in 37.2 %, while PD-L2 was expressed in 27.9%.  
 

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9 
There is scarcity of completed study of checkpoint inhibitors in high-grade neuroendocrine 
neoplasms, with the exception of Merkel-cell carcinoma and small cell lung carcinoma.  The 
SWOG DART study has 19 patients with high grade neuroendocrine tumors, with a good 
number of poorly differentiated NEC.  There was a very good response rate (>40%) to 
nivolumab/ipilimumab in this cohort as presented at the American Association for Cancer 
Research (AACR) 2019 annual meeting  (AACR Press Release, 31 March 2019). 
 
In patients with chemotherapy-refractory Merkel-cell carcinoma, avelumab showed an ORR of 
32%, with a complete response of 9% (Kaufman et al., 2016).  Pembrolizumab had an ORR of 
56%, of which 16% were complete responses (CRs) in treatment-naïve patients with advanced 
Merkle-cell carcinoma (Nghiem et al., 2016). 
 
In patients with chemotherapy-resistant extensive stage small cell lung cancer with PD-L1 
expression, pembrolizumab showed an ORR of 33% (Ott et al., 2017).  The median time to 
response was 2 months (range 1.7-3.7) and the median DOR was 19.4 months (range: 3.6-20).  
The median PFS was 1.9 months (95% confidence interval [CI], 1.7-5.9).  The median OS was 
9.7 months (95% CI, 4.1 to NR). 
 
A multicenter phase 1/2 study was conducted in patients with small cell lung cancer after the 
failure of at least one prior platinum-based chemotherapy regimen, using nivolumab alone or 
nivolumab and ipilimumab combination (Antonia et al., 2016).  Confirmed OR was seen in 10% 
of patients treated with nivolumab 3 mg/kg (n=98), in 23% of patients treated with nivolumab 1 
mg/kg plus ipilimumab 3 mg/kg (n=61), and 19% of patients treated with nivolumab 3 mg/kg 
plus ipilimumab 1mg/kg (n=54).  The median OS was 4.4 months (95% CI, 3.0–9.3) in the 
nivolumab 3 mg/kg cohort, 7.7 months (3.6–18.0) in the nivolumab 1 mg/kg plus ipilimumab 3 
mg/kg cohort, and 6.0 months (3.6–11.0) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg 
cohort.  Time to OR was 2 months for nivolumab alone, while it was 1.4 months in patients 
treated with nivolumab 3 mg/kg and ipilimumab 1 mg/kg.  The median PFS was 1.4 months 
(95% CI, 1.4-1.9), 2.6 months (95% CI, 1.4-4.1), and 1.4 months (95% CI, 1.3-2.2) in the 
nivolumab alone, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg and nivolumab 3 mg/kg plus 
ipilimumab 1 mg/kg cohorts respectively.  PD-L1 expression was checked in 148 patients, of 
whom 17% had PD-L1 expression of 1% or more. There was tumor response irrespective of PD-
L1 expression status. 
 
2.2 
CTEP IND Agents 
 
2.2.1 XL184 (cabozantinib) 
 
XL184 (cabozantinib, Cabometyx®, Cometriq®) is an oral multi-targeted inhibitor of receptor 
tyrosine kinases (RTKs) with half-maximal inhibitory concentrations (IC50) ranging from 2 to 
101 nM (XL184 [cabozantinib] Investigator’s Brochure, 2018).  The targets of XL184 
(cabozantinib) include several RTKs known to play important roles in tumor cell proliferation 
and/or tumor neovascularization, namely VEGFR2, MET, AXL, and RET.  Other recognized 
targets of XL184 (cabozantinib) include ROS1, TRKA, TRKB, TIE2, TYRO3, and MER, two 
additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely related RTKs 
KIT and FLT-3.  The mode of action for XL184 (cabozantinib) is similar to other drugs targeting 

NCI Protocol #:  10315 
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RTKs:  binding in a fully reversible manner to a region of the kinase domain (including the ATP-
binding site) which forces the kinase activation loop into a pseudo-inactive conformation, 
thereby inhibiting subsequent catalytic activity.  Both MET and VEGFR2 are important 
mediators of tumor growth and tumor angiogenesis, and in vivo pharmacodynamic activity of 
XL184 (cabozantinib) against MET and VEGFR2 has been demonstrated in both preclinical and 
clinical studies.  
 
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair (Christensen et al., 2005).  Dysregulation of RTKs by 
mutation, gene rearrangement, gene amplification, or overexpression of the receptor or its 
ligands have been implicated as causative factors in the development and progression of 
numerous cancers. 
 
The proto-oncogene MET encodes the high-affinity receptor for hepatocyte growth factor (HGF) 
(also known as scatter factor [SF]) (Christensen et al., 2005).  MET and HGF are each required 
for normal mammalian development and have been shown to be important in cell migration, 
morphogenic differentiation, and organization of three-dimensional tubular structures (e.g., renal 
tubular cells, gland formation, etc.), as well as cell growth, angiogenesis, and tumor invasiveness 
and metastasis.  Upregulation of MET is found in a wide range of malignancies including 
thyroid, prostate, ovarian, lung, and breast cancers, and is associated with more aggressive and 
invasive phenotypes of cancer cells in vitro and metastases in vivo (XL184 [cabozantinib] 
Investigator’s Brochure, 2018).  MET-driven metastasis may be exacerbated by a number of 
factors, including tumor hypoxia caused by selective inhibition of the VEGF pathway. 
 
Evidence linking MET and HGF as causative or progression factors in human cancers includes 
the overexpression of both receptors and ligands in neoplasms relative to surrounding tissues, the 
correlation of receptor and ligand overexpression with disease severity and outcome, and genetic 
alteration of MET by mutation or gene amplification in multiple cancer types (Christensen et al., 
2005).  Introduction of MET and HGF, or mutant MET into cell lines conferred the properties of 
tumorgenicity and metastatic propensity on engineered cells and introduction of MET or HGF as 
transgenes into the germline of mice resulted in primary and secondary neoplasms.  The 
inhibition of MET or HGF function with dominant-negative receptors, antibody antagonists 
(both MET and HGF), or biologic antagonists (e.g., NK4) have reversed cancer-associated 
phenotypes such as motility, invasion and proliferation of tumor cells, and tumor growth and 
dissemination in vivo. 
 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate 
dysregulated MET activity (Liu et al., 2010), either by means of MET kinase overexpression 
(Comoglio et al., 2008), activating MET gene mutations and/or amplification (Comoglio et al., 
2008; Jeffers et al., 1997; Schmidt et al., 1997), or increased autocrine and/or paracrine secretion 
of the MET ligand, HGF/SF (Birchmeier et al., 2003; Boccaccio and Comoglio, 2006).  These 
alterations have been implicated in tumor progression and metastasis, and high constitutive 
activation of MET has been correlated with poor clinical prognosis (Birchmeier et al., 2003). 
 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability (Roskoski, 2008).  Increased 

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expression of VEGFR2, often in combination with VEGFR3, has been observed in the tumor 
vascular endothelium in most common human solid tumor types, on tumor cells in melanoma 
and hematological malignancies, and in colitis-associated colon cancer (Tugues et al., 2011).  
High VEGFR2 expression is an unfavorable prognostic biomarker in hepatocellular carcinoma 
(HCC), and correlated with triple-negative (i.e., therapy-resistant) breast cancer (TNBC) and 
poor survival. 
 
2.2.1.1 
Nonclinical Development of XL184 (cabozantinib) 
 
2.2.1.1.1 
Nonclinical In Vivo Activity 
 
Data from pharmacodynamic experiments have shown that XL184 (cabozantinib) inhibits MET 
and VEGFR2 in vivo.  Oral administration of XL184 (cabozantinib) resulted in blockade of MET 
phosphorylation in human lung tumor xenografts grown in nude mice, blockade of MET 
phosphorylation in livers of mice, and blockade of VEGFR2 phosphorylation in mouse lung 
tissue.  For both targets, the duration of action for XL184 (cabozantinib) was sustained, with 
>50% inhibition observed for >8 hours post-dose at a single dose level of 100 mg/kg (Yakes et 
al., 2011).  In addition, oral administration of XL184 (cabozantinib) resulted in blockade of 
phosphorylation of mutationally activated RET in TT human MTC xenografts grown in nude 
mice (Bentzien et al. 2013). 
 
Treatment with XL184 (cabozantinib) results in anti-angiogenic effects in xenograft tumors, with 
disruption of the vasculature beginning within 24 hours after administration, and is associated 
with pro-apoptotic effects (Yakes et al. 2011).  These effects translate into significant tumor 
growth inhibition or tumor regression after XL184 (cabozantinib) treatment in multiple tumor 
models including MTC, breast cancer, lung carcinoma, and glioblastoma. 
 
Inhibition of the VEGF signaling pathway alone was previously shown to result in more invasive 
tumors in the transgenic RIP-Tag2 mouse model of neuroendocrine pancreatic cancer that 
spontaneously develops aggressive tumors (Pàez-Ribes et al. 2009).  Treatment with XL184 
(cabozantinib) for 3 weeks, from age 14 to 17 weeks, significantly prevented formation of liver 
metastases in the RIP-Tag2 model compared with anti-VEGF treatment or vehicle alone (P<0.05 
vs. vehicle and anti-VEGF antibody).  The number of liver metastases was 5-fold greater in anti-
VEGF antibody-treated animals compared with vehicle-treated animals, and no liver metastases 
were detected in XL184 (cabozantinib)-treated animals.  In addition, treatment with XL184 
(cabozantinib) from age 14 to 20 weeks improved survival.  Median survival was 14.7 weeks for 
vehicle-treated animals (n=12) and 16.4 weeks for anti-VEGF antibody-treated animals (n=7; 
P<0.05 vs. vehicle), and all XL184 (cabozantinib)-treated animals survived for the full 20 weeks 
of observation (n=6; P<0.05 vs. vehicle and anti-VEGF antibody). 
 
2.2.1.1.2 
Nonclinical Pharmacokinetics 
 
Nonclinical pharmacokinetics (PK) of XL184 (cabozantinib) was studied in mice, rats, dogs, and 
monkeys (XL184 [cabozantinib] Investigator’s Brochure, 2018).  Oral bioavailability was 
comparably high in rats (80-86%), dogs (87%) and monkeys (73%) and moderately high in mice 
(42-51%) when XL184 (cabozantinib) was formulated with an aqueous vehicle.  In rats, systemic 

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drug exposure parameters (maximum plasma concentration [Cmax] and area under the 
concentration-time curve [AUC] from 0 hours to a specific post-dose time [AUC0-t]) increased 
less than dose-proportionally in association with single XL184 (cabozantinib) oral doses, and 
generally dose-proportionally with moderate accumulation (≤4-fold) following repeat daily oral 
dosing.  In dogs, systemic drug exposure parameters increased less than dose-proportionally with 
increasing single XL184 (cabozantinib) oral doses, and generally dose-proportionally with little 
or no accumulation (≤2-fold increase) following repeat daily dosing. 
 
2.2.1.1.3 
Toxicology 
 
Toxicity associated with oral administration of XL184 (cabozantinib) was characterized in 
definitive (Good Laboratory Practice [GLP]-compliant) single-dose and repeat-dose studies in 
mice, rats, and dogs; a fertility study in rats; embryotoxicity/teratogenicity studies in rats and 
rabbits; juvenile toxicity studies in rats; in vitro and in vivo genotoxicity bioassays; and an in 
vitro phototoxicity study (XL184 [cabozantinib] Investigator’s Brochure, 2018).  Target tissues 
for XL184 (cabozantinib)-related toxicity identified in these studies include gastrointestinal (GI) 
tract, bone marrow, lymphoid tissues, reproductive tract tissues, endocrine tissues, kidney, and 
skin.  Histopathologic changes were also present in bone, central nervous system (CNS) tissues 
and liver/gall bladder.  Adverse findings associated with XL184 (cabozantinib) administration 
were observed in both rodent and non-rodent species and were generally dose-related and often 
correlative with clinical signs and/or clinical pathology parameter changes reflective of 
associated target tissue histopathologic findings.  Adverse findings were generally reversible 
upon discontinuation of treatment.  In definitive reproductive and developmental toxicity studies, 
XL184 (cabozantinib) reduced fertility in male and female rats, was embryotoxic in rats, 
produced a fetal soft-tissue malformation (small spleen) in rabbits, and produced fetal external 
malformations (cleft palate/lip, dermal aplasia and kinked or rudimentary tail) in rats.  XL184 
(cabozantinib) was negative in in vitro bacterial and mammalian genotoxicity, clastogenicity, 
and phototoxicity bioassays.  The metabolite present at highest plasma concentrations in humans 
administered XL184 (cabozantinib), EXEL-1644, was negative in an in vitro bacterial 
genotoxicity bioassay and caused no systemic tissue toxicity in rats dosed subcutaneously with 
EXEL-1644 for 2 weeks. 
 
2.2.1.2 
Clinical Development of XL184 (Cabozantinib) 
 
Patients have received XL184 (cabozantinib) in 18 Exelixis-sponsored clinical trials, 35 
investigator-sponsored studies, and 19 NCI Cancer Therapy Evaluation Program (CTEP)-
sponsored studies (XL184 [cabozantinib] Investigator’s Brochure, 2018).  The maximum 
tolerated dose (MTD) on once daily oral (PO) dosing schedule was determined to be 175 mg L-
malate salt (or approximately 138 mg freebase equivalent by weight).  Detailed information for 
each of these studies, including pharmacokinetic data, can be found in the XL184 (cabozantinib) 
Investigator’s Brochure (2018).  Safety and efficacy information from the 2018 XL184 
(cabozantinib) Investigator’s Brochure is summarized below. 
 
 
 

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2.2.1.2.1 
Safety 
 
Across Exelixis-sponsored studies with single-agent XL184 (cabozantinib), the most frequently 
observed adverse events (AEs) (≥20% of patients), regardless of causality, were diarrhea, 
fatigue, decreased appetite, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), 
vomiting, weight loss, constipation, hypertension, dysgeusia, dysphonia, and asthenia 
(Investigator’s Brochure, 2018).  The most frequently observed serious AEs (SAEs) (≥2% of 
patients), regardless of causality, were pulmonary embolism (PE), pneumonia, general physical 
health deterioration, vomiting, nausea, dehydration, anemia, and diarrhea.  In these single-agent 
studies, 42 patients had grade 5 AEs that were assessed as related to study treatment.  The only 
related grade 5 AEs that occurred more than once were PE (n=5), hepatic failure (n=3); death 
(unspecified; n=3), hemorrhage (n=2), respiratory failure (n=2), sudden death (n=2), and GI 
perforation (n=2).  In investigator-sponsored and CTEP-sponsored trials, the most frequent SAEs 
were embolism, nausea, dyspnea, dehydration, fatigue, and hypophosphatemia. 
 
2.2.1.2.2 
Efficacy 
 
The clinical activity of XL184 (cabozantinib) has been evaluated in pivotal trials in renal cell 
cancer (RCC), hepatocellular carcinoma (HCC), MTC, and castrate-resistant prostate cancer 
(CRPC) (XL184 [cabozantinib] Investigator’s Brochure, 2018).  In phase 1 and 2 studies, XL184 
(cabozantinib) has also demonstrated findings consistent with broad clinical antitumor activity in 
multiple tumor types. 
 
Phase 3, randomized, open-label, active-controlled Study XL184-308 was conducted in 658 
patients (330 XL184 [cabozantinib], 328 everolimus) with advanced RCC who had received 
prior treatment with at least one VEGFR-tyrosine kinase inhibitor (TKI) (XL184 [cabozantinib] 
Investigator’s Brochure, 2018).  XL184 (cabozantinib) demonstrated statistically significant 
improvements in the primary endpoint (PFS) and both secondary endpoints (ORR and OS) 
compared with the standard-of-care control treatment (everolimus).  In the primary PFS analysis 
performed in the first 375 patients randomized, the hazard ratio (HR) adjusted for stratification 
factors was 0.58 (95% CI, 0.45-0.74; stratified logrank P<0.0001), and the Kaplan-Meier 
estimates for median PFS were 7.4 months in the XL184 (cabozantinib) arm vs. 3.8 months in 
the everolimus arm.  The PFS analysis was repeated in all 658 patients, and the results (stratified 
HR = 0.51 [95% CI, 0.41-0.62]) were similar to those obtained from the initial analysis.  In the 
primary analysis of ORR, the ORRs for the XL184 (cabozantinib) and everolimus arms were 
17% (95% CI, 13%-22%) and 3% (95% CI, 2%-6%), respectively (unstratified P<0.0001).  
Kaplan-Meier estimates for median OS were 21.4 months in the XL184 (cabozantinib) arm and 
16.5 months in the everolimus arm.  Results for extensive subgroup analyses of PFS, OS, and 
ORR showed a consistent benefit for XL184 (cabozantinib) treatment versus everolimus. 
 
Phase 2, randomized, open-label, active-controlled Study A031203 (CABOSUN), was sponsored 
by CTEP and conducted by The Alliance for Clinical Trials in Oncology (Alliance) in 157 
patients (79 XL184 (cabozantinib), 78 sunitinib) with untreated clear cell locally advanced or 
metastatic RCC of intermediate or poor risk (XL184 [cabozantinib] Investigator’s Brochure, 
2018).  Compared with the standard-of-care control treatment, sunitinib, XL184 (cabozantinib) 
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secondary endpoint of ORR as well as a non-significant trend of improvement in the secondary 
endpoint of OS.  In the primary analysis performed by the Alliance, a benefit in PFS per 
investigator assessment was demonstrated for XL184 (cabozantinib) compared with sunitinib.  In 
Exelixis-initiated retrospective primary PFS and secondary ORR analyses based on blinded 
assessments, there was a statistically significant improvement in PFS for patients in the XL184 
(cabozantinib) arm compared with the sunitinib arm (HR=0.48 [95% CI, 0.31-0.74]; stratified 2-
sided logrank P=0.0008); median PFS was 8.6 months in the XL184 (cabozantinib) arm and 5.3 
months in the sunitinib arm.  Further, ORR (secondary endpoint) per IRC in the XL184 
(cabozantinib) arm was improved compared with the sunitinib arm:  20% vs. 9% (stratified 2-
sided P=0.0406).  In an OS (secondary endpoint) analysis of data, the Kaplan-Meier estimates 
for median OS were 30.3 months in the XL184 (cabozantinib) arm vs. 21.0 months in the 
sunitinib arm (stratified HR adjusted for stratification factors was 0.74 [95% CI, 0.47-1.14]; 
stratified 2-sided logrank P=0.1700). 
 
A total of 707 patients (470 XL184 (cabozantinib), 237 placebo) with advanced HCC who had 
received prior treatment with sorafenib were enrolled in phase 3, randomized, double-blinded, 
placebo-controlled Study XL184-309 through the 01 June 2017 database cutoff date (XL184 
[cabozantinib] Investigator’s Brochure, 2018).  In the study, XL184 (cabozantinib) demonstrated 
a robust and statistically significant improvement in OS, PFS, and ORR.  The analysis of 
duration of OS (primary endpoint) demonstrated a statistically significant improvement for 
patients in the XL184 (cabozantinib) arm compared with the placebo arm:  the HR, adjusted for 
stratification factors was 0.76 (95% CI, 0.63-0.92; stratified logrank P=0.0049).  The Kaplan-
Meier estimates for median OS were 10.2 months in the XL184 (cabozantinib) arm vs. 8.0 
months in the placebo arm.  A statistically significant improvement in PFS for patients in the 
XL184 (cabozantinib) arm compared with the placebo arm was also observed.  The HR, adjusted 
for stratification factors was 0.44 (95% CI, 0.36-0.52; stratified logrank P<0.0001).  The Kaplan-
Meier estimates for median PFS were 5.2 months in the XL184 (cabozantinib) arm vs. 1.9 
months in the placebo arm.  The ORR was 4% and 0.4% for patients in the XL184 
(cabozantinib) and placebo arms, respectively (stratified Cochran-Mantel-Haenszel [CMH] test 
P=0.0086). 
 
Phase 3, randomized, double-blind, placebo-controlled study XL184-301 was conducted in 330 
MTC patients (219 XL184 (cabozantinib), 111 placebo) (XL184 [cabozantinib] Investigator’s 
Brochure, 2018).  An increase in PFS (primary endpoint) was seen, with a median PFS of 11.2 
months in the XL184 (cabozantinib) arm compared with 4.0 months for placebo (HR=0.28 [95 
CI, 0.19-0.40]).  For the secondary endpoint of ORR, confirmed PRs occurred in 28% of XL184 
(cabozantinib)-treated patients and no placebo-treated patients and responses were durable 
(median DOR=14.6 months).  The final analysis of the secondary endpoint of OS included 218 
deaths and showed a non-significant trend for improved median OS in the XL184 (cabozantinib) 
arm compared with the placebo arm (26.6 months vs. 21.1 months; HR=0.85 [95% CI, 0.64-
1.12]; P=0.2409).  Because MTC is a relatively rare disease, the study was not designed to be 
large enough to provide high power to detect the minimum clinically significant difference in the 
secondary endpoint of OS.  The subgroup analysis of patients with a RET M918T mutation 
revealed a larger improvement in OS for the XL184 (cabozantinib) arm:  the median OS was 
44.3 months for the XL184 (cabozantinib) arm versus 18.9 months for the placebo arm 
(HR=0.60 [95% CI, 0.38-0.94]; P=0.0255, not adjusted for multiple subgroup analyses).  In all 

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patients, the median duration of XL184 (cabozantinib) treatment was 10.8 months, and the 75th 
percentile for duration of treatment was 24.8 months.  The maximum duration of treatment was 
59.4 months at the data cutoff of the final OS analysis. 
 
In addition to RCC, HCC, and MTC, XL184 (cabozantinib) has demonstrated findings consistent 
with broad clinical antitumor activity in multiple other tumor types (XL184 [cabozantinib] 
Investigator’s Brochure, 2018).  Observations of clinical activity have included decrease of soft 
tissue tumor lesions including visceral metastases, reduction in serum markers of bone resorption 
and formation, and reduction in circulating tumor cells (CTCs) in patients with prostate cancer.  
Though they failed to meet their respective primary endpoints of OS and pain response, phase 3 
studies XL184-307 and XL184-306 demonstrated clinical activity in CRPC including effects on 
PFS (XL184-307) and bone scan response (both studies).  Clinical antitumor activity has also 
been observed in company-sponsored phase 1 and 2 studies across indications including non-
small cell lung cancer (NSCLC), breast cancer, melanoma, ovarian cancer, glioblastoma (GB), 
and differentiated thyroid cancer (DTC). 
 
2.2.1.3 
Marketing Experience 
 
XL184 (cabozantinib) is approved in the United States as Cometriq® for the treatment of 
progressive, metastatic MTC and as Cabometyx® for advanced RCC (XL184 [cabozantinib] 
Investigator’s Brochure, 2018).  As of February 2018, commercial exposure in the post-
marketing setting to Cometriq® was estimated as >2000 patients and exposure to Cabometyx® 
was estimated as >12000 patients.  No new safety signals associated with Cometriq® or 
Cabometyx® were observed in post-marketing. 
 
2.2.2 Nivolumab 
 
Nivolumab (BMS-936558, MDX-1106, ONO-4538, Opdivo®) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for human PD-1, cluster of 
differentiation 279 (CD279) cell surface membrane receptor (Nivolumab Investigator’s 
Brochure, 2018).  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 a variety of 
cancers.  The combination of nivolumab and ipilimumab, an anti-cytotoxic T lymphocyte 
associated antigen-4 (anti-CTLA-4) agent, in a phase 1/2 trial showed markedly enhanced 
clinical activity with an acceptable safety profile in patients with melanoma (Wolchok et al., 
2013).  See Section 2.2.3 for more information about ipilimumab. 
 
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer (Nivolumab 
Investigator’s Brochure, 2018).  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 OS with or 
without radiographic responses or improved PFS; responses that may be delayed or occur after 

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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) (Nivolumab Investigator’s 
Brochure, 2018).  PD-1 is transiently, but highly expressed on activated T-cells and functions 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 (T-cell immunoglobulin mucin 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-β). 
 
Two ligands specific for PD-1 have been identified:  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 results in negative regulatory stimuli that down-modulate the activated T-cell 
immune response through SHP-1 phosphatase. 
 
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 (Nivolumab Investigator’s Brochure, 2018). 
 
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 

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mg/kg × 4) resulted in decreased viral loads and increased survival along with expanded T-cells 
with increased T-cell functionality.   
 
2.2.2.1 
Nonclinical Development of Nivolumab 
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab alone 
was well tolerated (Nivolumab Investigator’s Brochure, 2018).  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 dissociation constant (Kd) of 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. 
 
2.2.2.2 
Clinical Development of Nivolumab 
 
Nivolumab has demonstrated clinical activity, and has been approved for use in NSCLC, 
melanoma, RCC, classical Hodgkin’s Lymphoma (cHL), squamous cell carcinoma (SCC) of the 
head and neck, and urothelial carcinoma as monotherapy and in combination with ipilimumab 
and other therapeutics (Nivolumab Investigator’s Brochure, 2018).  It has also demonstrated 
activity in other tumor types.  The majority of responses were durable and exceeded 6 months.  
In randomized, controlled studies, nivolumab monotherapy demonstrated statistically significant 
improvement in OS over standard of care in patients with advanced or metastatic melanoma, 
patients with advanced or metastatic NSCLC, patients with advanced RCC, and patients with 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).  In randomized, 
controlled studies, nivolumab in combination with ipilimumab demonstrated statistically 
significant improvement in PFS and ORR over ipilimumab monotherapy in patients with 
advanced or metastatic melanoma. 
 
Nivolumab is also being evaluated in several other cancers, including small cell lung cancer 
(SCLC), gastric and esophageal cancer, hepatocellular carcinoma, colorectal cancer, GB, and 
Merkel cell carcinoma (MCC). 
 
2.2.2.2.1 
Pharmacokinetics 
 
PK of nivolumab was linear in the range of 0.3 to 10 mg/kg, with dose-proportional increases in 
Cmax and AUC from time zero to infinity (AUC0-∞), with low to moderate inter-patient variability 
observed at each dose level (Nivolumab Investigator’s Brochure, 2018).  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 nivolumab is 17 to 25 days consistent 
with the half-life of endogenous IgG4.   
 
 
 

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2.2.2.2.2 
Efficacy 
 
In a randomized, open-label, phase 3 trial, patients with unresectable or metastatic melanoma 
who had progressed after treatment with ipilimumab were given either IV nivolumab (3 mg/kg 
every 2 weeks) or investigator’s choice chemotherapy (ICC):  dacarbazine 1000 mg/m2 every 3 
weeks or paclitaxel 175 mg/m2 combined with carboplatin AUC=6 every 3 weeks) (Weber et al., 
2015).  Of the first 120 patients treated with nivolumab, objective responses (CR or PR) were 
seen in 38 (31.7%) versus 5 (10.6%) out of 47 patients in the ICC arm.  Grade 3-4 AEs related to 
nivolumab included increased lipase, increased alanine aminotransferase, anemia, and fatigue.  
Grade 3-4 drug-related SAEs were noted in 12 (5%) nivolumab-treated patients.  No treatment-
related deaths occurred. 
 
In a phase 1/2 trial, patients with virus-positive and -negative solid tumors, including MCC, were 
given 240 mg nivolumab IV every 2 weeks (Nivolumab Investigator’s Brochure, 2018).  As of 
the February 16, 2017 data cutoff, of 25 patients with MCC who had received nivolumab, 
objective responses (PR or CR) were seen in 16 patients (64%, 95% CI 42.5%-82%).  Median 
DOR, PFS, and OS have not been reached. 
 
In a randomized, open-label, phase 3 trial, patients with recurrent SCCHN were given either IV 
nivolumab (3 mg/kg every 2 weeks) or standard systemic therapy (methotrexate, docetaxel, or 
cetuximab) (Ferris et al., 2016).  The median OS was 7.5 months (95% CI, 5.5-9.1 months) in 
the nivolumab group versus 5.1 months (95% CI, 4-6 months) in the group that received standard 
therapy.  OS was significantly longer with nivolumab than with standard therapy (HR, 0.70 
[97.73% CI, 0.51-0.96]; P=0.01), and the estimates of the 1-year survival rate were 
approximately 19% higher with nivolumab than with standard therapy (36.0% vs. 16.6%).  The 
median PFS was 2 months (95% CI, 1.9-2.1 months) with nivolumab versus 2.3 months (95% 
CI, 1.9-3.1 months) with standard therapy (HR for disease progression or death, 0.89 [95% CI, 
0.70-1.13]; P=0.32).  The PFS rate at 6 months was 19.7% with nivolumab versus 9.9% with 
standard therapy.  The response rate was 13.3% in the nivolumab group versus 5.8% in the 
standard-therapy group.  Treatment-related AEs of grade 3 or 4 occurred in 13.1% of the patients 
in the nivolumab group versus 35.1% of those in the standard-therapy group.  Physical, role, and 
social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the 
standard-therapy group. 
 
In an open-label, phase 2 trial, patients with recurrent or metastatic colorectal cancer assessed as 
MSI-high were given 3 mg/kg IV nivolumab every 2 weeks as monotherapy, or in combination 
with 1 mg/kg IV ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg IV nivolumab 
every 2 weeks (Nivolumab Investigator’s Brochure, 2018; Overman et al., 2017).  As of the 
September 19, 2016 data cut-off, 74 patients had received nivolumab monotherapy and 30 had 
received combination nivolumab/ipilimumab therapy.  At a median follow-up of 12 months, 23 
of 74 nivolumab-treated patients (31.1% [95% CI, 20.8%-42.9%]) achieved an objective 
response and 51 patients (69% [95% CI, 57%-79%]) had disease control for 12 weeks or longer.  
As of the data cut-off, median DOR had not yet been reached; all responders were alive, and 
eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate, 86% [95% 
CI, 62%-95%]).  Median PFS was 7.6 months (95% CI, 3 months-not reached [NR]).  The 6- and 
12-month PFS rates were 51.5% (95% CI, 38.9%-62.8%) and 45.6% (95% CI, 32.2%-58.1%), 

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respectively.  The 6- and 12-month OS rates were 83.4% (95% CI, 72.5%-90.2%) and 73.8% 
(95% CI, 59.8%-83.5%), respectively.  The most common grade 3 or 4 drug-related AEs were 
increased concentrations of lipase (six patients, 8%) and amylase (two patients, 3%).  Twenty-
three patients (31%) died during the study; none of these deaths were deemed to be treatment 
related by the investigator.  Out of 30 patients who had received nivolumab and ipilimumab 
combination therapy, 27 were evaluable for response (Nivolumab Investigator’s Brochure, 
2018).  Of these, objective responses were seen in 9 patients (33.3%, 95% CI, 18.6%-50.9%).  
The 6-month PFS rate was 66.6% (95% CI, 45.5%-81.1%) and the 6-month OS rate was 85.1% 
(95% CI, 65.0%-94.2%). 
 
2.2.2.2.3 
Toxicology 
 
An MTD of nivolumab was not reached at any dose up to 10 mg/kg (Topalian et al., 2012; 
Nivolumab Investigator’s Brochure, 2018).  There was no pattern in the incidence, severity, or 
causality of AEs to nivolumab dose level.  Most AEs were low-grade (Grade 1-2) with relatively 
few drug-related high-grade (Grade 3-4) AEs.  The safety profile of nivolumab combination 
therapy varies with the agent combined with nivolumab but is generally consistent with the 
safety profiles observed with either agent alone and, in some cases, both frequency and severity 
of AEs were greater than that observed with either agent alone.  The safety profile of nivolumab 
+ ipilimumab combination therapy was consistent with the mechanisms of action of nivolumab 
and ipilimumab (Nivolumab Investigator’s Brochure, 2018).  A dose of 3 mg/kg nivolumab/3 
mg/kg ipilimumab exceeded the MTD, and both 1 mg/kg nivolumab/3 mg/kg ipilimumab and 3 
mg/kg nivolumab/1 mg/kg ipilimumab were identified as the MTD.  For nivolumab 
monotherapy and combination therapy, most high-grade events were manageable with use of 
corticosteroids or hormone replacement therapy (endocrinopathies). 
 
The overall safety experience with nivolumab is based on experience in approximately 16,900 
patients who received either nivolumab alone or in combination with other therapeutics 
(Nivolumab Investigator’s Brochure, 2018).  In general, for monotherapy, the safety profile is 
similar across tumor types.  The only exception is pulmonary inflammation AEs, which may be 
numerically greater in patients with NSCLC, possibly because in some cases, it can be difficult 
to distinguish between nivolumab-related and unrelated causes of pulmonary symptoms and 
radiographic changes.  The most frequently reported treatment-related AE is fatigue, which is 
almost always of low grade. 
 
2.2.2.2.4 
Pharmacodynamics/Biomarkers 
 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with ipilimumab 
with the use of immunohistochemistry (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) 

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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-gamma (IFN- γ), indoleamine 2,3 
dioxygenase (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. 
 
2.2.2.3 
Marketing Experience 
 
Nivolumab monotherapy (Opdivo®) was first approved in July 2014 in Japan for unresectable 
melanoma (Nivolumab Investigator’s Brochure, 2018).  Since then, it has been approved in 
multiple countries, including the US, and has been approved for several other indications, 
including metastatic NSCLC, advanced RCC, cHL, SCCHN, urothelial carcinoma, HCC, RCC, 
and adjuvant treatment of melanoma.  Nivolumab is also approved in combination with 
ipilimumab for unresectable or metastatic melanoma in multiple countries, including the US, and 
for previously untreated advanced RCC in the US.  Qualitative and quantitative safety data has 
been consistent with the established safety profile as observed in clinical trials.  No new safety 
concerns have been identified based on global post-marketing reports. 
 
2.2.3 Ipilimumab 
 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4, Yervoy®) is an Ig-G1κ HuMAb specific 
for human cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152), which is expressed on a subset 
of activated T-cells (Ipilimumab Investigator’s Brochure, 2018).  CTLA-4 is a negative regulator 
of T-cell activation.  Ipilimumab binds to CTLA-4 and inhibits its interaction with ligands on 
APCs.  Blockade of CTLA-4 has been shown to augment T cell activation and proliferation, 
including the activation and proliferation of tumor-infiltrating T-effector cells.  Inhibition of 
CTLA-4 signaling can also reduce Treg function, which may contribute to a general increase in 
T-cell responsiveness, including the anti-tumor response. 
 
2.2.3.1 
Nonclinical Development of Ipilimumab 
 
Ipilimumab has specificity and high affinity for human CTLA-4 (Ipilimumab Investigator’s 
Brochure, 2018).  The calculated dissociation constant value (KD) from an average of several 
studies was 5.25 nM.  Binding of ipilimumab to purified, recombinant human CTLA-4 antigen 
was also demonstrated by enzyme-linked immunosorbent assay with half-maximal binding at 15 
ng/mL, while saturation was observed at approximately 0.1 mcg/mL.  No cross-reactivity was 
observed against human CD28.  Ipilimumab completely blocked binding of the CTLA-4 ligands 
B7-1 and B7-2 to human CTLA-4 at concentrations higher than 6 mcg/mL and 1 mcg/mL, 
respectively. 
 
In vivo, blockade of CTLA-4, utilizing anti-CTLA-4 mAb, induced regression of established 
tumors and enhanced antitumor immune responses in several murine tumor models (Ipilimumab 
Investigator’s Brochure, 2018).  Blockade of CTLA-4-mediated signals is effective in inducing 
rejection of immunogenic cancers in mice.  Moreover, when anti-CTLA-4 mAb is used in 
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vaccines, poorly immunogenic cancers in mice are rejected.  These findings suggest that CTLA-
4 blockade, alone or in combination with antigenic stimulation and other immune modulating 
agents can induce a potent antitumor response.  Complete information on pre-clinical studies can 
be found in the ipilimumab Investigator’s Brochure (2018). 
 
2.2.3.2 
Clinical Development of Ipilimumab 
 
Bristol-Myers Squibb (BMS) and Medarex (acquired by BMS in September 2009) have co-
sponsored an extensive clinical development program for ipilimumab, encompassing >22,571 
patients in several cancer types in completed and ongoing studies, including a compassionate use 
program (Ipilimumab Investigator Brochure, 2018).  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, GI, 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. 
 
2.2.3.2.1 
Clinical Pharmacokinetics 
 
The PK of ipilimumab was studied in 499 patients with unresectable or metastatic melanoma 
who received doses of 0.3, 3, or 10 mg/kg administered once every 3 weeks (q3w) for four doses 
(Ipilimumab Investigator’s Brochure, 2018).  Cmax, trough concentration (Cmin), and AUC of 
ipilimumab were found to be dose proportional within the dose range examined.  Upon repeated 
dosing of ipilimumab administered q3w, ipilimumab clearance was found to be time-invariant, 
and minimal systemic accumulation was observed as evident by an accumulation index of 1.5-
fold or less.  Ipilimumab steady-state concentration was reached by the third dose.  The mean 
terminal half-life was 14.7 days, systemic clearance (CL) was 15.3 mL/h, and the volume of 
distribution at steady-state (Vss) was 7.21 L.  The mean ipilimumab Cmin achieved at steady-state 
with the 3-mg/kg regimen was 21.8 mcg/mL. 
 
2.2.3.2.2 
Safety 
 
The immune-based mechanism of action is reflected in the safety profile of ipilimumab 
(Ipilimumab Investigator’s Brochure, 2018).  The most common treatment-related AEs are 
inflammatory in nature, consistent with the mechanism of action of the drug and generally 
medically manageable with topical and/or systemic immunosuppressants.  Such immunological 
safety events are described as immune-related adverse events (irAEs) or immune mediated 
adverse reactions (imARs).  The irAEs are described as AEs of unknown etiology, which were 
consistent with an immune phenomenon and considered causally related to drug exposure by the 
investigators.  The irAEs primarily involve the GI tract and skin.  Immune-related AEs in the 
liver were also observed, particularly in patients receiving 10 mg/kg.  Endocrinopathy and 

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neuropathy were important irAEs that were observed less frequently.  The imARs were 
adjudicated in a blinded fashion based on sponsor-physician data review to exclude 
noninflammatory etiologies, such as infection or tumor progression, and to consider available 
evidence of inflammation, such as tumor biopsies or responsiveness to steroids, in an effort to 
determine whether specific AEs or abnormal hepatic laboratory values were likely to be immune 
mediated and associated with ipilimumab treatment.   
 
2.2.3.2.3 
Efficacy 
 
In melanoma, four completed phase 3 studies (MDX010-20, CA184024, CA184029, and 
CA184169) have demonstrated a clinically meaningful and statistically significant survival 
benefit in pretreated advanced melanoma, in previously untreated advanced melanoma, and in 
adjuvant melanoma (Ipilimumab Investigator’s Brochure, 2018). 
 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients (Ipilimumab Investigator’s Brochure, 2018).  Ipilimumab induces an 
immunologic response, and measurable clinical effects emerge after the immunological effects.  
Tumor infiltration with lymphocytes and the associated inflammation (documented by biopsy in 
some patients) is likely the cornerstone of the effect of ipilimumab and can manifest in various 
patterns of clinical activity leading to tumor control.  In some cases, inflammation may not be 
noted by radiological examination, and objective response is observed with the first tumor 
assessment in a manner seen in patients receiving other types of anti-cancer treatments.  In other 
cases, response may be preceded by an apparent increase in initial tumor volume and/or the 
appearance of new lesions, which may be mistaken for tumor progression on radiological 
evaluations.  Therefore, in patients who are not experiencing rapid clinical deterioration, 
confirmation of progression is recommended (at the investigator’s discretion) to better 
understand the prognosis, as well as to avoid unnecessarily initiating potentially toxic alternative 
therapies in patients who might be benefiting from treatment.  Immune-related response criteria 
were developed based on these observations to systematically categorize novel patterns of 
clinical activity and are currently being prospectively evaluated in clinical studies.  In metastatic 
diseases, stabilization is more common than response, and in some instances is associated with a 
slow, steady decline in tumor burden over many months, sometimes improving to PRs and/or 
CRs.  Thus, the immune-based mechanism of action of ipilimumab results in durable disease 
control, sometimes with novel patterns of response, which contribute to improvements in OS. 
 
Available preclinical data support the combinations of nivolumab and ipilimumab (Curran et al., 
2010).  The combination of ipilimumab with nivolumab has been reported to result in improved 
responses in advanced melanoma, including decreased time to response, increased number of 
responses, improved depth and duration of responses, and increased PFS and OS compared to 
single agent ipilimumab (Wolchok et al., 2013). 
 
2.2.3.3 
Marketing Experience 
 
Ipilimumab monotherapy (Yervoy®) was approved in the US in March 2011 for the treatment of 
advanced melanoma (Ipilimumab Investigator’s Brochure, 2018).  Ipilimumab has demonstrated 
long-term OS benefit extending beyond 5 years in both previously treated and untreated patients 

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with metastatic melanoma.  Ipilimumab continues to demonstrate an overall favorable benefit-
risk profile.  Based on review of nonclinical, clinical, and post-marketing data, there has been no 
change in the effectiveness or safety of ipilimumab for the approved indications.  The totality of 
data continues to support a significant clinical benefit for patients receiving ipilimumab with 
various other types of concomitant cancer stimulatory therapies. 
 
2.3 
Rationale 
 
The lack of permissive tumor microenvironment is one of the frequently cited reasons why poor 
response to immunotherapy has been seen in many patients with metastatic carcinomas 
(Spranger et al., 2013; Sharma et al., 2015).  Tumors that respond favorably to immunotherapy 
have been characterized as having more effector CD8+ T cell infiltrating the tumor stroma and 
fewer regulatory T cells (T regs), MDSCs, and TAMs amongst other factors.  Tumors that have 
not responded favorably to checkpoint inhibition have been shown to have fewer effector T cells 
and more immunosuppressive T regs, MDSCs, and TAMs infiltrating the tumor 
microenvironment. 
 
With the increasing understanding of the complexity of cancer and its progression, it has become 
increasingly clear that successful cancer treatment involves a combinatorial approach.  Although 
the benefits of cancer immunotherapy have been astonishingly durable, they are limited to a 
portion of patients with permissive tumor microenvironment.  Understanding the limitations of 
certain tumors with immunosuppressive microenvironment that do not respond to 
immunotherapy, a sound scientific argument is to attempt to convert a tumor phenotype to an 
“inflamed phenotype” which is likely to respond to immunotherapy.  Different strategies to alter 
the composition of the tumor microenvironment have been suggested, but none have shown 
clinical success in changing immunotherapy resistant tumors to a responsive one. 
 
In patients with refractory urothelial carcinoma who received XL184 (cabozantinib) treatment, 
there was a decreased level of T regs and increased expression of PD-1 by the T cells (Apolo et 
al., 2014).  In a novel chimeric mouse model of metastatic castration-resistant prostate cancer 
(mCRPC), there was a robust synergistic response when a checkpoint blockade was combined 
with XL184 (cabozantinib) and BEZ235 (inhibitor of PI3K/mTOR kinases) to attenuate MDSC 
activity, though the individual approaches showed only minimal responses (Lu et al., 2017). 
 
A phase 1 study of combination of XL184 (cabozantinib) with the checkpoint inhibitors, 
nivolumab and ipilimumab, was conducted in patients with refractory metastatic genitourinary 
cancers (Apolo et al., 2016; Apolo et al., 2017).  In part 1, patients received XL184 
(cabozantinib) with nivolumab, while in part 2 XL184 (cabozantinib) was given with nivolumab 
and ipilimumab.  In both parts of the study, the combination of was well tolerated with no dose 
limiting toxicities (DLTs).  The recommended dose for the combination was XL184 
(cabozantinib) 40 mg daily, nivolumab 3 mg/kg every 2 weeks from part 1 of the study, while 
XL184 (cabozantinib) 40 mg daily, nivolumab 3 mg/kg every 2 weeks, and ipilimumab 1 mg/kg 
every 3 weeks (ipilimumab for up to four doses) was recommended from the part 2 of the study.  
The ORR seen with the combination was 33% in part 1 and 32% in part 2, with all the responses 
ongoing at the time of report.  
 

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The findings of studies cited above suggest that the combination of immune checkpoint 
inhibitors with XL184 (cabozantinib) is well tolerated.  However, some potential overlapping 
toxicities might include fatigue, rash, diarrhea, and elevated lipase.  There is only one reported 
case of heart failure and one case of autoimmune hemolytic anemia in a phase 2 XL184 
(cabozantinib) study (Chan et al., 2017). 
 
This study utilizes ORR as the primary endpoint.  ORR is clinically relevant since traditional 
NET therapies have low response rates and there is an unmet medical need to improve response 
rate.  This is particularly important for patient with widely metastatic disease and visceral crisis.  
We hypothesize that this combination can potentially alter the composition of the tumor 
microenvironment favorably to improve its responsiveness to immunotherapy. 
 
2.4 
Correlative Studies Background 
 
A series of correlative studies are proposed to examine the impact of the multikinase inhibitor 
XL184 (cabozantinib) on biomarkers within the tumor microenvironment and systemically.  The 
primary scientific objectives are to perform Next Generation exome sequencing on pretreatment 
biopsy and RNA sequencing on pretreatment and on-treatment biopsies for molecular 
characterization of the neuroendocrine carcinomas.   
 
In addition to these integrated biomarkers, we will assess a number of exploratory biomarkers.   
like tumor infiltration by CD8+ T cells, MDSC, TAM, and PD-L1 expression in the context of 
correlative laboratory studies.  Infiltrating lymphocytes will be compared in the tumor 
microenvironment before and after exposure to XL184 (cabozantinib), nivolumab, and 
ipilimumab.  These are based on the rationale that (1) patients with greater PD-L1 expression or 
antigen presenting capacity (as measured by MHC expression) will have a better response to 
immunotherapy; (2) tumors with high infiltration with MDSC and TAM respond poorly to 
checkpoint inhibition. 
 
These correlative studies will help us better understand the molecular composition of the 
neuroendocrine tumors, mechanism(s) underlying the roles of MET, AXL, TYRO3, VEGF in 
modulating tumor immunity, and possibly help identify biomarkers that may predict response to 
therapy in the context of this clinical trial.  We hypothesize that patients receiving the 
combination of XL184 (cabozantinib), nivolumab, and ipilimumab will have increased CD8+ T 
cell infiltration of their tumors as compared to prior to exposure to these drugs.  Further, we 
hypothesize that patients with increased CD8+ T cell infiltration will have a better clinical 
outcome. 
 
2.4.1 Whole exome sequencing (WES) of tumor DNA and of matching germline DNA 
collected from peripheral blood 
 
This is an integrated biomarker for the study.  Next-Generation sequencing (NGS) of tumor 
DNA is crucial for molecular characterization of the poorly differentiated neuroendocrine 
carcinomas for better understanding of the disease biology and its treatment.  Among the 
different approaches for NGS, WES of tumor DNA combined with that of germline DNA from a 
matching peripheral blood sample is the most informative and possibly cost-effective. 

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WES will provide a systematic analysis of the tumor genome of each patient, thus establishing 
genomic signatures for testing of their predictive and prognostic value.  Tumor mutation burden 
(TMB) and microsatellite instability (MSI) will be assessed as part of the NGS.  The WES output 
from the germline DNA will facilitate, in addition to providing novel candidate genes for 
outcome testing, identifying new genes associated with the side effects of the study drugs. 
 
2.4.2 RNA sequencing 
 
RNA sequencing will be used to compare gene expression patterns prior to and after exposure to 
the study drugs, XL184 (cabozantinib), nivolumab, and ipilimumab.  This will help in better 
understanding of the disease biology and the effect of treatment on the behavior of disease and 
treatment emergent complications. 
 
2.4.3 Tumor infiltrating CD8+ T cells 
 
Various preclinical and early phase clinical studies have shown the impact of the multikinase 
inhibitor cabozantinib on the immune profile of the tumor microenvironment.  The targets of 
cabozantinib like TYRO3, MER, and AXL have been implicated in promoting tumor immune 
suppression (Okunishi et al., 2005; Coudriet et al., 2010; Kwilas et al., 2014).  MEK inhibition 
can enhance T cell infiltration into tumors in murine models, limit their apoptosis and 
subsequently enhance the efficacy of immune checkpoint blockade.  
 
In a mouse model, increased tumor infiltration by CD8+ T cells while reduced tumor infiltration 
by myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) creating 
an immune permissive environment was seen as a result of exposure to cabozantinib (Kwilas et 
al., 2014).  
 
We hypothesize that patients receiving the combination of cabozantinib, nivolumab and 
ipilimumab will have increased CD8+ T cell infiltration of their tumors as compared to prior to 
exposure to these drugs. Further, we hypothesize that patients with increased CD8+ T cell 
infiltration will have a better clinical outcome. 
 
2.4.4 Tumor infiltrating MDSCs 
 
Levels of immune suppressive MDSCs in the tumor microenvironment may impact the response 
to checkpoint inhibitors.  We will compare the tumor infiltrating MDSCs before and after 
exposure to XL184 (cabozantinib), nivolumab, and ipilimumab.  In vitro and in vivo models have 
shown increased expression of MHC-I, ICAM-1, Fas, calreticulin, as a result of exposure to 
XL184 (cabozantinib) that led to improved recognition and killing of cancer cells by T 
lymphocytes (Kwilas et al., 2014).  We hypothesize that treatment with the combination of 
XL184 (cabozantinib), nivolumab, and ipilimumab will decrease the MDSC infiltration in 
tumors as compared to prior to exposure to these drugs. 
 
 

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2.4.5 Tumor-associated macrophages 
 
Tumor-associated macrophages (TAM) are known to exert an immune suppressive effect in the 
tumor microenvironment.  MET signaling has been shown to suppress the inflammatory 
response of macrophages as well as the activation and function of dendritic cells (Kwilas et al., 
2014).  In a mouse model reduced tumor infiltration by TAM helped create an immune 
permissive environment as a result of exposure to XL184 (cabozantinib).  We will compare the 
TAM in the tumor microenvironment before and after exposure to XL184 (cabozantinib), 
nivolumab, and ipilimumab.  We hypothesize that treatment with the study drugs will decrease 
the extent of TAM in tumors as compared to prior to exposure to these drugs. 
 
2.4.6 PD-L1 expression on tumor and immune cells 
 
Tumors that have high expression of PD-L1 have been noted to have better response to immune 
checkpoint inhibitors (Chen et al., 2018; Yi et al., 2018).  We will study the expression of PD-L1 
in the tumors before and after exposure to the drugs XL184 (cabozantinib), nivolumab, and 
ipilimumab. 
 
 
 
 

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3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have metastatic, histologically confirmed poorly-differentiated 
neuroendocrine neoplasms per 2018 WHO classification, with the exception of small cell 
lung cancer and Merkel cell carcinoma.  All variations of poorly differentiated 
neuroendocrine carcinoma (small cell, large cell and mixed cells) are eligible.  
 
3.1.2 Failure of only one line of prior systemic cancer treatment. 
 
3.1.3 Patients must have measurable disease as defined by Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1.  See Section 12 (Measurement of Effect) for the evaluation 
of measurable disease. 
 
3.1.4 Patients must have lesions that can be safely biopsied and be willing to have a pre-
treatment and an on-treatment biopsy (after 1 month of treatment with the combination 
regimen) and a blood collection at baseline. 
 
3.1.5 Prior systemic cancer therapy must have been completed at least 4 weeks prior to Cycle 1 
Day 1 of treatment with the combination regimen 
 
3.1.6 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of XL184 (cabozantinib), nivolumab, and ipilimumab in patients <18 years of age, 
children are excluded from this study, but may be eligible for future pediatric trials. 
 
3.1.7 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes  
 
≥3,000/mcL 
− 
absolute neutrophil count 
 
≥1,500/mcL without granulocyte-colony stimulating 
(GCSF) factor support 
− 
hemoglobin 
≥9 g/dL 
− 
serum TSH 
within institutional normal limits 
− 
platelets  
 
≥100,000/mcL 
− 
total bilirubin 
 
≤1.5 × institutional upper limit of normal (ULN); 
≤3.0 × ULN for patients with Gilbert’s syndrome 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN 
− 
alkaline phosphatase 
≤3.0 × institutional ULN; ≤5.0 × ULN with 
documented bone metastases 
− 
creatinine 
≤ institutional ULN  
 
 
OR 
− 
creatinine clearance (CrCl) 
≥50 mL/min/1.73 m2 (using the Cockcroft-Gault 
formula, see Appendix B) 
− 
serum albumin 
≥2.8 g/dL 

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− 
lipase 
<2.0 × ULN and no radiologic or clinical evidence 
of pancreatitis 
− 
urine protein/creatinine ratio 
 
(UPCR) 
≤1 mg protein/mg creatinine 
− 
serum phosphorus, calcium, 
magnesium, and potassium 
  within institutional normal limits 
− 
prothrombin time (PT)/International 
Normalized Ratio (INR) and partial 
thromboplastin time (PTT) test 
<1.3 × ULN 
 
3.1.9 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy utilizing agents that do not strongly induce or inhibit cytochrome P450 (CYP) 
3A4 with undetectable viral load within 6 months prior to study registration are eligible 
for this trial. 
 
3.1.10 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.11 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.12 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression and are 
off steroid support for at least 4 weeks after treatment for metastases is complete and 
within 28 days prior to the first dose of study treatment.  Radiotherapy should have been 
stopped at least 4 weeks prior to study registration.  Brain surgery should not have 
occurred within 3 months of study registration to be eligible.  
 
3.1.13 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.14 The effects of XL184 (cabozantinib), nivolumab, and ipilimumab on the developing 
human fetus are unknown.  For this reason, women of child-bearing potential (WOCBP) 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation.  
WOCBP should use an adequate method to avoid pregnancy for 5 months after the last 
dose of study therapy.  Women of childbearing potential must have a negative serum or 
urine pregnancy test (minimum sensitivity:  25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG]) within 24 hours prior to the start of study therapy.  
Women must not be breastfeeding.  Men who are sexually active with WOCBP must use 
any contraceptive method with a failure rate of <1% per year.  Men who receive study 
therapy and who are sexually active with WOCBP will be instructed to adhere to 
contraception for a period of 7 months after the last dose of study therapy.  Women who 

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29 
are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as 
well as azoospermic men do not require contraception.   
 
WOCBP is defined as any female who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not 
postmenopausal.  Menopause is defined clinically as 12 months of amenorrhea in a 
woman over 45 in the absence of other biological or physiological causes.  In addition, 
women under the age of 55 must have a documented serum follicle stimulating hormone 
(FSH) level <40 mIU/mL. 
 
WOCBP and men who are sexually active with WOCBP will be instructed to adhere to 
contraception for a period of 5 and 7 months, respectively, after the last dose of study 
therapy.  These durations have been calculated using the upper limit of the half-life for 
nivolumab (25 days) and are based on the protocol requirement that WOCBP use 
contraception for 5 half-lives plus 30 days and men who are sexually active with 
WOCBP use contraception for 5 half-lives plus 90 days. 
 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she (or the participating partner) must inform the treating 
physician immediately. 
 
3.1.15 Patients must be able to swallow tablets 
 
3.1.16 Ability to understand and the willingness to sign a written informed consent document.  
Participants with impaired decision-making capacity (IDMC) who have a legally-
authorized representative (LAR) and/or family member available will also be eligible. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients must not require systemic corticosteroids treatment (≥10 mg/day prednisone 
equivalents) or other immunosuppressive medications within 28 days prior to study drug 
administration.  Inhaled or topical steroids and adrenal replacement doses <10 mg/day 
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 in patients with adrenal insufficiency are permitted, even if ≥10 
mg/day prednisone equivalents.  A brief course of corticosteroids for prophylaxis or for 
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted, as is steroid pre-medication for contrast allergy. 
 
3.2.2 Patients must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-
stimulation or immune checkpoint pathways. 
 

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3.2.3 Patients must not have had prior treatment with XL184 (cabozantinib), or any MET-
targeting TKI, or any MET-targeting monoclonal antibody (MetMAb), such as 
onartuzumab. 
 
3.2.4 Patients must not have received radiation therapy to any part of the body within 28 days 
 
3.2.5 Patients must not have clinically relevant, ongoing complications from prior radiation 
therapy.  No radiation therapy is allowed while the patient is on study.  Palliative 
radiation therapy, if needed, should be completed at least 28 days prior to enrollment into 
the study as described above. 
 
3.2.6 Patients must not require concomitant treatment with oral anticoagulants (e.g., warfarin, 
direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel).  The 
following anticoagulants are allowed: 
• Low-dose aspirin for cardioprotection (per local applicable guidelines), 
• Low-dose low molecular weight heparins (LMWH), 
• Therapeutic doses of LMWH are allowed in patients without known brain metastases 
who are on a stable dose of LMWH for at least 6 weeks before the first dose of study 
treatment, and who have had no clinically significant hemorrhagic complications 
from the anticoagulation regimen or the tumor. 
 
3.2.7 Patients must not have had major surgery (e.g., GI surgery or removal or biopsy of brain 
metastasis) within 4 weeks before first dose of study treatment.  Complete wound healing 
from major surgery must have occurred 1 month before the first dose of study treatment 
and from minor surgery (e.g., simple excision or tooth extraction) at least 10 days before 
the first dose.  Patients with clinically relevant ongoing complications from prior surgery 
are not eligible. 
 
3.2.8 Patients must not have received cytotoxic chemotherapy (including investigational 
cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 
weeks, or nitrosoureas/ mitomycin C within 4 weeks, before the first dose of study 
treatment.  Patients may continue on bone-modifying agents (denosumab or 
bisphosphonates) with caution. 
 
3.2.9 Patients who have not recovered to baseline from adverse events due to prior anti-cancer 
therapy (i.e., have residual toxicities > Grade 1) according to Common Terminology 
Criteria for Adverse Events (CTCAE) v0.5 unless the AEs are clinically nonsignificant 
and/or stable on supportive therapy, with the exception of alopecia. 
 
3.2.10 Patients who are receiving any other investigational agents.  Patients must not have 
received any other type of investigational agent within 4 weeks before the first dose of 
study treatment to be eligible. 
 

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3.2.11 Patients must not have a corrected QT interval calculated by the Fridericia formula 
(QTcF) >500 msec by electrocardiogram (EKG) within 28 days before the first dose of 
study treatment. 
 
Note:  If a single EKG shows a QTcF with an absolute value >500 msec, two additional 
EKGs at intervals of approximately 3 min must be performed within 30 min after the 
initial EKG, and the average of these three consecutive results for QTcF will be used to 
determine eligibility. 
 
3.2.12 Patients should not have known, untreated brain metastases or leptomeningeal metastases 
because of poor prognosis and concerns that progressive neurologic dysfunction could 
confound the evaluation of neurologic and other adverse events. 
 
3.2.13 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to agents used in study. 
 
3.2.14 Patients must not have a history of severe hypersensitivity reactions to any monoclonal 
antibodies. 
 
3.2.15 Patients must not require concomitant treatment with strong CYP3A4 inducers (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, 
or St. John’s Wort).  Because lists of these agents are constantly changing, it is important 
to regularly consult a frequently-updated medical reference.  As part of the 
enrollment/informed consent procedures, patients will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. 
 
Appendix C contains a patient clinical trial wallet card that can be given to patients. 
 
3.2.16 Patients must not have uncontrolled, significant intercurrent or recent illness including, 
but not limited to, the following conditions:   
• Cardiovascular disorders: 
o Congestive heart failure New York Heart Association (NYHA) Class 3 or 4, 
unstable angina pectoris, serious cardiac arrhythmias. 
o Uncontrolled hypertension defined as sustained blood pressure (BP) >140 mm Hg 
systolic or >90 mm Hg diastolic despite optimal antihypertensive treatment within 
seven days prior to the first dose of study treatment. 
o Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or 
other ischemic event, or thromboembolic event (e.g., deep venous thrombosis 
[DVT], pulmonary embolism [PE]) within 6 months before first dose. 
• GI disorders including those associated with a high risk of perforation or fistula 
formation: 
o The patient has evidence of tumor invading the GI tract, active peptic ulcer 
disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute 

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32 
obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction. 
o Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months before first dose.  Complete healing of an intra-abdominal 
abscess must be confirmed before first dose. 
• Clinically significant hematuria, hematemesis, or hemoptysis or other history of 
significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose. 
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease 
manifestation. 
• Lesions invading or encasing any major blood vessels. 
• Other clinically significant disorders that would preclude safe study participation. 
o Serious non-healing wound/ulcer/bone fracture.  
o Uncompensated/symptomatic hypothyroidism. 
o Moderate to severe hepatic impairment (Child-Pugh B or C). 
 
3.2.17 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.18 Pregnant women are excluded from this study because XL184 (cabozantinib) has the 
potential for teratogenic or abortifacient effects, and the effects of nivolumab and 
ipilimumab on the developing fetus are not well known.  Because there is an unknown 
but potential risk for AEs in nursing infants secondary to treatment of the mother, 
breastfeeding must be discontinued if the mother is treated with XL184 (cabozantinib), 
nivolumab, or ipilimumab. 
 
3.2.19 Patients with active autoimmune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including high dose systemic corticosteroids, should be excluded.  These include but are 
not limited to:  immune-related neurologic disease, such as multiple sclerosis, 
autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, or myasthenia 
gravis; systemic autoimmune disease such as Systemic Lupus Erythematosus (SLE), 
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, 
ulcerative colitis, or 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, type I diabetes mellitus (DM), or endocrine deficiencies (e.g., 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, (e.g., 
antinuclear antibodies (ANA) or anti-thyroid antibodies) should be evaluated for the 
presence of target organ involvement and potential need for systemic treatment but 
should otherwise be eligible. 
 
 

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33 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Please refer to the table in Section 9.2 for the planned distribution of patients by sex, race, and 
ethnicity. 
 
 
 
 

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2. Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
3. Act as the site-protocol Principal Investigator (PI) on the IRB approval.  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, must 
be rostered at the enrolling site with a participating organization (i.e., Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRB Manager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 

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36 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and their associated investigators and staff on a participating roster.  
To view/download site registration forms:   
• Log in to the CTSU members’ website (https://www.ctsu.org),  
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-MD017, and 
protocol number 10315, 
• Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided.  (Note:  For sites 
under the CIRB, IRB data will load automatically to the CTSU.) 
 
 
4.2.2 Submitting Regulatory Documents 
 
 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website. 
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application which is accessible 
via the Delegation Log link on the CTSU members’ website or directly at https://dtl.ctsu.org.  
The Clinical Investigator (CI) is required to review and electronically sign the DTL prior to the 
site receiving an approved site registration status and enrolling patients to the study.  To maintain 
an approved site registration status the CI must re-sign the DTL at least annually and when a new 
version of the DTL is released; and activate new task assignments requiring CI sign-off.  Any 
individual at the enrolling site on a participating roster may initiate the site DTL.  Once the DTL 
is submitted for CI approval, only the designated DTL Administrators or the CI may update the 
DTL.  Instructions on completing the DTL are available in the Help Topics button in the DTL 

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application and describes DTL task assignments, CI signature, and CTEP registration 
requirements, as well as include a Master Task List. 
 
The DTL for this study has training requirements as follows: 
 
All staff assigned the Rave CRA task on the DTL for this study must complete the Theradex 
Specimen Tracking System (STS) Training course.   
 
1. The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study with the same course 
requirement, the training does not need to be completed again.  However, new versions of 
the Specimen Tracking System may require new training. 
 
A task-related training requirement is satisfied by completing the course in the Compliance, 
Learning, and SOP Solutions (CLASS) application at https://classlms.org; until that takes place, 
the task assignment will remain in a Pending status. 
 
• When a Rave CRA is assigned the task on an ETCTN DTL, the system will check to see 
if they have completed the appropriate course, and if not, they will be automatically 
enrolled in the course.  They will receive an enrollment email from 
CLASSHelpDesk@westat.com that will include instructions on how to access the course. 
 
When an assignee completes the necessary course, their completion will be automatically 
communicated from CLASS to the DTL application and the task status will go to Active or 
Awaiting CI Approval, depending on the situation (please allow up to four hours for this to 
happen).  The DTL cannot be submitted for CI sign-off until the minimum number of persons are 
assigned to the task(s) and have met all task requirements including any training requirements. 
 
4.2.3 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  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. 
 
4.3 
Patient Registration 
 

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4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study. 
 
 
4.3.2 OPEN/IWRS Questions? 
 

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Further instructional information on OPEN is provided on the OPEN link 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.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within a minimum of 7 days and 
no more than 14 days.  Issues that would cause treatment delays should be discussed with the 
Principal Investigator.  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
 
 

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41 
 
Biopsy #:  2 
Trial Time Point:  Cycle 2 (within Days 28 – 35) 
IR Biopsy Definition:  Research – No Clinical Impact (All cores from a single biopsy 
procedure impact research goals, but do not directly impact patient care or benefit the patient.) 
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated  
RNA 
sequencing 
>50% 
Formalin-fixed 
2 
Exploratory 
Tumor 
infiltrating 
lymphocytes 
>50%  
Formalin-fixed 
3 
Exploratory 
Tumor 
infiltrating 
MDSCs, 
Tumor-
associated 
macrophages 
>50%  
Formalin-fixed 
4 
Exploratory 
PD-L1 
expression 
>50%  
Formalin-fixed 
 
Note:  Pre-biopsy assessments will be reported and tracked through a trial-specific case report 
form (CRF) within the CTEP Medidata Rave system (see Appendix D).  
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of specimens to the EET Biobankcan be ordered online via 
the Kit Management system: (https://ricapps.nationwidechildrens.org/KitManagement).  
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kit types per protocol per day (daily max = 6 kits).  
Kits are shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for 
each kit type is located on the Kit Management system website. 
 
Note:  Kits or supplies are only provided for specimens shipped to the Biorepository. 
Institutional supplies must be used for all other specimen collection and processing.  
 
5.3.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue:  
• Tumor tissue specimens collected during biopsy procedures and fixed in formalin must 
be shipped on the same day of collection. 

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• Tissue in formalin can be collected Monday through Wednesday and shipped overnight 
for arrival on Tuesday through Thursday at the EET Biobank at Nationwide Children’s 
Hospital. 
 
• Fresh blood specimens may be collected and shipped Monday through Friday.  
 
5.4 
Specimen Tracking System Instructions 
 
This Study will use the ETCTN Specimen Tracking System (STS). 
 
• All biospecimens collected for this trial must be submitted using the ETCTN STS unless 
otherwise noted. 
• The system is accessed through Rave user roles: “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions. The “Biorepository” role is 
assigned to users receiving the specimens for processing and storage at reference labs and 
the NCI Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, 
formerly known as the EET Biobank). 
 
Important:  Failure to complete required fields in STS may result in a delay in sample 
processing.  Any case reimbursements associated with sample submissions will not be credited 
if samples requiring STS submission are not logged into STS. 
 
Detailed instructions on use of the STS can be found below. 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 0. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this protocol that uses the ETCTN Specimen Tracking System.  The 
UPID contains no information or link to the treatment protocol.  IWRS will maintain an 
association between the UPID for ETCTN biobanking and molecular characterization and any 
treatment protocols the patient participates in, thereby allowing analysis of the molecular 
characterization results with the clinical data.   
 

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Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, initials, medical record 
number, and patient contact information from the institutional pathology report prior to 
submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date [if the study also requires recording the collection time on the label, 
include the time] (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, Fresh Tissue in Media, etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Collection date and time (to be added by hand) 
 

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5.4.2.3 Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. 
Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. 
Block ID or blank if not relevant 
3. 
SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 

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Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date and time on each label. 
• After collection, store labeled specimens as described in Section 5.4.2. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Pathology Verification form (when applicable).  
Return to Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per specimen).  
Uploaded reports should have protected health information (PHI) data, like name, 
mailing address, medical record number or social security number (SSN), redacted.  Do 
not redact SPID, block number or relevant dates, and include the UPID and patient study 
ID on each document.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 

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Step 7:  Ship the specimen(s). 
 
5.5 
Specimen Collection  
 
5.5.1 Formalin-Fixed Tumor Biopsies  
 
1. Label formalin-filled containers according to instructions in Section 5.4.2.  
2. Obtain [number] 16-gauge or 18-gauge core needle biopsy specimens, and place one core 
in each cassette.  
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying.  Up to two cassettes 
may be placed in one formalin jar. 
4. Secure the container lids and package containers into the shipping kit according to 
instructions in Section 5.6.  Keep tissue in formalin jars at room temperature until 
shipment to theEET Biobank.  
 
 
5.5.2 Blood Collection  
 
5.5.2.1 Collection of Blood in cfDNA Streck Tube 
 
1. Label one 10 mL cfDNA Streck tube according to the instructions in Section 5.4.2.  
2. Collect 10 mL of blood into the pre-labeled tube and gently invert to mix.  Note:  blood 
must be thoroughly mixed to ensure preservation of specimen.  [Include the following 
language if patients may have an indwelling catheter:  heparin should be avoided in pre-
collection flush procedures.  If therapeutic heparin dosing contamination is a possibility, 
then venipuncture is recommended as a first choice collection method.  If a cfDNA 
Streck tube immediately follows a heparin tube in the draw order, then collecting an 
EDTA tube as a waste tube prior to collection in the Streck Cell-Free DNA BCT is 
recommended.] 
3. After collection, blood in cfDNA Streck tubes should never be refrigerated, as this 
will compromise the specimen.  Blood collected in cfDNA Streck tubes is stable at room 
temperature.  
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank 
 
5.6.1 General Shipping Information 
 
Core biopsies that are fixed in formalin and fresh blood should be shipped as one shipment at 
ambient temperature, whenever possible.  The same box sent with kit contents should be used to 
ship specimens to theEET Biobank.  In winter months, please include extra insulation, such as 
bubble wrap, inside the shipping container. 
 

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For formalin-fixed biopsies, if the corresponding anatomical pathology report is not available at 
the time of shipment, then the surgical and/or radiology report must be uploaded to the ETCTN 
specimen tracking system and included in the package, or the specimen will not be processed. 
  
5.6.2 Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday. 
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday.  
 
5.6.2.1 
Shipping Blood in an Ambient Shipper 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.   
2. Prepare the SAF-T-TEMP Gel Pak for shipment.  Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth.  Do not refrigerate, freeze, 
or microwave.  
3. Place the SAF-T-TEMP Pak in bottom of insulated chest.  Note:  The insulated chest 
must be shipped inside the provided cardboard box(es).  
4. Place the blood collection tubes in zip-lock bags.   
5. Next, place blood into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
7. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System on top of SAF-T-TEMP Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Attach a shipping label to the top of the shipping container.  
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.2.2 
Shipping Ambient Tissue and Blood in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.  Formalin jars should be wrapped in parafilm.  
2. Place the specimens in zip-lock bags.  Use a separate bag for each specimen type. 
3. Place specimens into a biohazard envelope with absorbent material.  Expel as much air as 
possible and seal the envelope securely.  
4. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 

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5. Place the specimen(s) and a copy of the shipping manifest and corresponding reports 
such as surgical or radiology reports into the insulated shipping container. In winter 
months, please include extra insulation, such as bubble wrap, inside the shipping 
container, to prevent specimens from freezing.  
6. Place the lid on top of the container.  Close the outer flaps and tape shut. 
7. Attach a shipping label to the top of the shipping container.  
8. Attach an Exempt Human Specimen sticker to the side of the container. 
9. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.3 Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org  
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank 
Toll-free Phone: (614) 722-2865 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories  
 
N/A 
 
Biomarker Plan  
 
 
 

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5.8 
Integrated Correlative Studies 
 
5.8.1 Whole Exome Sequencing (WES) 
 
5.8.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be sectioned 
to generate an initial H&E-stained slide, and for nucleic acid extractions, additional RNase-free 
slides. 
 
Whole blood collected in Streck tubes will be centrifuged to separate buffy coat and plasma and 
will be stored in a -80°C freezer. 
 
DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to 
determine concentration and quality.  Aliquots of DNA and RNA will be shipped to the central 
sequencing laboratory for analysis. 
 
5.8.1.2 
Site Performing Correlative Study 
 
WES will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov).  
 
5.8.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.8.1.4 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov  
 
RNA Sequencing (RNAseq) 
5.8.1.5 
Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be sectioned 
to generate an initial H&E-stained slide, and for nucleic acid extractions, additional RNase-free 
slides. 
 
DNA and RNA will be co-extracted from tumor tissue.  The nucleic acids will be analyzed to 
determine concentration and quality.  Aliquots of DNA and RNA will be shipped to the central 
sequencing laboratory for analysis. 

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5.8.1.6 
Site Performing Correlative Study 
 
RNAseq will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.8.1.7 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.8.1.8 Contact information for notification of specimen shipment 
 
Thomas Forbes, mochasamplereceiving@nih.gov  
 
5.9 
Exploratory/Ancillary Correlative Studies 
 
5.9.1 Tumor Infiltrating CD8+ T Cells 
 
5.9.1.1 Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded and sectioned.  FFPE tumor tissue 
will be used to produce 20 unstained sections, cut at 5 micrometers thickness and mounted on 
glass slides.  About 5 slides will be used for each exploratory assay. 
 
5.9.1.2 
Site Performing Correlative Study 
 
This assay will be conducted at Wayne State University under the leadership of Kang Chen, 
Ph.D.  Samples from EET Biobank should be shipped to address below: 
 
Kang Chen 
421 East Canfield Street, Room 2221 
Detroit, MI 48202 
Phone number:  313-578-4339 
Email:  kang@wayne.edu  
 
5.9.2 Tumor Infiltrating MDSCs 
 
5.9.2.1 Specimens Receipt and Processing at the EET Biobank 
 

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Tumor tissue received in formalin will be paraffin-embedded and sectioned.  FFPE tumor tissue 
will be used to produce 20 unstained sections, cut at 5 micrometers thickness and mounted on 
glass slides.  About 5 slides will be used for each exploratory assay. 
 
5.9.2.2 
Site Performing Correlative Study 
 
This assay will be conducted at Wayne State University under the leadership of Kang Chen, 
Ph.D.  Samples from EET Biobank should be shipped to address below: 
 
Kang Chen 
421 East Canfield Street, Room 2221  
Detroit, MI 48202 
Phone number:  313-578-4339 
Email:  kang@wayne.edu  
 
5.9.3 Tumor Associated Macrophages 
 
5.9.3.1 Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded and sectioned.  FFPE tumor tissue 
will be used to produce 20 unstained sections, cut at 5 micrometers thickness and mounted on 
glass slides.  About 5 slides will be used for each exploratory assay. 
 
5.9.3.2 
Site Performing Correlative Study 
 
This assay will be conducted at Wayne State University under the leadership of Kang Chen, 
Ph.D.  Samples from EET Biobank should be shipped to address below: 
 
Kang Chen 
421 East Canfield Street, Room 2221 
Detroit, MI 48202 
Phone number:  313-578-4339 
Email:  kang@wayne.edu  
 
5.9.4 PD-L1 Expression on Tumor and Immune Cells 
 
5.9.4.1 Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded and sectioned.  FFPE tumor tissue 
will be used to produce 20 unstained sections, cut at 5 micrometers thickness and mounted on 
glass slides.  About 5 slides will be used per each exploratory assay. 
 
5.9.4.2 
Site Performing Correlative Study 
 
This assay will be conducted at Wayne State University under the leadership of Kang Chen, 
Ph.D. using a commercial kit.  Samples from EET Biobank should be shipped to address below: 

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Kang Chen 
421 East Canfield Street, Room 2221 
Detroit, MI 48202 
Phone number:  313-578-4339 
Email:  kang@wayne.edu  
 
 
 

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6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Cycles 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
1-4 
XL184 
(cabozantinib) 
XL184 (cabozantinib) 
should be taken on an 
empty stomach.  Patients 
should not eat for at least 
2 hours before, and 1 hour 
after each dose. 
40 mg 
PO 
Days 1-21 
21 days  
(3 weeks) 
Nivolumab 
N/A 
3 mg/kg 
IV 
Day 1 of Cycles 
1-4 
(4 total doses)  
Ipilimumab 
N/A 
1 mg/kg 
IV 
Day 1 of Cycles 
1-4 
(4 total doses) 
5+ 
XL184 
(cabozantinib) 
XL184 (cabozantinib) 
should be taken on an 
empty stomach.  Patients 
should not eat for at least 
2 hours before, and 1 hour 
after each dose. 
40 mg 
PO 
Days 1-28 
28 days 
(4 weeks) 
Nivolumab 
N/A 
480 mg 
IV 
Day 1of Cycles 
5+ 
PO = Oral; IV = Intravenous 
Treatment will be continued until criteria for removal from the study are met (See Section 6.5 
Duration of Therapy) 
 
Screening and baseline biopsy will be done within 28 days prior to starting treatment.   
 
Patients will receive XL184 (cabozantinib) 40 mg by mouth (PO) once daily.  Nivolumab will be 
given at a dose of 3 mg/kg on Day 1 (±3 days) of each 3-week cycle for the first 4 cycles (12 
weeks).  Ipilimumab is to be administered at a dose of 1 mg/kg immediately following 
nivolumab administration on Day 1 of each 3-week cycle for the first 4 cycles.  No more than 
four doses of ipilimumab should be administered. 
 

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Starting Cycle 5, patients will continue to take cabozantinib 40 mg PO daily and receive IV 
infusion of nivolumab 480 mg every 4 weeks.  Treatment will be continued until criteria for 
removal from the study is met (See Section 6.5 Duration of Therapy).  The study is projected to 
complete accrual in about 2 years.  All patients will be followed until death unless consent has 
been withdrawn. 
 
The frequency of nivolumab and ipilimumab infusion is supported by the label insert and prior 
studies, respectively (Nivolumab Package Insert, 2014; Ansell et al., 2009).  The dose level of 
XL184 (cabozantinib), in combination with nivolumab, and ipilimumab was selected as this was 
shown to be very well tolerated in this combination (Apolo et al., 2017).   
 
6.1.1 XL184 (cabozantinib) 
 
Patients will receive XL184 (cabozantinib) PO at a dose of 40 mg once daily.  XL184 
(cabozantinib) must be taken on an empty stomach.  Patients should be instructed not to eat for at 
least 2 hours before and at least 1 hour after taking XL184 (cabozantinib).  Patients should be 
instructed to take their dose at approximately the same time every day.  If a patient misses a 
dose, the dose may be taken later only if it is within 12 hours of when the missed dose should 
have been taken.  The missed dose should not be made up if it is within 12 hours of the next 
scheduled dose.  If a patient vomits after taking a dose, the dose should not be made up.  The 
patient should be instructed to take the next dose at the regularly scheduled time. 
 
XL184 (cabozantinib) tablets should be swallowed whole with at least 8 ounces of water.  The 
tablets should not be crushed.  Grapefruit, grapefruit juice, Seville oranges, and their products 
should be avoided by patients taking XL184 (cabozantinib).  Patients will be asked to maintain a 
medication diary for each dose of medication (Appendix E).  The medication diary should be 
returned to clinic staff at the end of each month. 
 
Dose reductions and delays to manage toxicity are allowed under the guidelines in Section 7.1 
below.  XL184 (cabozantinib) administration will continue until disease progression or 
unacceptable toxicity. 
 
6.1.2 Nivolumab 
 
Nivolumab will be given at a dose of 3 mg/kg on Day 1 (±3 days) of each 3-week cycle for the 
first 4 cycles (12 weeks).  Starting with Cycle 5, nivolumab will be given every 4 weeks (±3 
days) at a dose of 480 mg on Day 1 of each 4-week cycle.  No dose modifications are allowed 
for Nivolumab.  Nivolumab administration will continue until disease progression or 
unacceptable toxicity. 
 
Nivolumab is to be administered as an approximate 30-minute IV infusion, using a volumetric 
pump with a 0.2-1.2 micron in-line filter.  When the dose is based on patient weight (i.e., mg/kg), 
nivolumab injection can be infused undiluted, or diluted with 0.9% normal saline or 5% dextrose 
in water to protein concentrations as low as 0.35 mg/mL. When the dose is fixed (e.g., 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 kg, the total volume of infusion 

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must not exceed 4 mL per kg of patient weight.  It is not to be administered as an IV push or 
bolus injection.  At the end of the infusion, flush the line with a sufficient quantity of normal 
saline. 
 
Nivolumab dosing calculations should be based on the actual body weight.  If the patient’s 
weight differs by >10% from the weight used to calculate the original dose, the dose may be 
recalculated.  All doses should be rounded to the nearest milligram. 
 
When infusions of ipilimumab and nivolumab are given on the same day, the preferred treatment 
is to give nivolumab followed by ipilimumab.  Separate infusion bags and filters must be used 
for each drug.  The infusion line must be flushed with normal saline between infusions. 
 
Toxicity management should follow the guidelines and algorithms provided in Section 7 and 
Appendix E. 
 
6.1.3 Ipilimumab 
 
Ipilimumab is to be administered as an approximate 90-minute IV infusion at a dose of 1 mg/kg 
immediately following nivolumab administration on Day 1 of each 3-week cycle for the first 4 
cycles (12 weeks), using a volumetric pump with a 0.2-1.2 micron in-line filter.  The drug can be 
diluted with 0.9% normal saline for delivery or 5% dextrose in water, but the total drug 
concentration of the solution must stay within the range of 1 mg/mL to 4 mg/mL.  It is not to be 
administered as an IV push or bolus injection.  At the end of the infusion, flush the line with a 
sufficient quantity of normal saline.  No more than four doses of ipilimumab should be 
administered. 
 
Ipilimumab dosing calculations should be based on the actual body weight.  If the patient’s 
weight differs by >10% from the weight used to calculate the original dose, the dose may be 
recalculated.  All doses should be rounded to the nearest milligram. 
 
Toxicity management for ipilimumab should follow the same guidelines and algorithms that are 
provided in Section 7 and Appendix E. 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of XL184 (cabozantinib) with other concomitantly 
administered drugs, the CRF must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The PI should be alerted if the patient is taking any agent 
known to affect or with the potential for drug interactions.  For example, the potential targets for 
drug interaction can involve, but are not limited to CYPs 450, glucuronidation, P-glycoprotein, 
protein binding, or reduced absorption from proton-pump inhibitors.  Check the Investigator’s 
Brochures for each study agent for potential sources of drug interactions.  The study team should 
check a frequently-updated medical reference for a list of drugs to avoid or minimize use of.  
Appendix B (Patient Clinical Trial Wallet Card) should be provided to patients if available. 
 

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6.2.1 Concomitant Medications and Therapies  
 
6.2.1.1 
Anticancer Therapy  
 
If a patient requires additional systemic anticancer treatment, study treatment must be 
discontinued.  Patients who require palliative radiation therapy while being treated in the study 
will need to come off the study.  The need for local intervention will be considered a clinical 
disease progression.  The addition of radiation therapy to a combination of immunotherapeutic 
agents may also make the interpretation of the results of this study difficult through the abscopal 
effect.  Patients who may benefit from palliative radiation therapy must complete such 
intervention prior to enrollment into the study. 
 
6.2.1.2 
Other Medications 
 
Patients must be instructed to inform the treating physicians of the current or planned use of all 
other medications during the study (including prescription medications, over-the-counter 
medications, vitamins, and herbal and nutritional supplements).  It is the responsibility of the 
treating physician to ensure that details regarding all medications are documented. 
 
Bisphosphonates or denosumab started prior to screening activities or initiated during the course 
of the study to control bone pain may be used with caution.  Start date and end dates for such 
treatments must be documented. 
 
Pain medications administered as dictated by standard practice are acceptable while the patient is 
enrolled in the study. 
 
No concurrent investigational agents are permitted. 
 
6.2.1.3 
Potential Drug Interactions 
 
6.2.1.3.1 
Cytochrome P450 
 
Co-administration of XL184 (cabozantinib) with strong inducers of the CYP3A4 family (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. 
John’s Wort) may significantly decrease XL184 (cabozantinib) concentrations.  The chronic use 
of strong CYP3A4 inducers should be avoided.  Other drugs that induce CYP3A4 (e.g., chronic 
use of modafinil) should be used with caution because these drugs have the potential to decrease 
exposure to XL184 (cabozantinib).  Selection of alternate concomitant medications with no or 
minimal CYP3A4 enzyme induction potential is recommended.  In addition, caution must be 
used when discontinuing treatment with a strong CYP3A4 inducer in a patient who has been 
concurrently receiving a stable dose of XL184 (cabozantinib), as this could significantly increase 
the exposure to XL184 (cabozantinib). 
 
Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, 
nefazodone, nelfinavir, and ritonavir) and other drugs that inhibit CYP3A4 should be avoided 
because these drugs have the potential to increase exposure to XL184 (cabozantinib).  

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Grapefruit, grapefruit juice, and Seville oranges may also increase plasma concentrations of 
XL184 (cabozantinib).  Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme inhibition potential is recommended. 
 
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYPs (e.g., CYP2C8, 
CYP2C19, CYP2B6, CYP1A2) to alter XL184 (cabozantinib) exposure is not known.  
Therefore, these drugs should be used with caution when given with XL184 (cabozantinib). 
 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference.  As part of the enrollment/informed consent procedures, 
the patient will be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product. 
 
6.2.1.3.2 
Protein Binding 
 
XL184 (cabozantinib) is highly protein bound (approximately 99.9%) to human plasma proteins.  
Therefore, highly-protein-bound drugs should be used with caution with XL184 (cabozantinib) 
because the potential displacement interaction could increase free concentrations of XL184 
(cabozantinib) and/or co-administered highly protein-bound drugs and lead to corresponding 
increases in pharmacologic effect(s).  Factors that influence plasma protein binding may affect 
individual tolerance to XL184 (cabozantinib).  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 narrow therapeutic index, administration 
of warfarin at therapeutic doses should be avoided in patients receiving XL184 (cabozantinib) 
due to the potential for a protein binding displacement interaction. 
 
6.2.1.3.3 
Drugs Associated with QTc Prolongation 
 
Treatment with XL184 (cabozantinib) has been associated with a mild prolongation of the QTc 
interval.  Caution should be used when treating patients on XL184 (cabozantinib) with other 
drugs associated with QTc prolongation (see http://www.qtdrugs.org).  Additional QTc 
monitoring is suggested for patients who are treated concomitantly with QTc-prolonging drugs. 
 
6.2.1.3.4 
Other Interactions 
 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers, or antacids has had no 
clinically relevant effect on XL184 (cabozantinib) plasma PK in healthy volunteers; thus, 
concomitant use of these drugs with XL184 (cabozantinib) is allowed. 
 
In vitro data suggest that XL184 (cabozantinib) is unlikely to be a substrate for P glycoprotein 
(P-gp), but it does appear to have the potential to inhibit the P-gp transport activity. 
 
Additional details related to these overall conclusions are provided in the most recent version of 
the XL184 (cabozantinib) Investigator’s Brochure. 

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6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for until one 
of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) (See also Section 7 and specific algorithms in Appendix 
E) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.4 
Duration of Follow-Up 
 
Patients will need to come in for an initial clinical follow up at 4 weeks after the last dose of the 
study drugs.  Thereafter, patients will be followed as part of the off-study evaluation every 3 
months until death or withdrawal of consent.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  Off study 
follow-up can occur via a phone call.  
 
 
 

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7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicity evaluation will be done monthly for as long as the patient is on active treatment.  
Complete blood counts with differential, comprehensive metabolic panel, and TSH will be done 
the beginning of each treatment cycle. 
 
XL184 (cabozantinib), and nivolumab and ipilimumab have class-specific safety profiles based 
on their mechanisms of action, but may also cause AEs that overlap.  The management of these 
toxicities generally includes holding drug for moderate (Grade 2) toxicities and using systemic 
immunosuppression for severe (Grade 3/4) or prolonged moderate (> 1 week) toxicities per the 
treating clinician’s discretion as guided by the package insert of the respective drugs. Additional 
immunosuppression (e.g., anti-TNFα therapy, infliximab) may be used if IV steroids are 
ineffective at the discretion of the treating clinician using the package insert as a guide. 
 
For management of AEs which can be clearly attributed to either XL184 (cabozantinib) or 
immunotherapy, independent dose modification for either component of study treatment is 
allowed.  Examples of VEGFR TKI-associated AEs caused by XL184 (cabozantinib) are 
hypertension and hand-foot syndrome.  Examples of immune-related AEs caused by nivolumab 
and ipilimumab are pneumonitis and endocrinopathies.  For AEs without clear attribution to 
either component of study treatment, management of toxicity should include dose modifications 
of XL184 (cabozantinib) and immunotherapy, at the discretion of the investigator.  Examples of 
overlapping AEs are diarrhea and transaminase increases.  Patients who experience a Grade 3 or 
greater toxicity that is attributed to study medication and cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted until the toxicity improves 
to Grade 2 or lower. Patients may subsequently be re-started on study drug, including at a 
reduced dose in the case of XL184 (cabozantinib). 
 
7.1 
XL184 (Cabozantinib) 
 
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruption): 
 
• As a general approach all AEs should be managed with supportive care at the earliest 
signs of toxicity considered related to the study treatment.  Should this be ineffective, 
dose interruptions and/or reductions should be considered to prevent worsening of 
toxicity.  
• The assigned starting dose for XL184 (cabozantinib) is 40 mg/day.  Two dose reduction 
levels of XL184 (cabozantinib) are permitted (see Section 7.1.2). 
• Study treatment dose adjustment is only needed if the AE is deemed possibly, probably, 
or definitely related to XL184 (cabozantinib) treatment. 
• Dose modification criteria for XL184 (cabozantinib) are shown below in Section 7.1.2.  
Dose interruptions and/or reductions should be implemented for unacceptable toxicity.  
Doses may be modified at any time while a patient is on treatment. 
• Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined below, if the investigator feels it is in the interest of a patient’s safety and will 
optimize drug tolerability. 

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• XL184 (cabozantinib) should be held for 2 days (48 hours) prior to any biopsy procedure, 
and may be resumed 2 days (48 hours) following the procedure, unless there is evidence 
of biopsy wound-related complications or incomplete wound healing.  Due to the risk of 
perforation and fistula with XL184 (cabozantinib), transesophageal and other 
transluminal biopsies should not be performed, and biopsies should not be performed in 
areas of prior fistula formation, surgery, or radiation. 
• In patients requiring interruption of XL184 (cabozantinib) treatment due to any reason for 
>4 consecutive weeks, XL184 (cabozantinib) should be discontinued.  In this situation, a 
patient may continue to receive ipilimumab and/or nivolumab per the discretion of the 
investigator. 
• Patients on CaboNivoIpi who require permanent discontinuation of XL184 
(cabozantinib) due to any reason may continue with nivolumab and ipilimumab at the 
investigator’s discretion.  Patients on XL184 (cabozantinib) plus nivolumab who require 
permanent discontinuation of XL184 (cabozantinib) due to any reason may continue with 
nivolumab at the investigator’s discretion. 
 
Many AEs can occur early (within the first few weeks) in the course of treatment, as XL184 
(cabozantinib) is expected to reach steady state exposure at approximately 2 weeks following the 
first dose.  General guidelines for the management of non-hematologic and hematologic 
toxicities are provided below. 
 
7.1.1 Potential Adverse Events 
 
Calcium, magnesium, potassium, and phosphorus should be kept above the LLN.  For more 
specific guidelines on GI AEs (GI perforation, GI fistula, intra-abdominal and pelvic abscess, 
diarrhea, nausea/vomiting, stomatitis/mucositis), non-GI fistula, hepatobiliary disorders, 
pancreatic conditions, thromboembolic events, hypertension, skin disorders (e.g., palmar-plantar 
erythrodysesthesia syndrome [PPES]), wound healing and surgery, proteinuria, nervous system 
disorders, infections and infestations, corrected QT prolongation, electrolyte disorders, and 
endocrine disorders, refer to Section 7.1.3 below.  
 
Guidance for the management of fatigue; anorexia; weight loss; eye disorders; musculoskeletal 
and connective tissue disorders; nervous system disorders; respiratory/thoracic/mediastinal 
disorders; and congenital, familial, and genetic disorders can be found in the XL184 
(cabozantinib) Investigator’s Brochure. 
 
Patients will be monitored for AEs from the time of signing informed consent through their last 
follow-up visit.  Patients will be instructed to notify their physician immediately at the onset of 
any AE.  Seriousness, severity grade, and relationship to study treatment of AEs will be 
determined by the investigator.  AE severity will be graded by the investigator in accordance 
with CTCAE v5.0.  Management of severe or intolerable adverse reactions may require 
temporary dose reduction and/or interruption. 
 
The most frequent AEs experienced by ≥20% of patients treated with XL184 (cabozantinib) in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, weight 
decreased, PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and 

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dyspnea.  For a full description of the safety profile of XL184 (cabozantinib), refer to the most 
recent Investigator’s Brochure. 
 
Other medically important but less frequent AEs including arterial thrombotic AEs (e.g., TIA, 
and MI) and venous thrombotic AEs (e.g., DVT and PE), severe hemorrhagic events, proteinuria, 
wound healing complications, gastrointestinal (GI) perforation, abscesses including intra-
abdominal and pelvic abscess, GI and non-GI fistula formation, osteonecrosis, and reversible 
posterior leukoencephalopathy syndrome (RPLS). 
 
Adverse events associated with laboratory abnormalities experienced by ≥5% of patients treated 
with XL184 (cabozantinib) in descending order of frequency were anemia, AST increased, ALT 
increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, 
hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, 
hyponatremia, ALP increased, leukopenia, and hyperglycemia. 
 
Adverse events may occur within the first few weeks in the course of treatment with XL184 
(cabozantinib), as the drug is expected to reach steady-state exposure at approximately 2 weeks 
following first dose.  Events that generally have an early onset include hypocalcemia, 
hypokalemia, thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, 
constipation, diarrhea, and vomiting.  AEs should be managed with supportive care at the earliest 
signs of toxicity.  Dose reductions and treatment interruptions should be considered.  Dose 
reductions are recommended for events that, if persistent, could become serious or intolerable. 
 
XL184 (cabozantinib) should be discontinued for the following AEs:  visceral perforation or 
fistula formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic 
syndrome, hypertensive emergency, persistent uncontrolled hypertension despite optimal 
medical management, and RPLS. 
 
7.1.2 General Dose Modifications for XL184 (Cabozantinib) 
 
Dose Reductions of XL184 (cabozantinib) 
 
Dose Level 
XL184 (cabozantinib) dose 
1 
40 mg PO daily 
-1 
20 mg PO daily 
-2 
20 mg PO every other day 
PO=orally 
 
If a patient experiences several AEs, and there are conflicting recommendations, the treating 
physician should use the recommended dose adjustment that reduces the dose to the lowest level. 
 

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7.1.2.1 
XL184 (Cabozantinib) Dose Re-institution and Re-escalation 
 
If the patient recovers from an AE to  grade 1 or to baseline, and the toxicity was deemed at 
least possibly related to study treatment, then study treatment may be resumed at a reduced dose 
(see above for the schedule of dose reductions). 
 
Patients receiving a daily dose of 20 mg (Dose Level -1) may resume at the same dose if deemed 
safe at the investigator’s discretion.  Patients unable to tolerate Dose Level -1 should be reduced 
to receiving 20 mg every other day (Dose Level -2). 
 
Re-escalation to the previous XL184 (cabozantinib) dose may be allowed after the first six 
months of study treatment, at the investigator’s discretion, for AEs which have resolved to grade 
1 (or baseline) and deemed tolerable and easily managed by optimized supportive treatment.  
Dose re-escalation is not allowed after drug-related dose reductions triggered by grade 4 
hematological AEs or by grade 4 AEs affecting major organs (e.g., central nervous, cardiac, 
hepatic, or renal systems).  The XL184 (cabozantinib) dose should not exceed 40 mg/day. 
 
7.1.2.2 
Dose Modifications for Treatment-Related Non-Hematologic Adverse Events 
 
CTCAE v5.0 Grade 
Recommended Dose Management 
Grade 1 AEs 
Add supportive care as indicated.  Continue XL184 
(cabozantinib) therapy at the current dose level if AE is 
manageable and tolerable. 
 
Grade 2 AEs which are 
subjectively tolerable and 
easily managed 
 
Add supportive care as indicated.  Continue XL184 
(cabozantinib) therapy at the current dose level with supportive 
care. 
 
Grade 2 AEs which are 
intolerable to the patient, 
deemed unacceptable in the 
treating physician’s 
judgment, recur after 
previously improving to ≤ 
grade 1, or are not easily 
managed or corrected. 
Add supportive care as indicated and reduce the XL184 
(cabozantinib) dose by one level.  If the AE does not improve to 
≤ grade 1 or baseline within 10 days, or worsens at any time, hold 
XL184 (cabozantinib).  Upon resolution to baseline or ≤ grade 1, 
the previously reduced dose should be restarted.  If the AE 
resolves to ≤ grade 1 or baseline without a dose interruption, 
continue at the reduced dose. 
 
Grade 3 AEs that occur 
without optimal prophylaxis 
or which is easily managed 
by medical intervention or 
resolves quickly 
Add supportive care as indicated and hold XL184 (cabozantinib).  
For AEs that are easily managed (e.g., electrolyte correction) and 
resolve to baseline or ≤ grade 1 within 24 hours, XL184 
(cabozantinib) may be resumed at either the same dose or one 
dose level lower, at the investigator’s discretion.  If supportive 
care is required, XL184 (cabozantinib) should be held while 
supportive care is initiated and optimized.  If this is a recurring 
AE, reduce the XL184 (cabozantinib) dose by one level. 
 

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CTCAE v5.0 Grade 
Recommended Dose Management 
Grade 3 AEs that occur 
despite optimal prophylaxis 
or are not easily managed 
by medical intervention 
 
Hold XL184 (cabozantinib) until recovery to ≤ grade 1 or 
baseline, then resume at one dose level lower. 
Grade 4 AEs 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or ≤ grade 1 within 24 hours, hold 
XL184 (cabozantinib) until resolution then resume one dose level 
lower.  For other AEs, permanently discontinue XL184 
(cabozantinib) unless it is determined that the patient is 
unequivocally deriving clinical benefit.  In this case, upon 
recovery to ≤ grade 1 or baseline, the patient may be re-treated at 
a reduced dose, as determined by the treating physician and 
protocol chair (or co-chair) after consultation with the study 
sponsor (CTEP). 
 
Note:  Dose reductions or delays may occur in the setting of lower grade toxicity than defined 
above if the treating physician believes that it is in the interest of the patient’s safety. 
 
Note:  The dose modification and management guidelines for specific medical conditions are 
provided below.  For re-treatment and re-escalation criteria, see Section 7.1.4. 
 
7.1.2.3 
Dose Modifications for XL184 (Cabozantinib) for Treatment-Related Hematologic 
Adverse Events 
 
Neutropenia 
Recommended Guidelines for Management 
Grade 3 with documented 
infection, Grade 3 lasting 
≥5 days or Grade 4 
Hold XL184 (cabozantinib) until resolution to ≤ grade 1, then 
resume with a one dose level reduction. 
 
Thrombocytopenia 
Recommended Guidelines for Management 
Grade 3 with clinically 
significant bleeding or 
Grade 4 
Hold XL184 (cabozantinib) until platelet count is ≥100,000/mm3, 
then resume with a one dose level reduction. 
 
Febrile Neutropenia 
Recommended Guidelines for Management 
Grade 3 
Hold XL184 (cabozantinib) until recovery of ANC to ≤ grade 1 
and temperature to ≤38 °C and resume with a one dose level 
reduction.  Provide supportive care as indicated. 
 

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Febrile Neutropenia 
Recommended Guidelines for Management 
Grade 4 
Permanently discontinue XL184 (cabozantinib) therapy unless 
the investigator determines that the patient is unequivocally 
deriving clinical benefit.  In this case, upon recovery to ≤ grade 1, 
the patient may be re-treated at a reduced dose, as determined by 
the treating physician and protocol chair (or co-chair) in 
consultation with the study sponsor (CTEP). 
 
Anemia 
Recommended Guidelines for Management 
Grade 4 
 
Permanent XL184 (cabozantinib) discontinuation for grade 4 
anemia is not required.  Dose reductions or delays for anemia 
should be applied as clinically indicated.  Supportive care such as 
red blood cell transfusions should be managed according to 
institutional guidelines. 
 
Other Hematological AEs Recommended Guidelines for Management 
Grade 4 
Permanently discontinue XL184 (cabozantinib) therapy unless 
the investigator determines that the patient is clearly deriving 
clinical benefit.  In this case, upon recovery to ≤ grade 1 or 
baseline, the patient may be re-treated at a reduced dose, as 
determined by the treating physician and protocol chair (or co-
chair) in consultation with the study sponsor (CTEP). 
 
7.1.3 Guidelines for Management of Potential Adverse Events 
 
7.1.3.1 
Gastrointestinal Disorders 
 
7.1.3.1.1 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess 
 
GI perforation/fistula have been reported with FDA-approved drugs that inhibit VEGF pathways 
as well as with XL184 (cabozantinib).  Carefully monitor for episodes of abdominal pain, 
especially in patients with known risk factors for developing GI perforation/fistula or non-GI 
fistula, to allow for early diagnosis.  Such risk factors include (but may not be limited to) the 
following: 
 
• 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 XL184 (cabozantinib). 
 

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Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be 
confirmed prior to initiating treatment with XL184 (cabozantinib).  After starting cabozantinib, 
subjects should be monitored for early signs of GI perforation such as abdominal pain, nausea, 
emesis, constipation, and fever especially if known risk factors for developing GI perforation or 
fistula are present.  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. 
 
Permanently discontinue XL184 (cabozantinib) therapy and initiate appropriate management in 
patients who have been diagnosed with GI perforation or fistula. 
 
Rectal and perirectal abscesses have been reported, sometimes in patients with concurrent 
diarrhea.  These should be treated with appropriate local care and antibiotic therapy.  XL184 
(cabozantinib) should be held until adequate healing has taken place. 
 
7.1.3.1.2 
Diarrhea 
 
Patients should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  Administration of 
antidiarrheal/antimotility agents is recommended at the first sign of treatment-related diarrhea as 
initial management.  Loperamide is recommended as standard first line therapy.  Alternatively, 
diphenoxylate/atropine can be used.  Additional agents to consider in patients with diarrhea that 
is refractory to the above include deodorized tincture of opium and colestipol.  Some patients 
may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized 
tincture of opium to control diarrhea.  Infectious work-up may be carried out as needed per 
physician discretion.  Dose modification guidelines for non-hematologic AEs should be 
followed.  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 XL184 (cabozantinib).  Infections of the perianal 
region should be treated per local guidelines. 
 
7.1.3.1.3 
Nausea and vomiting 
 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  The dose modification guidance for non-hematologic AEs in 
Section 7.1.1.1 should be followed.  5-HT3 receptor antagonists are recommended over chronic 
use of NK-1 receptor antagonists and dexamethasone (NK-1 receptor antagonists and 
glucocorticoids can interact with CYP3A4 and thus change XL184 [cabozantinib] exposure).  
Caution is also recommended with the use of nabilone, which is a weak inhibitor of CYP3A4.  
Please note that caution should be used when using ondansetron (a 5-HT3 antagonist) as it can 
prolong QTc intervals.  Dehydration and electrolyte abnormalities may be associated with 

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vomiting and monitoring for and correction of fluid and electrolyte imbalances should be 
implemented. 
 
7.1.3.1.4 
Stomatitis and Mucositis 
 
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before XL184 (cabozantinib) therapy 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 XL184 (cabozantinib) therapy, good oral 
hygiene and standard local treatments such as non-traumatic and non-irritating cleansing, and 
oral rinses (e.g., 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. 
 
7.1.3.2 
Non-Gastrointestinal Fistula 
 
Complications from radiation therapy especially of the thoracic cavity including mediastinum 
have been identified as a possible predisposing risk factor for non-GI fistula formation in patients 
undergoing treatment with VEGF pathway inhibitors.  In addition, patients who have undergone 
extensive surgery may be at increased risk of developing a fistula of the involved organs.  
Permanently discontinue XL184 (cabozantinib) therapy and initiate appropriate management in 
patients who have been diagnosed with a non-GI fistula. 
 
7.1.3.3 
Hepatobiliary disorders 
 
7.1.3.3.1 
Elevation of aminotransferases (ALT and AST): 
 
Evaluation of patients with elevated transaminases or bilirubin should be individualized and 
guided by the presence of specific risk factors such as liver conditions (e.g., liver cirrhosis, 
metastases to the liver, thrombosis of portal or hepatic vein, hepatocellular carcinoma, or 
hepatitis), concomitant hepatotoxic medication, alcohol consumption, and cancer related causes. 
 
Elevations of transaminases have been observed during treatment with XL184 (cabozantinib).  In 
general, it is recommended that patients with elevation of ALT, AST, and/or bilirubin have more 
frequent liver function tests (LFTs).  If possible, hepatotoxic concomitant medications and 
alcohol should be discontinued in patients who develop elevated transaminases.  Since patients 
may enter the study with elevations of AST/ALT at baseline, the following guideline should be 
used for dose modifications: 
 
Transaminase Elevation 
Intervention 
Grade 1 
No change in XL184 (cabozantinib) dose, and no additional tests 
unless clinically indicated. 
 

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Transaminase Elevation 
Intervention 
Grade 2 
Continue XL184 (cabozantinib) with at least twice weekly 
monitoring of LFTs for 2 weeks.  Then weekly for 4 weeks.  If 
LFTs continue to rise within grade 2, hold XL184 (cabozantinib), 
and continue with at least weekly LFTs until improvement to 
≤ grade 1.  XL184 (cabozantinib) may then be resumed with a 
one dose level reduction. 
 
Grade 3 
Hold XL184 (cabozantinib) and monitor with at least twice 
weekly LFTs until ≤ grade 2, then with at least weekly LFTs until 
≤ grade 1.  XL184 (cabozantinib) may then be resumed with a 
one dose level reduction. 
 
Grade 4 
Permanently discontinue XL184 (cabozantinib) therapy.  LFTs 
should be monitored as clinically indicated, at least 2-3 times per 
week, until improvement to ≤ grade 1.  If the patient was 
unequivocally deriving clinical benefit, XL184 (cabozantinib) 
may be restarted at a reduced dose, as determined by the treating 
physician and protocol chair (or co-chair) in consultation with the 
study sponsor (CTEP). 
 
XL184 (cabozantinib) treatment should also be interrupted when transaminase increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests 
(e.g., International Normalized Ratio [INR]).  Monitoring of transaminases should be intensified 
(2-3 times per week) and XL184 (cabozantinib) should be held until the etiology of the 
abnormalities is determined and these abnormalities are corrected or stabilize at clinically 
acceptable levels (INR <1.5 × ULN, total bilirubin <1.5 × ULN, aminotransferases ≤ baseline 
grade). 
 
XL184 (cabozantinib) should be permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation > 1.5 x ULN unless 
Gilbert’s syndrome), in the absence of evidence of biliary obstruction (i.e., significant elevation 
of alkaline phosphatase), or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), as the combined finding represents a signal of a potential for the drug to cause severe 
liver injury (i.e., Hy’s Law cases). 
 
All patients who develop isolated bilirubin elevations of grade 3 should have XL184 
(cabozantinib) held until recovery to ≤ grade 1 or baseline (or lower).  If this occurs within 4 
weeks of the dosing delay, XL184 (cabozantinib) therapy may continue with a one dose level 
reduction.  In patients without biliary obstruction and grade 4 bilirubin elevation, or with 
recurrence of grade 3 bilirubin elevation after a dose reduction, XL184 (cabozantinib) therapy 
must be discontinued. 
 

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7.1.3.4 
Pancreatic conditions 
 
Amylase and lipase elevations have been observed in clinical studies with XL184 (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 patients with 
lipase elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of 
lipase and/or amylase (2-3 times per week).  Patients with symptomatic pancreatitis should be 
treated with standard supportive measures. 
 
Asymptomatic Lipase or 
Amylase Elevations 
Intervention 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is 
recommended. 
 
Grade 3 
Hold XL184 (cabozantinib) and monitor lipase and amylase 
twice weekly.  Upon improvement to ≤ grade 1 or baseline, 
XL184 (cabozantinib) therapy may resume at the same dose or 
one dose level lower, at the investigator’s discretion.  If re-
treatment following grade 3 lipase or amylase elevation is at the 
same dose and grade 3 or 4 elevations recur, then XL184 
(cabozantinib) must be held again until lipase and amylase levels 
have resolved to ≤ grade 1 or baseline and re-treatment must be 
with a one dose level reduction. 
 
Grade 4 
Hold XL184 (cabozantinib) and monitor lipase and amylase 
twice weekly.  Upon resolution to ≤ grade 1 or baseline, and if 
resolution occurred within four days, XL184 (cabozantinib) 
therapy may resume at the same dose or one dose level lower, at 
the investigator’s discretion.  If resolution takes more than four 
days, the dose must be reduced, provided that resolution occurs 
within 4 weeks.  If XL184 (cabozantinib) is resumed at the same 
dose following a grade 4 lipase or amylase elevation and grade 3 
or 4 elevations recur, then XL184 (cabozantinib) must be held 
again until lipase and amylase have resolved to ≤ grade 1 or 
baseline and must be resumed with a one dose level reduction. 
 
Pancreatitis 
Intervention 
Grade 2 
Continue at current dose level.  More frequent monitoring of 
lipase and amylase and radiographic evaluation is recommended. 
 
Grade 3 
Hold and monitor lipase and amylase twice weekly.  Upon 
resolution to ≤ grade 1 or baseline, XL184 (cabozantinib) may be 
resumed with a one dose level reduction, if resolution occurs 
within 4 weeks. 
 

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Pancreatitis 
Intervention 
Grade 4 
Permanently discontinue XL184 (cabozantinib) therapy.  
However, if the patient was unequivocally deriving benefit from 
XL184 (cabozantinib) therapy, treatment may be restarted at a 
reduced dose, as determined by treating physician and protocol 
chair (or co-chair) in consultation with the study sponsor (CTEP). 
 
7.1.3.5 
Hemorrhage 
 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
XL184 (cabozantinib).  Patients should be monitored for bleeding events with serial complete 
blood counts and physical examination while on study.  The risk of hemorrhage in XL184 
(cabozantinib)-treated patients with brain metastases has not been thoroughly analyzed.  Patients 
enrolled with treated and stable brain metastases should be monitored with a high index of 
suspicion if symptoms attributable to CNS hemorrhage occur. 
 
XL184 (cabozantinib) therapy should be permanently discontinued in patients with serious and 
life-threatening bleeding events or recent clinically significant hemoptysis.  Treatment with 
XL184 (cabozantinib) should be held if less severe forms of clinically significant hemorrhage 
occur.  After the cause of hemorrhage has been identified and the risk of bleeding has subsided, 
XL184 (cabozantinib) may be resumed at a dose agreed to by the protocol chair  (or co-chair) 
and the treating physician.  Therapy of bleeding events should include supportive care and 
standard medical interventions. 
 
7.1.3.6 
Thromboembolic events 
 
Thromboembolic events are frequent in cancer patients due to procoagulant changes induced by 
the malignancy or anticancer therapy.  DVT and PE have been observed in clinical studies with 
XL184 (cabozantinib), including fatal events.  Patients who develop DVT and/or PE should have 
study treatment interrupted until therapeutic anticoagulation is established.  Treatment with 
XL184 (cabozantinib) may be resumed at one dose level lower in patients with uncomplicated 
PE or DVT if it is determined that the patient is deriving clinical benefit from XL184 
(cabozantinib) treatment and that anticoagulation does not place them at a significant risk that 
outweighs the benefit of resuming treatment per discretion of the investigator and according to 
individual protocols.  Patients with life-threatening DVT or PE should have XL184 
(cabozantinib) therapy discontinued unless toxicity can be managed, and the patient is deriving 
clear clinical benefit as determined by the treating physician in consultation with the study 
sponsor (CTEP).  Venous filters (e.g. vena cava filters) are not recommended due to the high 
incidence of complications associated with their use.  Once a patient is fully anticoagulated, 
treatment can be restarted at the investigator’s discretion with a one dose level reduction.  XL184 
(cabozantinib) therapy should be permanently discontinued after a second thrombotic event.  
Although routine prophylactic anticoagulation is not necessary for all patients, prophylactic 
anticoagulation is allowed for individual patients at the investigator’s discretion.  Low molecular 
weight heparins are the preferred management for thrombotic events; oral anticoagulants (e.g., 
warfarin or other coumarin-related agents, direct thrombin, direct factor Xa inhibitors, 

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antiplatelet agents, or chronic use of aspirin above low dose levels for cardioprotection) are not 
allowed. 
 
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with XL184 
(cabozantinib).  Further treatment with XL184 (cabozantinib) should be permanently 
discontinued in patients who develop an acute MI, cerebral infarction, or any other clinically 
significant arterial thromboembolic complication. 
 
7.1.3.7 
Hypertension 
 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in XL184 (cabozantinib) clinical studies.  Decisions to decrease or hold the dose 
of XL184 (cabozantinib) must be based on BP readings taken by a medical professional and 
must be confirmed with a second measurement at least 5 minutes following the first 
measurement.  Patients with known hypertension should be optimally managed prior to study 
entry.  Clinical judgment should be used in deciding whether new or worsened hypertension 
emerging during treatment requires immediate therapy, or whether therapeutic intervention can 
be delayed in order to confirm the finding of new or worsened hypertension at a second visit 
before taking new therapeutic action.  It is recommended that this second visit occur within one 
week (such a visit can be with a local physician or a study physician).  BP should be monitored 
in a constant position visit to visit, either sitting or supine. 
 
XL184 (cabozantinib) should be held in patients with severe hypertension (≥180 mm Hg systolic 
or ≥120 mm Hg diastolic; or sustained ≥160 mm Hg systolic or ≥110 diastolic) who cannot be 
controlled with medical interventions and should be permanently discontinued in patients with 
hypertensive emergency.  The table below provides treatment guidelines for hypertension 
deemed related to XL184 (cabozantinib).  BP should be monitored in a constant position visit to 
visit, either sitting or supine in a relaxed setting.  XL184 (cabozantinib) dose modification 
decisions must be based on BP readings taken by a medical professional and must be confirmed 
with a second measurement at least 5 minutes following the first measurement. 
 
Criteria for Dose 
Modifications 
Treatment/XL184 (cabozantinib) Dose Modification 
Patients NOT receiving optimized anti-hypertensive therapy 
Systolic ≥140 and 
<160 mm Hg 
 
OR 
 
Diastolic ≥90 and 
<110 mm Hg 
 
Optimize antihypertensive therapy (i.e., increase dose of existing 
medications and/or add new antihypertensive medications) and 
continue XL184 (cabozantinib) with no change.  If optimal 
antihypertensive therapy (usually to include three agents) does 
not result in BP <140 mm Hg systolic and <90 mm Hg diastolic, 
or if the patient is symptomatic, the dose of XL184 
(cabozantinib) should be reduced by one level. 
 

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Criteria for Dose 
Modifications 
Treatment/XL184 (cabozantinib) Dose Modification 
Systolic ≥160 and 
<180 mm Hg 
 
OR 
 
Diastolic ≥110 and 
<120 mm Hg 
Reduce XL184 (cabozantinib) by one dose level.  Optimize 
antihypertensive therapy (i.e., increase the dose of existing 
medications and/or add new antihypertensive medications).  
Monitor the patient closely for hypotension.  If optimal 
antihypertensive therapy (usually to include three agents) does 
not result in BP <140 mm Hg systolic and <90 mm Hg diastolic, 
the dose of XL184 (cabozantinib) should be reduced further. 
 
Systolic ≥180 mm Hg 
 
OR 
 
Diastolic ≥120 mm Hg 
Hold XL184 (cabozantinib) and add new or additional anti-
hypertensive medications and/or increase the dose of existing 
medications.  Monitor the patient closely for hypotension.  When 
BP <140 mm Hg systolic and <90 mm Hg diastolic, resume 
XL184 (cabozantinib) treatment with a one dose level reduction.  
If optimal antihypertensive therapy (usually to include three 
agents) does not result in BP <140 systolic or < 90 diastolic, the 
dose should be reduced further. 
 
Hypertensive emergency* Permanently discontinue XL184 (cabozantinib) therapy. 
 
* Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of 
progressive or impending end-organ damage (e.g., myocardial infarction/ischemia, 
intracranial hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, or kidney 
damage). 
 
Note: If systolic and diastolic BP meet different criteria in the table, manage according to the 
higher dose-modification criterion. 
 
Note: In patients deemed to have a component of white coat hypertension, a home BP log can 
be used at the investigator’s discretion. 
 
7.1.3.8 
Palmar-plantar erythrodysesthesia syndrome (PPES) 
 
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 XL184 (cabozantinib).  All 
patients on study should be 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. 

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Aggressive management of symptoms is recommended, including early dermatology referral.  
Treatment recommendations in response to PPES are summarized below. 
 
PPES 
Action to be Taken 
Grade 1 
XL184 (cabozantinib) may be continued at the current dose if 
PPES is clinically insignificant and tolerable.  Otherwise, the 
XL184 (cabozantinib) dose should be reduced by one level.  
Start or continue treatment with urea 20-40% cream twice daily 
and high potency steroid cream (e.g. clobetasol 0.05% cream 
twice daily).  A topical lidocaine 5% ointment or 
NSAIDs/GABA agonists/narcotics may also be used for pain 
control.  Patients should be reassessed at least weekly for 
changes in severity.  Patients should be instructed to notify their 
treating physician immediately if severity worsens. 
 
Grade 2 
XL184 (cabozantinib) may be continued at the same dose level 
if PPES is tolerated.  The XL184 (cabozantinib) dose should be 
reduced or held if PPES is intolerable.  Start or continue 
treatment with urea 20-40% cream twice daily and high potency 
steroid cream (e.g. clobetasol 0.05% cream twice daily).  A 
topical lidocaine 5% ointment or NSAIDs/GABA 
agonists/narcotics may also be used for pain control.  Patients 
should be reassessed at least weekly for changes in severity.  If 
XL184 (cabozantinib) was held (but not reduced), it may be 
resumed at the same dose or one dose level lower upon 
resolution to ≤ grade 1.  If a second interruption is required, the 
XL184 (cabozantinib) dose must be reduced by one level when 
treatment resumes.  Patients should be instructed to notify their 
treating physician immediately if the severity worsens.  If the 
severity worsens at any time, or affects self-care, proceed to the 
management guidelines for grade 3 PPES. 
 
Grade 3 
Hold XL184 (cabozantinib) until severity decreases ≤ to grade 1.  
Start or continue treatment with urea 20-40% cream twice daily 
and high potency steroid cream (e.g. clobetasol 0.05% cream 
twice daily).  A topical lidocaine 5% ointment or 
NSAIDs/GABA agonists/narcotics may also be used for pain 
control.  Resume XL184 (cabozantinib) at one dose level lower 
upon resolution to ≤ grade 1.  Permanently discontinue XL184 
(cabozantinib) therapy if PPES worsens or does not improve 
within 4 weeks. 
 

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7.1.3.9 
Osteonecrosis 
 
Osteonecrosis has been reported in patients treated with XL184 (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 patients regarding oral hygiene practice and to quickly report symptoms 
to investigator.  Caution should be used in patients receiving bisphosphonates. 
 
Invasive dental procedures should be avoided.  In cases where dental procedures are 
unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as well 
as the risk of developing osteonecrosis of the jaw need to be considered when deciding on the 
duration of a temporary treatment interruption of XL184 (cabozantinib).  If clinically possible, 
treatment with XL184 (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. 
 
Patients with any documented case of osteonecrosis should stop XL184 (cabozantinib) therapy, 
and appropriate clinical management should be initiated.  Re-initiation of study treatment must 
be discussed with and approved by the study sponsor (CTEP) on a case by case basis 
 
7.1.3.10 
Wound healing and surgery 
 
XL184 (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 XL184 
(cabozantinib) treatment but must also be monitored for wound dehiscence, wound infection, and 
other signs of impaired wound healing while the patient is being treated.  If dehiscence occurs, 
XL184 (cabozantinib) treatment should not be restarted until complete healing has taken place. 
 
Treatment with XL184 (cabozantinib) must be interrupted for any wound healing complication 
which needs medical intervention.  Treatment with XL184 (cabozantinib) can be resumed once 
wound healing has occurred unless otherwise prohibited in specific protocols.  XL184 
(cabozantinib) should be discontinued in patients with serious or chronic wound healing 
complications.  
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined.  In general, XL184 (cabozantinib) should be stopped at 
least 3 weeks (5 half-lives) prior to elective major surgery.  The decision to resume treatment 
with XL184 (cabozantinib) after surgery should be based on clinical judgment of adequate 
wound healing. 
 

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7.1.3.11 
Proteinuria 
 
Proteinuria has been reported with XL184 (cabozantinib).  Proteinuria should be monitored by 
measuring UPCR.  The following table provides treatment guidelines for proteinuria deemed 
related to XL184 (cabozantinib).  XL184 (cabozantinib) should be permanently discontinued in 
patients who develop nephrotic syndrome (proteinuria >3.5 grams per day in combination with 
hypoalbuminemia, edema, and hyperlipidemia). 
 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤1 mg/mg 
(≤113.1 mg/mmol) 
 
No change in XL184 (cabozantinib) dose or UPCR monitoring 
>1 and ≤2 mg/mg 
(>113.1 and ≤226.2 
mg/mmol) 
 
No change in XL184 (cabozantinib) dose.  A nephrology 
consultation is recommended.  Monitor UPCR once a week.  If 
UPCR ≤1 mg/mg on two consecutive readings, UPCR 
monitoring can revert to protocol-specific times.  The 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 one 
month, or is determined to be stable (<20% change) for one 
month, UPCR monitoring can revert to protocol-specific times 
and as clinically indicated. 
 
>2 and <3.5 mg/mg 
(>226.2 and <395.9 
mg/mmol) 
Hold XL184 (cabozantinib).  A nephrology consultation is 
recommended.  24-hour urine protein assessment must be sent 
off within 7 days.  If urine protein is >2 mg/mg, continue to hold 
XL184 (cabozantinib), check UPCR again within 7 days, and 
repeat once a week until UPCR decreases to ≤2 mg/mg.  Resume 
XL184 (cabozantinib) at 1 dose level lower once UPCR is ≤2 
mg/mg.  Repeat UPCR test within 7 days of resuming XL184 
(cabozantinib).  Monitoring of UPCR 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, UPCR monitoring can revert to 
protocol-specific times and as clinically indicated. 
 

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Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≥3.5 mg/mg 
(≥395.9 mg/mmol) 
Hold XL184 (cabozantinib).  A nephrology consultation is 
mandatory.  24-hour urine for protein assessment must be sent 
off within 7 days.  If 24-hour urine protein is ≥3.5 mg/mg, 
continue to hold XL184 (cabozantinib), check UPCR again 
within 7 days and repeat once a week.  If UPCR decreases to ≤2 
mg/mg, restart XL184 (cabozantinib) treatment at one dose level 
lower than previous dose.  Repeat UPCR within 7 days of 
resuming XL184 (cabozantinib).  Monitoring of UPCR 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, UPCR 
monitoring can revert to protocol-specific times and as clinically 
indicated. 
 
Nephrotic syndrome 
Permanently discontinue XL184 (cabozantinib) therapy 
 
7.1.3.12 
Nervous System Disorders 
 
XL184 (cabozantinib) appears to represent minimal risk of adverse neurological effects based on 
nonclinical toxicology studies.  However, dysphonia, dysgeusia, headache, dizziness, confused 
state, convulsion, depression, memory impairment, hypoesthesia, peripheral neuropathy, 
insomnia, ataxia, and encephalopathy have been observed in clinical studies with XL184 
(cabozantinib).  The development of any new or progressive, unexplained neurological 
symptoms should be assessed for underlying causes. 
 
RPLS has been reported and should be considered in any patient presenting with seizures, 
headache, visual disturbances, confusion or altered mental function.  XL184 (cabozantinib) 
therapy should be permanently discontinued in patients with RPLS. 
 
7.1.3.13 
Infections and Infestations 
 
Infections are commonly observed in cancer patients.  Risk factors include decreased immune 
status (e.g., after myelosuppressive anticancer therapies or splenectomy), destructive growth of 
the underlying malignancy including bone marrow infiltration with suppression of normal 
hematopoiesis, and the presence of IV devices.  Infections and abscesses should be treated with 
appropriate local care and systemic therapy.  XL184 (cabozantinib) should be held until adequate 
healing has taken place. 
 
7.1.3.14 
QTc Prolongation 
 
Review of the larger safety database (~5000 patients exposed to XL184 (cabozantinib) in clinical 
trials and in post-marketing experience) showed no safety concerns associated with QT 
prolongation.  There were no events of torsades de pointes reported. 
 

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Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may increase 
XL184 (cabozantinib) plasma concentrations, should be avoided.  If at any time on study there is 
an increase in QTcF to an absolute value >500 msec, two additional EKGs must be performed 
with intervals not less than 3 min apart within 30 min after the initial EKG.  If the average QTcF 
from the three EKGs is >500 msec, the following actions must be taken: 
 
• Hold XL184 (cabozantinib) 
• Hospitalize symptomatic patients (e.g., with palpitations, dizziness, syncope, orthostatic 
hypotension, or a significant ventricular arrhythmia on EKG) for a thorough cardiology 
evaluation and management 
o Consider cardiology consultation for asymptomatic patients for evaluation and 
management 
• Check electrolytes, especially magnesium, potassium, and calcium; correct abnormalities 
as clinically indicated 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
• Repeat EKG triplicates hourly until the average QTcF is ≤500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert. 
 
Patients with QTc prolongation and symptoms must be monitored closely until the QTc elevation 
and symptoms have resolved.  XL184 (cabozantinib) treatment may be resumed at a reduced 
dose level if all of the following conditions are met: 
 
• Symptoms are determined to be unrelated to the QT interval prolongation, 
• The QTcF value >500 msec is not confirmed, 
• XL184 (cabozantinib) has been held through a minimum of 1 week following the return 
of the QTcF to ≤500 msec, 
• QT prolongation can be unequivocally associated with an event other than XL184 
(cabozantinib) administration and is treatable/has been resolved. 
 
Once XL184 (cabozantinib) therapy has resumed, EKGs must be repeated weekly for 2 weeks, 
then every 2 weeks for 1 month, then according to the protocol-defined time points.  XL184 
(cabozantinib) therapy must be permanently discontinued if either of the following applies: 
 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation 
• Recurrence of QTc prolongation after re-initiation of study treatment at a reduced dose 
 
7.1.3.15 
Electrolyte Disorders 
 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with XL184 (cabozantinib), and serum 
electrolyte levels should be monitored frequently while receiving XL184 (cabozantinib).  
Clinically relevant electrolyte disorders should be managed according to the dose modification 

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guidelines or as clinically indicated.  Standard clinical practice guidelines should be used for 
management of electrolyte disorders and may include oral or intravenous replacement. 
 
7.1.3.16 
Endocrine Disorders 
 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed with 
XL184 (cabozantinib) treatment.  Currently available data are insufficient to determine the 
mechanism of thyroid function test alterations and its clinical relevance.  Management of thyroid 
dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical practice 
guidelines. 
 
Other endocrine disorders leading to hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of patients.  Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiating and during XL184 
(cabozantinib) therapy is required.  XL184 (cabozantinib) therapy should be discontinued in 
patients with severe or life-threatening endocrine dysfunction. 
 
7.2 
Nivolumab and Ipilimumab 
 
Patients receiving ipilimumab in combination with nivolumab that have drug-related toxicities 
that meet the criteria for dose delay, should have both drugs (ipilimumab and nivolumab) 
delayed until retreatment criteria are met (see tables below). 
 
1. In addition to the AEs identified in the tables below, ipilimumab and nivolumab doses 
should be delayed for any AE, laboratory abnormality or intercurrent illness which, in the 
judgment of the investigator, warrants a delay. 
(a) Patients who develop alopecia and/or altered taste may continue treatment without 
reduction or interruption.  In addition, no dose reductions or interruptions will be 
required for anemia (nonhemolytic) as it can be satisfactorily managed by transfusion. 
2. Patients requiring a delay of >4 weeks due to ipilimumab- and/or nivolumab-related AEs 
or who experience immune-related toxicity requiring ≥10 mg/day prednisone must 
permanently discontinue nivolumab and ipilimumab therapy, but may continue XL184 
(cabozantinib) therapy. 
(a) Patients who receive systemic corticosteroids for management of any drug-related 
immunologic toxicity must be off corticosteroids or must have tapered down to a dose 
equivalent to <10 mg/day prednisone. 
3. Patients requiring a delay of >4 weeks due to non-immune related AE from nivolumab- 
and/or ipilimumab should permanently discontinue nivolumab and ipilimumab therapy, 
but may continue XL184 (cabozantinib) therapy. 
4. Doses missed due to adverse events or toxicity will not be made up. 
5. Allowance for dose synchronization: 
(a) Nivolumab is allowed to be delayed until the next planned ipilimumab dose if the 
next ipilimumab dose is scheduled within the next 12 days. 
(i) 
Nivolumab and ipilimumab doses can be re-synced, at the investigator’s 
discretion, where possible, within the guidance indicated above. 

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(ii) This will permit periodic ipilimumab dosing to be synchronized with nivolumab 
dosing. 
(iii) Patients who require treatment-related delay of nivolumab should be re-
evaluated weekly, or more frequently if clinically indicated, and may resume 
nivolumab dosing when re-treatment criteria are met. 
Assessments should continue even if dosing is delayed. 
(b) Allowance for ipilimumab dose delays: 
(i) 
In general, patients who meet criteria to resume ipilimumab will also have met 
criteria to resume nivolumab with ipilimumab, so it should be feasible to 
synchronize dosing of both drugs when resuming ipilimumab.  In order to 
facilitate this, the dosing days of nivolumab and ipilimumab may be adjusted 
within a ±5-day window, as long as consecutive nivolumab doses are given at 
least 12 days apart. 
(ii) If an ipilimumab dose is delayed for >4 weeks from the prior dose, then 
subsequent doses should be rescheduled to maintain at least a 6-week interval 
between consecutive ipilimumab doses. 
(iii) Dosing delays up to 6 weeks to manage drug-related adverse events, such as 
prolonged steroid tapers, are allowed. 
Assessments should continue even if dosing is delayed. 
(iv) In the event that a patient experiences a grade 2 AE while on combination 
CaboNivoIpi therapy, the patient may resume treatment/may be continued on 
nivolumab and XL184 (cabozantinib) therapy, at the discretion of the treating 
investigator (ipilimumab will not be given without nivolumab). 
 
If a patient experiences several AEs, and there are conflicting recommendations, the investigator 
should use the recommended treatment modification for the most serious event when that has a 
higher level of modification, i.e. discontinuing versus holding drug. 
 
Below are AE management tables for nivolumab and combination nivolumab with ipilimumab 
for the following treatment-related adverse events.  Please use as written and contact the drug 
monitor for any proposed changes. 
 
Please refer to the most recent Nivolumab and Ipilimumab Investigator’s Brochures or Appendix 
F for toxicity management algorithms which include specific treatment guidelines.  These 
algorithms should be followed unless there are specific clinical circumstances for which the 
treating physician decides an alternative treatment approach is clinically appropriate.  
Consultation with the study PI or drug monitor is recommended.  In several places there are 
differences from the algorithms regarding protocol directed drug modifications.  In these cases, 
please follow the protocol-specific guidelines in this section.  Generally, we strongly encourage 
early evaluation while withholding drug, and appropriate treatment as indicated in the 
management tables and event specific guidelines. 
 
 
 
 

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7.2.1 Guidelines for Management of Potential Adverse Events 
 
Skin Rash and 
Oral Lesions 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change.* 
No change.* 
Grade 2-3 
Hold* nivolumab until ≤ grade 1, 
then resume. 
Hold* both drugs until ≤ grade 1, 
then resume. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, TEN, or 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.  Skin rash typically occurs early 
and may be followed by additional events, particularly during steroids tapering. 
 
Recommended management:  AE management guidelines. 
 
Drug-related 
uveitis, eye pain, 
blurred vision 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change.* 
No change.* 
Grade 2 
Hold* until < grade 1 or baseline, 
then resume at same dose.  If a 
grade 2 event does not respond to 
topical therapy and does not 
improve to grade 1 within the re-
treatment period OR requires 
systemic therapy, permanently 
discontinue nivolumab therapy. 
Hold both drugs until ≤grade 1 or 
baseline, then resume at same 
doses.  If grade 2 event does not 
respond to topical therapy and does 
not improve to grade 1 within the 
re-treatment period OR requires 
systemic therapy, permanently 
discontinue nivolumab and 
ipilimumab therapy. 
Grade 3 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
ipilimumab and hold nivolumab 
until ≤ grade 1 and then resume 
nivolumab monotherapy.  If grade 
3 event does not respond to topical 
therapy and does not improve to 
grade 1 within the re-treatment 
period OR requires systemic 
therapy, permanently discontinue 
nivolumab as well. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
Recommended management:  AE management guidelines. 
 

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Liver Function 
AST, ALT, 
Bilirubin   
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
Hold nivolumab, at investigator’s 
discretion, until values return to 
ULN or baseline, then resume. 
Hold both drugs, at investigator’s 
discretion, until values return to 
ULN or baseline, then resume. 
Grade 2 
(3-5 × ULN) 
Hold nivolumab until values return 
to baseline or ≤ grade 1, then 
resume. 
Hold both drugs until values return 
to baseline or ≤ grade 1, then 
resume. 
Grade 3 
(5-20 × ULN) 
Hold nivolumab and monitor with 
at least weekly LFTs until grade 
≤2.  Then resume nivolumab and 
continue with at least weekly LFTs 
until improvement to grade ≤ 1.  If 
no improvement is seen, or the 
condition worsens by 4 weeks, 
nivolumab should be held, and 
steroid treatment initiated.  If 
AST/ALT >8 × ULN or bilirubin 
>5 × ULN, permanently 
discontinue nivolumab therapy. 
Hold both drugs and monitor with 
at least weekly LFTs until grade 
≤2.  Then resume both drugs and 
continue with at least weekly LFTs 
until improvement to grade ≤1.  If 
no improvement is seen, or the 
condition worsens by 4 weeks, both 
drugs should be held, and steroid 
treatment initiated.  If AST/ALT 
>8 × ULN or bilirubin >5 × ULN, 
ipilimumab should be permanently 
discontinued.  Manage subsequent 
events according to nivolumab 
guidelines. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
ipilimumab and hold nivolumab.  
Monitor with at least weekly LFTs 
until grade ≤2, then resume 
nivolumab.  Continue with at least 
weekly LFTs until improvement to 
grade ≤1.  Manage subsequent dose 
delays under Management/Next 
Dose for Nivolumab alone.  If no 
improvement is seen, or the 
condition worsens by 4 weeks, hold 
nivolumab and initiate steroid 
treatment. 
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. 
Note:  Grades for liver function follow multiples of ULN, rather than multiples of baseline. 
 
Recommended management:  see Hepatic AE management algorithm. 
 

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Diarrhea 
(immune related 
enterocolitis) 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change. 
No change. 
Grade 2 
Hold nivolumab until ≤ grade 1.  
Treat symptomatically, and resume 
nivolumab if improved to ≤ grade 
1, at investigator’s discretion.  If 
after 4 weeks no improvement is 
seen, the condition worsens, or 
colitis is documented by 
colonoscopy, permanently 
discontinue nivolumab therapy and 
initiate steroid treatment. 
Hold both drugs until ≤grade 1.  
Treat symptomatically, and resume 
both drugs if improved to 
≤ grade 1, at investigator’s 
discretion.  If after 4 weeks, no 
improvement is seen, the condition 
worsens, or colitis is documented 
by colonoscopy, permanently 
discontinue ipilimumab and 
manage according to nivolumab 
guidelines. 
Grade 3 
Hold nivolumab until ≤ grade 1 and 
obtain colonoscopy.  Treat 
symptomatically, and resume 
nivolumab if colonoscopy shows 
no colitis and patient improves to 
≤ grade 1, at investigator’s 
discretion.  If after 4 weeks no 
improvement is seen, the condition 
worsens, or colitis is documented 
by colonoscopy, permanently 
discontinue nivolumab therapy and 
initiate steroid treatment. 
Permanently discontinue 
ipilimumab.  Hold nivolumab until 
≤ grade 1 and obtain colonoscopy.  
Treat symptomatically, and resume 
nivolumab if colonoscopy shows 
no colitis and patient improves to 
≤ grade 1, at investigator’s 
discretion.  If after 4 weeks no 
improvement is seen, the condition 
worsens, or colitis is documented 
by colonoscopy, permanently 
discontinue nivolumab therapy and 
initiate steroid treatment. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution.  Patients who require systemic steroids should be taken off study treatment.  
Evaluate pituitary function prior to starting steroids if possible without compromising acute 
care.  Patients should be evaluated for additional causes including C. diff, acute and self-limited 
infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD at the discretion of the 
treating physician. 
 
Recommended management:  see GI AE management Algorithm. 
 

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Amylase/Lipase 
Increased and 
Pancreatitis 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
(Amylase/Lipase 
Increased Only) 
Continue nivolumab therapy, if 
asymptomatic, at the investigator’s 
discretion. 
Continue both drugs, if 
asymptomatic, at the investigator’s 
discretion. 
Grade 2 
Continue nivolumab therapy, if 
asymptomatic, at the investigator’s 
discretion.  If symptomatic, resume 
nivolumab therapy once resolved. 
Continue both drugs, if 
asymptomatic, at the investigator’s 
discretion.  If symptomatic, resume 
nivolumab and ipilimumab therapy 
once resolved. 
Grade 3 
Amylase/Lipase 
Increased 
Continue nivolumab, at the 
investigator’s discretion.  Monitor 
lipase and amylase once or twice 
weekly.  Radiographic evaluation is 
optional if asymptomatic with no 
evidence of pancreatitis-associated 
gallbladder disease, no evidence of 
worsening, or no new onset of DM. 
Continue both drugs, at the 
investigator’s discretion.  Monitor 
lipase and amylase once or twice 
weekly.  Radiographic evaluation is 
optional if asymptomatic with no 
evidence of pancreatitis-associated 
gallbladder disease, no evidence of 
worsening, or no new onset of DM. 
Grade 3 
Pancreatitis 
Continue nivolumab therapy, if 
asymptomatic, at investigator’s 
discretion.  Patients should have 
imaging done when clinically 
indicated (i.e., grade 3 pancreatitis) 
before resuming treatment.  
Patients who develop symptomatic 
pancreatitis or DM should 
permanently discontinue nivolumab 
therapy. 
Continue both drugs, if 
asymptomatic, at investigator’s 
discretion.  Patients should have 
imaging done when clinically 
indicated (i.e., grade 3 pancreatitis) 
before resuming treatment.  
Patients who develop symptomatic 
pancreatitis or DM should 
permanently discontinue nivolumab 
and ipilimumab therapy. 
Grade 4 
Hold nivolumab until grade 2.  
Resume if asymptomatic.  Patients 
should have imaging done before 
resuming treatment, and when 
clinically indicated.  Patients who 
develop symptomatic pancreatitis 
or DM should permanently 
discontinue nivolumab therapy. 
Hold both drugs until grade 2.  
Resume if asymptomatic.  Patients 
should have imaging done before 
resuming treatment, and when 
clinically indicated.  Patients who 
develop symptomatic pancreatitis 
or DM should permanently 
discontinue nivolumab and 
ipilimumab therapy. 
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as DM and 
diabetic ketoacidosis.  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 re-treated. 
 
For treatment management of symptomatic pancreatitis please follow the Hepatic Adverse 
Event Management Algorithm  

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Pneumonitis, 
Bronchospasm, 
Pulmonary 
Toxicity, or 
Interstitial Lung 
Disease 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
Hold nivolumab pending 
evaluation and resolution to 
baseline, including baseline O2 
saturation.  Resume after 
pulmonary and/or infectious 
disease consultation excludes 
lymphocytic pneumonitis. 
Hold both drugs pending evaluation 
and resolution to baseline including 
baseline O2 saturation.  Resume 
after pulmonary and/or infectious 
disease consultation excludes 
lymphocytic pneumonitis. 
Grade 2  
Hold nivolumab pending 
evaluation.  Resume after 
pulmonary and/or infectious 
disease consultation excludes 
associated lymphocytic 
pneumonitis as the cause of the 
pneumonitis.  Patients should 
permanently discontinue nivolumab 
therapy if steroids are required. 
Hold both drugs pending 
evaluation.  Resume after 
pulmonary and/or infectious 
disease consultation excludes 
ipilimumab and associated 
lymphocytic pneumonitis as the 
cause of the pneumonitis.  Patients 
should permanently discontinue 
nivolumab and ipilimumab therapy 
if steroids are required. 
Grade 3 
Hold nivolumab pending 
evaluation.  Resume after 
pulmonary and/or infectious 
disease consultation excludes 
associated lymphocytic 
pneumonitis as the cause of the 
pneumonitis.  Patients should 
permanently discontinue nivolumab 
therapy if steroids are required. 
Hold both drugs pending 
evaluation.  Resume after 
pulmonary and/or infectious 
disease consultation excludes 
ipilimumab and associated 
lymphocytic pneumonitis as the 
cause of the pneumonitis.  Patients 
should permanently discontinue 
nivolumab and ipilimumab therapy 
if steroids are required. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab 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.  Seasonal influenza 
killed vaccine is recommended for all patients.  The above does not include infusion 
reactions. 
 
Recommended management:  See Pulmonary Adverse Event Management Algorithm. 

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Other GI 
Nausea-Vomiting 
Management/Next Dose for 
Nivolumab Monotherapy 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change. 
No change. 
Grade 2 
Hold nivolumab pending 
evaluation for gastritis duodenitis 
and other immune AEs or other 
causes.  Resume after resolution to 
≤ grade 1. 
Hold both drugs pending evaluation 
for gastritis duodenitis and other 
immune AEs or other causes.  
Resume after resolution to 
≤ grade 1. 
Grade 3 
Hold nivolumab until resolution to 
≤ grade 1.  If symptoms do not 
resolve within 7 days with 
symptomatic treatment, 
permanently discontinue nivolumab 
therapy. 
Hold both drugs until resolution to 
≤ grade 1.  If symptoms do not 
resolve within 7 days with 
symptomatic treatment, 
permanently discontinue nivolumab 
and ipilimumab therapy. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
Patients with grade 2 or 3 nausea or vomiting should be evaluated for upper GI inflammation 
and other immune related events. 
 
Fatigue  
Management/Next Dose for 
Nivolumab Monotherapy 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 2 
No change in dose. 
 
No change in dose. 
 
Grade 3 
Hold until ≤ grade 2. 
Permanently discontinue 
ipilimumab.  Hold both drugs until 
≤ grade 2, then resume both drugs. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue both 
drugs. 
Fatigue is the most common adverse event associated with immune checkpoint therapy.  
Fatigue ≥ grade 2 should be evaluated for associated or underlying organ involvement 
including pituitary, thyroid, and hepatic, or muscle (CPK) inflammation. 
 

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Neurological events 
Management/Next Dose for 
Nivolumab Monotherapy 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
Hold pending evaluation and 
observation.  Resume when 
resolved to baseline. 
Hold both drugs pending evaluation 
and observation.  Resume when 
resolved to baseline. 
Grade 2 
Hold nivolumab pending 
evaluation and observation.  
Resume when improved to 
≤ grade 1 or baseline.  Patients 
should permanently discontinue 
nivolumab therapy if treatment 
with steroids is required. 
Hold both drugs pending evaluation 
and observation.  Resume when 
improved to ≤ grade 1 or baseline.  
Patients should permanently 
discontinue nivolumab and 
ipilimumab therapy if treatment 
with steroids is required. 
Grade 3 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
ipilimumab.  Hold nivolumab until 
improved to ≤ grade 1 or baseline, 
then resume.  Manage subsequent 
events according to nivolumab 
guidelines. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
Recommended management:  See Neurologic Adverse Event Management Algorithm  
 
Cardiac*  
Management/Next Dose for Nivolumab or Nivolumab plus 
Ipilimumab 
≤ Grade 1 
Hold dose pending evaluation.**  Evaluate for signs and symptoms of 
CHF, ischemia, arrhythmia, or myositis.  Obtain history EKG, CK (for 
concomitant myositis), and CK-MB.  Repeat troponin, CK and EKG 
after 2-3 days.  If troponin and labs normalize, patient may resume 
therapy.  If labs worsen or symptoms develop then treat as below. 
≥ Grade 2 with 
suspected 
myocarditis 
Hold dose pending evaluation.**  Admit to hospital and consult with a 
cardiologist.  Rule out MI and other causes of cardiac disease.  Continue 
to monitor and obtain echocardiogram.  Also consider cardiac MRI and a 
cardiac biopsy.  Initiate high dose methylprednisolone.  If no 
improvement is seen within 24 hours, add either infliximab, ATG, or 
tacrolimus.  Resume therapy if there is a return to baseline AND 
myocarditis is excluded or considered unlikely. 
≥ Grade 2  with 
confirmed 
myocarditis 
Permanently discontinue nivolumab and ipilimumab therapy and admit 
to CCU.  Treat as above.  Consider high dose methylprednisolone and 
electrophysiology consultation.  Begin telemetry or event monitoring.  
Add ATG or tacrolimus if no improvement is seen. 

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Cardiac*  
Management/Next Dose for Nivolumab or Nivolumab plus 
Ipilimumab 
Grade 4 
Permanently discontinue nivolumab or nivolumab and ipilimumab 
therapy. 
* Including CHF, LV systolic dysfunction, Myocarditis, CPK elevation, and troponin. 
** Patients with evidence of myositis without myocarditis may be treated according to “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. 
 
Endocrine 
(Hypophysitis, 
Adrenal 
Insufficiency, Type 
1 Diabetes) 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab and Ipilimumab 
≤ Grade 1 
No change. 
No change. 
Grade 2-3 
Hold until ≤ grade 1 and patients 
are on a stable replacement 
hormone regimen.  If treated with 
steroids, patients must be stable off 
steroids for 2 weeks. 
Hold both drugs until ≤ grade 1 and 
patients are on a stable replacement 
hormone regimen.  If treated with 
steroids, patients must be stable off 
steroids for 2 weeks. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue 
nivolumab and ipilimumab therapy. 
Note:  Symptomatic pituitary enlargement, exclusive of hormone deficiency, but including 
severe headache or enlarged pituitary on MRI should be considered a grade 3 event.  Isolated 
thyroid or testosterone deficiency may be treated as grade 2 if there are no other associated 
deficiencies and adrenal function is monitored.  Evaluate pituitary function before beginning 
steroid therapy or hormone replacement therapy of any kind. 
 
Note:  Patients with thyroiditis may be re-treated on replacement therapy.  Patients must be 
evaluated to rule out pituitary disease prior to initiating thyroid hormone replacement. 
 
Recommended management:  See Endocrinopathy Management Algorithm. 
 
Nephritis 
(Creatinine 
Increased*) 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change. 
No change. 
Grade 2-3 
Hold until ≤ grade 1, then resume. 
Hold both drugs until ≤ grade 1, 
then resume. 

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Nephritis 
(Creatinine 
Increased*) 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue both 
drugs. 
* Rule out noninflammatory (non-immune-mediated) causes.  If cause is non-inflammatory, 
treat accordingly and continue immunotherapy. 
 
Patients with fever should be evaluated as clinically appropriate.  Isolated fever may occur 
during infusion reactions or up to several days after infusion.  Evaluate over 1-2 weeks for 
other autoimmune events that may present as fever. 
 
Recommended management:  See Renal AE Management Algorithm. 
 
Infusion/ 
Hypersensitivity 
reactions* 
Management/Next Dose for Nivolumab and Nivolumab plus 
Ipilimumab 
≤ Grade 1 
Remain at bedside and monitor patient until symptoms recover.  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 rate.  
Monitor patient closely.  The following pre-medications are 
recommended at least 30 minutes before future infusions:  
diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325-1000 mg.  Slowing the infusion rate as 
above is also recommended. 
Grade 2 
Stop infusion, begin an IV infusion of normal saline, and treat the patient 
with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325-1000 mg; remain at bedside and 
monitor patient until symptoms resolve.  Corticosteroid (e.g. 
hydrocortisone 50-100 mg) and/or bronchodilator therapy may also be 
administered as appropriate if reaction is severe or patient does not 
respond to diphenhydramine or acetaminophen.  When symptoms 
resolve, restart infusion at 50% of the original rate; 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, then no further drug should be administered at that 
visit.  Administer diphenhydramine 50 mg IV, remain at bedside, and 
monitor the patient until symptoms resolve.  The amount of study drug 
infused must be recorded on the CRF.  The following prophylactic pre-
medications are recommended at least 30 minutes before future study 
drug administrations:  diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325-1000 mg.  If those are not sufficient to 

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Infusion/ 
Hypersensitivity 
reactions* 
Management/Next Dose for Nivolumab and Nivolumab plus 
Ipilimumab 
prevent infusion reactions, corticosteroids (up to 25 mg of 
methylprednisolone or equivalent) may be used. 
Grade 3 or 4 
Immediately discontinue infusion.  Begin an IV infusion of normal saline 
and treat the patient as follows: 
• Bronchodilators (recommended) such as epinephrine 0.2-1 mg of a 
1:1000 solution for subcutaneous administration or 0.1-0.25 mg of a 
1:10,000 solution injected slowly for IV administration; 
• diphenhydramine 50 mg IV; 
• methylprednisolone 100 mg IV (or equivalent), as needed. 
 
Patient should be monitored until the investigator is comfortable that the 
symptoms will not recur.  Permanently discontinue nivolumab therapy in 
patients on nivolumab and permanently discontinue both ipilimumab and 
nivolumab in patients on the combination.  Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis.  Remain at 
bedside and monitor patient until recovery.  In case of late-occurring 
hypersensitivity symptoms, symptomatic treatment may be given (e.g., 
oral antihistamine or corticosteroids). 
* Manifestation may include fever, chills, rigors, headache, rash, pruritus, arthralgia, 
hypotension, hypertension, and/or bronchospasm. 
 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the Study Chair or 
co-Chair AND reported as an SAE if criteria are met.  Infusion reactions should be graded 
according to NCI CTCAE v5.0 guidelines. 
 
Note:  Treatment guidelines may be modified based local institutional standards, as appropriate. 
 
Fever  
Management/Next Dose for 
Nivolumab Monotherapy 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
Evaluate and continue nivolumab 
therapy. 
Evaluate and continue both drugs. 
Grade 2-3 
Hold until ≤ grade 1, then resume 
nivolumab. 
Hold both drugs until ≤ grade 1, 
then resume both drugs. 
Grade 4 
Permanently discontinue 
nivolumab therapy. 
Permanently discontinue both 
drugs. 
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. 
 
Also consult the guidelines for infusion reactions, above. 
 

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All Other Events 
Management/Next Dose for 
Nivolumab 
Management/Next Dose for 
Nivolumab plus Ipilimumab 
≤ Grade 1 
No change in dose. 
No change in dose. 
Grade 2 
Hold nivolumab until ≤ grade 1 or 
baseline (exceptions as noted below) 
then resume nivolumab. 
Hold both drugs until ≤ grade 1 
or baseline (exceptions as noted 
below), then resume both drugs. 
Grade 3 
Hold nivolumab until ≤ grade 1 or 
baseline, then resume nivolumab. 
Permanently discontinue 
ipilimumab.  Hold nivolumab 
until ≤ grade 1 or baseline, then 
resume nivolumab alone. 
Grade 4 
Permanently discontinue nivolumab 
therapy. 
Permanently discontinue 
nivolumab and ipilimumab 
therapy. 
Recommended management:  As clinically indicated. 
 
If a patient has any AE, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, presents a substantial clinical risk to the patient with continued study drug 
dosing should go off protocol treatment. 
 
If a patient has any grade 3 or 4 drug-related laboratory abnormality (except those mentioned 
above) or electrolyte abnormality, that can be managed indecently from the underlying organ 
pathology with electrolyte replacement, hormone replacement, insulin, or that does not require 
treatment does not require discontinuation. 
 
If treatment is delayed >4 weeks for an AE, nivolumab or nivolumab and ipilimumab therapy 
should be permanently discontinued. 
 
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 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. 
 
Any patients who require additional immune suppressive treatment beyond steroids should go off 
study treatment 
 
Patients requiring more than two dose delays for the same event should permanently discontinue 
nivolumab or nivolumab and ipilimumab therapy. 
 
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. 
 

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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. 
 
Doses may be delayed for evaluation and patients may resume depending on results.  Any patient 
started on corticosteroids initially who is determined to not require steroid treatment for an 
autoimmune adverse event may resume therapy after a 2-week observation period without 
further symptoms at the discretion of the treating investigator. 
 
 
 
 

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8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
8.1.1 XL184 (cabozantinib), NSC 761968 
 
Chemical Name:  N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl) 
cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
 
Other Names:  Cabozantinib s-malate, EXEL-7184, EXEL-02977184, Cabometyx® 
 
Classification:  Receptor Tyrosine Kinases Inhibitor (RTK) 
 
CAS Registry Number:  1140909-48-3  
 
Molecular Formula:  C28H24FN3O5·C4H6O5  
M.W.: 635.6 Daltons (L-malate salt) 
 
Mode of Action:  XL184 (cabozantinib) 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. 
 
How Supplied:  Exelixis supplies and the PMB, CTEP, DCTD, NCI distributes XL184 
(cabozantinib) tablets.  The composition of the tablets is listed in the table below.  The yellow 
film-coated tablets are available in the following free-base equivalent strengths and bottle 
configurations: 
1. 20 mg: round (5.6 mm); 30 tablets per HDPE bottle 
 
XL184 (cabozantinib)Tablet Components and Composition 
Ingredient 
Function 
% w/w 
XL184 (cabozantinib) malate (25% drug load as cabozantinib) Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
• HPMC 2910 / Hypromellose 6 cp  
• Titanium dioxide  
• Triacetin  
• Iron Oxide Yellow 
Film Coating 
4.00 
 

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Storage:  Store intact bottles at controlled room temperature 20°C  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 outside of 15°C and 30°C (59°F to 86°F) is identified, 
promptly return XL184 (cabozantinib) to 20°C to 25°C (68°F 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:  Refer to the drug label for expiration date. Dispense XL184 (Cabozantinib) in original 
bottles. 
 
However, if dispensing the exact quantity of cabozantinib tablets is an institutional guideline: 
 
• 
Removing the extra tablets from the original bottle is allowed, and it must be used within 
30 days of the preparation date. Document the extra tablets as waste in Oral DARF. 
• 
Adding additional cabozantinib tablets into the original bottle in which the original bottle 
is exceeding its 30 Count bottle, is Not Allowed. 
  
 
Repackaging XL184 (cabozantinib) for a short period of time is acceptable and limited to: 
• Up to 24 hours when dispensed in an open container such as a pill cup. 
• Up to 7 days when dispensed in a closed container (e.g., a pharmacy dispensing bottle). 
 
Route of Administration:  Oral. 
 
Method of Administration:  Take XL184 (cabozantinib) on an empty stomach; i.e., do not eat 2 
hours before and 1 hour after each dosing.  Take the dose with a full glass of water at 
approximately the same time each day.  Do not crush or chew.  Do not take a missed dose within 
12 hours of the next dose. 
 
Potential Drug Interactions: 
 
CYP450 isozymes: 
In vitro, XL184 (cabozantinib) is a substrate of CYP3A4 and a weak substrate of CYP2C9.  In 
healthy volunteers, XL184 (cabozantinib) AUC increased 38% with co-administration of 
ketoconazole, a strong inhibitor of CYP3A4, and decreased by 77% with a strong CYP3A4 
inducer rifampin.  Therefore, avoid chronic use of strong CYP3A4 inducers such as rifampin, 
dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort while taking XL184 (cabozantinib).  Avoid chronic use of strong CYP3A4 inhibitors such 
as ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir.  
Use alternative medications.  
 

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Note:  Use caution when discontinuing medication that is a strong inducer of CYP3A4 in 
patients who have been on stable doses of XL184 (cabozantinib), as this could significantly 
increase the exposure to XL184 (cabozantinib). 
 
XL184 (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 microsomal (HLM) 
stability assays.  IC50 values >20 µM were observed for CYP1A2, CYP2D6, and CYP3A4 
isozymes.  XL184 (cabozantinib) 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 (cabozantinib) is an inhibitor of P-glycoprotein transport 
activity (IC50 = 7.0 µM).  Co-administration of XL184 (cabozantinib) with a P-gp substrate may 
result in an increase in P-gp substrate plasma concentration.  Therefore, use caution when 
administering XL-184 (cabozantinib) with drugs known to be P-gp substrates (e.g., fexofenadine, 
aliskiren, ambrisentan, digoxin, colchicine, maraviroc, posaconazole, tolvaptan, etc.). 
 
XL184 (cabozantinib) is also a substrate of drug transporter MRP2, which may result in an 
increase plasma concentration of XL184 (cabozantinib) when administered with an inhibitor of 
MRP2.  Use caution and monitor adverse events when administering XL184 (cabozantinib) with 
MRP2 inhibitors such as cyclosporine, delavirine, efavirenz, or emtricitabine. 
 
Protein binding: 
XL184 (cabozantinib) is highly protein bound (≥99.9%).  Use caution when co-administering 
XL184 (cabozantinib) with medications that are highly protein-bound (e.g., diazepam, 
furosemide, dicloxacillin, or propranolol).  Avoid administration of warfarin with XL184 
(cabozantinib) 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 (cabozantinib) plasma PK in healthy volunteers; thus, 
concomitant use of these drugs with XL184 (cabozantinib) is allowed. 
 
QTc prolongation: 
Use caution when administering XL184 (cabozantinib) in patients with QT prolongation risk, a 
history of QT interval prolongation, or who are receiving antiarrhythmic drugs.  Concomitant use 
of strong CYP3A4 inhibitors should be avoided as it may increase XL184 (cabozantinib) plasma 
concentrations.  Refer to the protocol for QTcF criteria.  
 
Potential Food Effect 
A high fat meal increased both XL184 (cabozantinib) Cmax and AUC values by 41% and 57%, 
respectively, relative to fasted conditions.  Therefore, XL184 (cabozantinib) should be taken on 
an empty stomach (fasting is required 2 hours before and 1 hour after each dose). 

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Patient Care Implications:  Women of childbearing potential must use highly effective 
contraception while receiving XL184 (cabozantinib) and for 4 months after the last dose.  
Breastfeeding is not allowed while on study.  Sexually active males must use highly effective 
contraception while on study and for 4 months after the last dose. 
 
Availability:  XL184 (cabozantinib) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
If the study agent is provided by the NCI under a Collaborative Agreement with the agent 
manufacturer, the text below must be included in the protocol.  Information on the study agent’s 
Collaborative Agreement status will be provided in the approved LOI response letter.  
 
XL184 (cabozantinib) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.2 Nivolumab (NSC 748726) 
 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
 
Other Names:  BMS-936558, MDX1106 
 
Classification:  Anti-PD-1 mAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:  Nivolumab targets the PD-1, 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, PD-L1 and 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. 
 
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). 
 
How Supplied:  Nivolumab is supplied by Bristol-Myers Squibb (BMS) and distributed by the 
Pharmaceutical Management Branch (PMB), CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) 
with a 0.7 mL overfill.  It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-
laminated rubber stoppers and aluminum seals. 
 

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Preparation:  Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose.  When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to protein concentrations as low 
as 0.35 mg/mL. When the dose is fixed (e.g., 240 mg, 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 kg, the total volume of infusion must not exceed 
4 mL per kg of patient weight.  During drug product preparation and handling, vigorous mixing 
or shaking is to be avoided. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
 
Storage:  Vials of Nivolumab injection must be stored at 2-8 °C (36-46 °F) and protected from 
light and freezing.  The unopened vials can be stored at room temperature (up to 25 °C, 77 °F) 
and room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2-8 °C (36-46 °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:   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 7 days in a refrigerator at 2°-8°C 
(36°46°F) and a maximum of 8 hours of the total 7 days can be at room temperature (up to 25°C, 
77°F) and room light. The maximum 8-hour period under room temperature and room light 
conditions 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.  
 
Route of Administration:  Intravenous infusion over 30 minutes.  Do not administer as an IV 
push or bolus injection. 
 
Method of Administration:  Administer through a 0.2 micron to 1.2-micron pore size, low-
protein binding (polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions:  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. 
 
Patient Care Implications:  WOCBP receiving nivolumab must continue contraception for a 
period of 5 months after the last dose of nivolumab.  Men receiving nivolumab and who are 

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98 
sexually active with WOCBP must continue contraception for a period of 7 months after the last 
dose of nivolumab. 
 
Availability:  Nivolumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
If the study agent is provided by the NCI under a Collaborative Agreement with the agent 
manufacturer, the text below must be included in the protocol.  Information on the study agent’s 
Collaborative Agreement status will be provided in the approved LOI response letter.  
 
Nivolumab is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.3 Ipilimumab (NSC 732442) 
 
Other Names:  BMS-734016, BMS-734016-01, Anti-CTLA-4 monoclonal antibody, MDX-010, 
Yervoy™ 
 
Classification:  Human monoclonal antibody 
 
M.W.:  147,991 Daltons 
 
Mode of Action:  CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a mAb that 
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.  Blockade 
of CTLA-4 has been shown to augment T cell activation and proliferation, including the 
activation and proliferation of tumor-infiltrating T-effector cells.  Inhibition of CTLA-4 signaling 
can also reduce Treg function, which may contribute to a general increase in T-cell 
responsiveness, including the anti-tumor response.  
 
Description:  Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1κ consisting of 4 
polypeptide chains; 2 identical heavy chains primarily consisting of 447 amino acids each with 2 
identical kappa light chains consisting of 215 amino acids each linked through inter-chain disulfide 
bonds.  Ipilimumab is produced from cell culture using a Chinese Hamster Ovary (CHO) cell line.   
  
How Supplied:  Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI.  Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is 
packaged in a 50-cc Type I flint molded glass vials, stoppered with 20-mm gray butyl rubber 
stoppers, and sealed with 20-mm aluminum flip-off seals.  Each vial includes a 2.6-mL overfill 
for vial, needle, and syringe holdup. 
 
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 (20 to 80 C) or at room 
temperature/ room light.  

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99 
 
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets. 
  
Storage:  Store intact vials refrigerated at (20 to 80 C), protected from light.  Do not freeze. 
 
Stability:  Refer to the package label for expiration.  Solution as described above is stable up to 24 
hours refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  Use 
prepared IV solution immediately. Discard partially used vials.  
 
Route of Administration:  Intravenous infusion at the protocol-specific rate.  Do not administer 
ipilimumab as an IV push or bolus injection. 
 
Method of Administration:  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). 
 
Patient Care 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 when considering the use of 
ipilimumab in a patient who has previously experienced a severe or life-threatening skin adverse 
reaction on a prior cancer immune stimulating therapy. 
 
Availability:  Ipilimumab (BMS-734016, MDX-010) is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
If the study agent is provided by the NCI under a Collaborative Agreement with the agent 
manufacturer, the text below must be included in the protocol.  Information on the study agent’s 
Collaborative Agreement status will be provided in the approved LOI response letter.  
 
Ipilimumab (BMS-734016, MDX-010) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.4 Agent Ordering and Agent Accountability 
 
8.1.4.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 

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100 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Sites may request a starter supply (2 bottles of cabozantinib 20 mg, 4 vials of 
ipilimumab, and 5 vials of nivolumab) once a patient is in screening. 
 
Submit agent requests through the PMB AURORA application.  Access to AURORA requires 
the establishment of credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems, maintenance of an “active” account status, a “current” password, 
and active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time or use the dialog function in AURORA to 
communicate with PMB staff.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
8.1.4.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a complete accountability 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. 
 
Product Quality Complaint (PQC): A product quality complaint is defined as any 
suspicion of a product defect related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage or 
distribution of the product, or delivery system.  Not all PQCs involve a study subject.  
Lot or batch numbers are of high significance and need to be provided where and 
when possible. PQC must be reported to the PMB as soon as the PQC is identified. 
Report PQC to PMB at PMBAfterHours@mail.nih.gov or by using the dialog 
function in AURORA to communicate with PMB staff. 
 
8.1.5 Material Safety Data Sheets 
 
The current versions of the material safety data sheets (MSDS or SDS) for PMB-distributed 
agents will be accessible to site investigators and research staff through the PMB AURORA 
application. Questions about MSDS access may be directed to the PMB at 
PMBAfterHours@mail.nih.gov or by using the dialog function in AURORA to communicate 
with PMB staff. 
 
8.1.6 Investigator Brochure Availability 
 

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101 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB AURORA application.  Access to AURORA requires the 
establishment of credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems, maintenance of an “active” account status, a “current” 
password and active person registration status.  Questions about IB access may be 
directed to the PMB IB Coordinator via email. 
8.1.7 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 PMB Agent Inventory Management System 
(AURORA) application: https://ctepcore.nci.nih.gov/aurora/login  
• 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) 
 
8.1.8 Agent Shortages 
 
Specific guidance on how to address agent shortages for patients already enrolled on a clinical 
study as well as how to manage potential enrollment of new patients is provided at 
https://ctep.cancer.gov/branches/pmb/drug_shortages.htm.   
Treatment plan modifications being made to avoid immediate hazard to patients is permissible 
under the Department of Health and Human Services (HHS) regulations at 45 CFR 
46.103(b)(4)(iii). In accordance with HHS regulations, local investigators must promptly inform 
the IRB of record of this unanticipated problem and the management plan for the trial. 
 
 

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102 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This phase 2 study has a two-stage Simon minimax design with a primary endpoint of overall 
response rate (ORR) (complete responses [CRs] plus partial responses [PRs]).  The hypothesis of 
the study is that combination of XL184 (cabozantinib), nivolumab, and ipilimumab improves 
ORR in the treatment of poorly differentiated neuroendocrine carcinomas, after the failure of at 
least one line of prior systemic cancer treatment, to more than 45%.  The null hypothesis is a 
45% true response rate versus alternative hypothesis of 70% true response.  This design will have 
a type 1 error of 0.10 and 90% power (β=0.10).  The response rate will be determined by the 
number of patients, each, who reach a PR or CR within 6 months of their initiation of treatment.   
 
For the primary objective, the binary endpoint will be the achievement of either a CR or a PR 
(yes/no).  Response will be determined via the RECIST v1.1 criteria (See Section 12.0).  The 
relevant statistical endpoint will be the CR+PR rate, evaluated for all registered patients, and for 
all response-evaluable (r-e) patients.  The r-e population is defined as patients who receive at 
least one dose of the study drugs, have measurable disease at baseline, and have at least 1 post-
baseline disease assessment.  CR+PR rate will be summarized with a point estimate and a 2-
sided Wilson type CI estimate. These two estimates will be made for all registered and for all r-e 
patients.  For the primary and the interim analyses, the confirmed responses need to be seen 
within 6 months of treatment initiation. Further patient enrollment may be suspended while 
already enrolled patients continue their treatment until the needed response rate is observed as 
described below in Section 9.2.  Patients already on treatment will continue their treatment as 
long as any criterion for discontinuation is not met. 
 
The study design will include the following interim safety analysis.  If 4 or fewer of the first 15 
patients experience a delay in any of the study therapies, lasting at least four weeks, due to 
toxicity, or is discontinued due to toxicity, and the first stage response target (i.e. at least 7 out of 
15 achieved an objective response) is reached, the trial could proceed to the second stage.  
However, if at least 5 of the first 15 patients experience such a treatment delay or discontinuation 
(and the first stage response target is reached), accrual would remain suspended and these 
findings would need to be discussed with CTEP.  Note that if the first stage response target is not 
reached, the study would be closed due to futility, regardless of the level of toxicity. 
 
This is not a stratified study design, although the primary organ of origin, if known and 
morphologic description of the poorly differentiated NECs (small cell, large cell or mixed 
histology) will be recorded, when available, for descriptive purposes. 
 
9.2 
Sample Size/Accrual Rate 
 
The overall sample size is 25 patients.  In order to allow for occasional ineligibility or response 
inevaluability, this trial will have a maximum accrual goal of 30 patients.  Stage 1 will recruit up 
to 18 patients to obtain 15 eligible and treated patients, and Stage 2 (if needed) will recruit up to 
12 patients to obtain 10 eligible and treated patients.  If there are 7 or more objective responses 
in Stage 1, the study will advance to Stage 2, otherwise the study will be terminated early for 

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105 
5.0 criteria as defined in Section 12.0.  The t-e population is defined as all patients who have 
received the study treatment.  The resulting binary endpoints of each toxicity type at a specific 
grade(s), will all be summarized with point estimates and 2-sided Wilson type CI estimates.  The 
grade of each type of toxicity will also be summarized with 1-way frequency distributions. 
 
9.4.3 DCR 
 
The hypothesis is that the combination of XL184 (cabozantinib), nivolumab, and ipilimumab 
will improve DCR to more than 50%. The binary endpoint of DCR will be defined as the 
achievement of either CR, or PR, or SD (yes/no).  The resulting binary endpoints of DCR will all 
be summarized with point estimates and 2-sided Wilson type CI estimates.  DCR estimates will 
be calculated for all r-e patients. 
 
9.4.4 DOR 
 
DOR is measured from the time measurement criteria are met for CR/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 censored time-to-event distributions of DOR will be analyzed with 
standard Kaplan-Meier methodology. Point and CI estimates of the median and various time 
point-specific rates will be derived from the Kaplan-Meier life table. Censored DOR will be 
analyzed for the combination of all patients who achieve either a CR or a PR 
 
9.4.5 Correlative Studies 
 
To determine effects of the combination of XL184 (cabozantinib), nivolumab and ipilimumab on 
multiple biomarkers of disease or treatment, analysis of available paired tumor biopsy samples 
will be done using methods that include but are not limited to IHC of intratumoral immune cells 
and flow cytometry.  The antibodies that will be used for the IHC assays are listed below. 
 
Antigen 
Clone 
Manufacturer 
Cat. No. 
Regulatory Status 
Target cell 
CD4 
4B12 
DAKO 
M731001-2 
IVD 
CD4 T cell 
CD8a 
C8/144B 
DAKO 
M710301-2 
IVD 
CD8 T cell 
Foxp3 
EP340 
Cell Marque 
AC-0304RUOC IVD 
  
PD-1 
NAT105 
Cell Marque 
315M 
IVD 
  
IFN-g 
B27 
BD Biosciences 
550011 
RUO 
  
PD-L1 
22C3 
DAKO 
M3653 
IVD 
  
Elastase 
NP57 
DAKO 
M075201-2 
IVD 
TAN 
CD68 
PG-M1 
DAKO 
M087601-2 
IVD 
TAM 
CD163 
MRQ-26 
Cell Marque 
163M 
IVD 
TAM 
Arg1 
SP156 
Cell Marque 
380R 
IVD 
  
 
 

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For all correlative objectives, the continuously distributed correlative endpoints (CD8+ T 
lymphocytes, MDSC, and TAM) will be summarized with descriptive statistics (N, mean, 
standard deviation, median, interquartile range (IQR), minimum, maximum, and a CI for the 
mean).  Statistical graphics (e.g., box plots, dot plots, etc.) will also be created to illustrate the 
distributions of the various correlative endpoints.  All of these descriptive statistical analyses and 
graphical analyses will be performed separately for:  a) the pre-treatment biopsy correlatives; b) 
the on-treatment biopsy correlatives; and c) the pre/post biopsy difference in the correlatives. 
 
9.5 
Reporting and Exclusions 
 
9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with any of the 
three investigational agents - XL184 (cabozantinib), nivolumab, or ipilimumab. 
 
All toxicities will be graded as per NCI CTCAE version 5.0.  Toxicity evaluation will be done at 
the start of each cycle for as long as the patient is on active treatment. 
 
Patients who experience a Grade 3 or greater toxicity that is attributed to study medication and 
cannot be ameliorated by the use of adequate medical intervention should have their treatment 
interrupted until the toxicity improves to a Grade 2 or lower severity.  Patients may subsequently 
be re-started on the study drugs, including at a reduced dose for XL184 (cabozantinib). 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  

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

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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; 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. 
 
10.1.2 Nivolumab  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Nivolumab (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/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
Nivolumab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 

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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Nivolumab 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 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. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with 
accompanying fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have 
occurred in patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These 
complications may occur despite intervening therapy between receiving Nivolumab and allo-
SCT. 
 
7Infusion 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 Nivolumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital 
edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 

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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders - Other (limbic 
encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; 
Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Pain of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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122 
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. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in 
association with subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients 
receving 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. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia 
gravis). 
 
6Gastrointestinal 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. 
 
7Infection 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 

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123 
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; 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) 
 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) 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. 
 
10.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  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/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through Medidata Rave only if the 
grade is above the grade provided in the SPEER. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of Adverse Events (AEs) entered in Rave to 

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124 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.  Sites must initiate all AEs for this study in 
Medidata Rave. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period.  AEs that occur 30 days after the last 
administration of the investigational agent/intervention are collected using the Late 
Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the 
box Send All AEs for Evaluation and save the form).  Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting.  A report is initiated 
in CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form.  Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
 
• Study specific documents:   Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting, and 
• Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website: 
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 

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126 
NOTE:   Protocol-specific exceptions to expedited reporting of SAEs are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timeframes are defined as: 
o 
“24-Hour notification, 5 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report. 
o 
“24-Hour notification, 10 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 10 calendar days of 
the initial 24-hour report. 
1SAEs 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 notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 3-5 SAEs 
• 
Within 10 calendar days for Grade 1-2 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
 
Effective Date: August 30, 2024 
 
10.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through Medidata Rave must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.5 Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via Medidata Rave.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
 

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127 
10.6 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via Medidata Rave.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is 
required. 
 
10.7 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
 
 

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128 
11. STUDY CALENDAR 
 
Following registration, patients should begin protocol treatment within a minimum of 7 days and 
no more than 14 days.  Baseline evaluations are to be conducted within 1 week prior to start of 
protocol therapy.  Scans and x-rays must be done <4 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 

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129 
 
Pre-study 
(≤30 days 
prior to 
registration) 
 
Cycles 1 - 4:  Cycle length = 3 weeks 
Cycles 5+:  
Cycle length = 
4 weeks 
At disease 
progression 
4 weeks after 
last dose of 
study drugD 
Long term 
follow-up off 
study treatmentE 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5+ 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Day 
1 
XL184 (cabozantinib)A 
 
X———————————————————————————————————————————X 
 
 
 
NivolumabB 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
IpilimumabC 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X————————————————————————————————————————————X 
 
 
 
Physical exam, Vital signs, Weight, 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential and platelets 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
Serum ChemistryF 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
PT/INR, PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
XM 
 
Urine protein to creatinine ratio 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
Amylase and lipase 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
Pregnancy testG 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
TSH (with reflex T3/T4, if abnormal) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
Adrenocorticotropic hormone 
(ACTH)H 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
XM 
 
Serum cortisol 
(AM measurement preferred)H 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
XM 
 
Troponin, 2D echocardiogram, and 
cardiac historyI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG J 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
XM 
 
Adverse event evaluation 
 
X————————————————————————————————————————————X 
X 
X 
 
Radiologic evaluation K 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
XN 
X 
 
 

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130 
 
Pre-study 
(≤30 days 
prior to 
registration) 
 
Cycles 1 - 4:  Cycle length = 3 weeks 
Cycles 5+:  
Cycle length = 
4 weeks 
At disease 
progression 
4 weeks after 
last dose of 
study drugD 
Long term 
follow-up off 
study treatmentE 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5+ 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Week 
1 
Week 
2 
Week 
3 
Day 
1 
Ki-67 index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy for correlative studies L 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood collection in cfDNA streck 
tubes L 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up (via phone is allowed in 
case the patient cannot make the clinic 
visit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
A: XL184 (cabozantinib):  40 mg PO once daily until disease progression or death. 
B: Nivolumab:  3 mg/kg IV on Day 1 of  Cycles 1-4 and 480 mg IV on Day 1 of Cycle 5 and subsequent cycles until disease progression or death.  May be given ±3 days from a scheduled start of dosing. 
C: Ipilimumab:  1 mg/kg IV on Day 1 of Cycles 1-4 (total of four doses).  May be given ±3 days from a scheduled start of dosing.  When scheduled for the same day, ipilimumab should be given immediately 
following nivolumab administration. 
D:  Patients will need to come in for an initial clinical follow up at 4 weeks after the last dose of the study drug. 
E: Off-study evaluation:  Patients will be followed every 12 weeks after the 4-week clinical visit for 2 years after discontinuation of study treatment or until death, whichever occurs first.  In addition, patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.  Follow-up may be by phone interview. 
F: To include albumin, alkaline phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, creatinine, GGT, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total bilirubin, and total 
protein. 
G: Serum pregnancy test (women of childbearing potential only) will be performed at least seven days before beginning study therapy.  A negative serum or urine pregnancy test is also required at the beginning of 
each treatment cycle. 
H: ACTH and serum cortisol will be tested at C1D1 and C3D1 prior to ipilimumab and nivolumab administration, C5D1 prior to nivolumab administration, and every other cycle thereafter. 
I: 
Troponin assessment and cardiac history should be obtained at baseline and subsequently as clinically indicated.  A 2D echocardiogram  should be obtained at baseline for patients with a history of CHF and at the 
investigator’s discretion, and may be repeated as clinically indicated. 
J: 
EKG will be performed at baseline, on Day 1 of Cycles 1 to 5, and then every 8 weeks (every other cycle). 
K: CT or MRI scans of chest, abdomen, and pelvis will be done at baseline and to assess the response per RECIST v1.1 criteria.  CTs or MRIs with IV contrast are encouraged but will be done at the investigator’s 
discretion.  CT imaging of the neck could be added at the investigator’s discretion.  IV Contrast enhanced CT imaging of chest, abdomen, and pelvis should occur every 2 cycles for the first 6 months and every 3 
cycles thereafter until disease progression. 
L: Mandatory 
M: Should be done if clinically indicated. 
N: Tumor measurements are to be repeated every 2 cycles for the first 6 months and every 3 cycles thereafter. 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CBC=complete blood count, CT=computed tomography, EKG=electrocardiogram, GGT=γ-glutamyl transferase, 
IV=intravenous, MRI=magnetic resonance imaging, PO=orally, TSH=thyroid stimulating hormone. 

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12. MEASUREMENT OF EFFECT 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 2 cycles for the 
first 6 months on treatment and every 3 cycles thereafter. In addition to a baseline scan, 
confirmatory scans should also be obtained in case of suspected psuedoprogression at 6 weeks 
following initial documentation of objective response.  If clear progression is observed i.e. new 
lesions etc., no additional scan is needed for confirmation.  CT scan of the chest, abdomen, and 
pelvis with contrast will be used for evaluation of disease at baseline, every 2 cycles for the first 
6 months and every 3 cycles thereafter until disease progression.  MRI of the brain may be used 
in addition, if prior brain involvement is known and should coincide with the CT scan schedule. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with XL184 (cabozantinib), nivolumab, and ipilimumab. 
 
Evaluable for objective response.  All eligible patients who have measurable disease present at 
baseline, have received at least one dose 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 dose 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.1.2 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 (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 

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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 

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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 (≥1 cm) 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 (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  Hence it 
should not be used for tumor response assessment in the evaluation of patients enrolled in the 
study. 
 
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. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 

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Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET.  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
 
 
 

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135 
12.1.4 Response Criteria 
 
12.1.4.1 
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 (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
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). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (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. 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 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). 

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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. 
 
 
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.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.1.7 Response Review 
 
TBD 
 
12.2 Other Response Parameters 
 
N/A 
 
 
 

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13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
The Protocol Principal Investigator will have, at a minimum, quarterly conference calls with the 
Study Investigators and the CTEP Medical Officer(s) to review accrual, progress, and 
pharmacovigilance.  Decisions to proceed to the second stage of a Phase 2 trial will require sign-
off by the Protocol Principal Investigator and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 Data Reporting 
 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
 
Requirements to access Rave via iMedidata: 
 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
o Rave role requirements: 
▪ 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type, 
▪ 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 

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139 
▪ 
Rave Read Only or Rave SLA role must have at a minimum an Associate 
(A) registration type. 
o Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
• 
DTL Rave CRA task assignment requirements (for write access): 
o Corresponding role (Rave CRA or Rave CRA (Lab Admin)) on the site roster; 
and 
o Completion of the Theradex Specimen Tracking System (STS) Training course in 
CLASS (see Section 4.2.3 – Delegation of Tasks Log (DTL)). 
 
13.2.1 Protocol Specific Requirements For Rave Access 
 
• Specimen Tracking System Training Requirement for full read/write Rave access: 
o All site staff assigned the Rave CRA task on the DTL must complete the online 
specimen tracking training, which is administered via the Compliance, Learning, and 
SOP Solutions (CLASS) system. 
o Completion of the training will be automatically communicated to the CTSU 
Regulatory application and to Medidata Rave, and the individual will receive an 
invitation to [protocol #] in Rave. There is no need to submit a training completion 
certificate to the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study (either within CLASS, or 
via the procedure in place prior to CLASS), the training does not need to be 
completed again.  However, new versions of the Specimen Tracking System training 
course may require new training. 
o For questions about the training content or the tracking system itself, please contact 
STS Support at Theradex (STS.Support@theradex.com). 
o For questions or concerns about accessing the training in CLASS, please contact the 
CLASS Help Desk CLASSHelpDesk@westat.com. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata.  No action will be required; each study invitation will be automatically accepted and 
study access in Rave will be automatically granted.  Site staff 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 
eLearning link in the Tasks pane located in the upper right corner of the iMedidata screen.  If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning will appear 
under the study name in the Studies pane located in the center of the iMedidata screen; once the 
successful completion of the eLearning has been recorded, access to the study in Rave will be 
granted, and a Rave EDC link will replace the eLearning link under the study name. 
 
Action will be required by site staff (to activate their account) who have not previously activated 
their iMedidata/Rave account at the time of initial site registration approval for the study in the 
Regulatory application. Account activation instructions are located on the CTSU website in the 
Data Management section under the Data Management Help Topics > Rave Resources > 

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140 
Medidata Account Activation and Study Invitation (to activate your iMedidata account).  
Additional information on iMedidata/Rave is available on the CTSU members’ website in the 
Data Management Rave Resources section or by contacting the CTSU Help Desk at 1-888-823-
5923 or by email at ctsucontact@westat.com. 
 
13.2.2 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.3 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D) and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 

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141 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm). 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status, and timeliness reports.  Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website.  Staff who have Rave study access can access the Rave study data via 
direct links available on the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in. Additional site staff can subscribe and unsubscribe to 
these notifications using the CTSU Report and Information Subscription Portal on the 
CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
13.4 CTEP Multicenter Guidelines 
N/A  
 

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13.5 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
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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143 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 

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144 
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2018.  Bristol-Myers Squibb.  Lawrenceville, NJ.   
 
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Kolby, L., G. Persson, S. Franzen, and B. Ahren.  (2003).  Randomized clinical trial of the effect 
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Kwilas, A.R., A. Ardiani, R.N. Donahue, et al.  (2014).  Dual effects of a targeted small-
molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor 

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carcinomas with combined etoposide and cisplatin.  Evidence of major therapeutic activity in the 
anaplastic variants of these neoplasms.  Cancer.  68:227-232. 
 
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advanced Merkel-cell carcinoma.  N Engl J Med.  374:2542-2552 
 
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Okunishi, K., M. Dohi, K. Nakagome, et al.  (2005).  A novel role of hepatocyte growth factor as 
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Sorbye, H., S. Welin, S.W. Langer, et al.  (2013).  Predictive and prognostic factors for treatment 
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Yakes, F.M., Chen, J., Tan, J., et al.  (2011).  XL184 (cabozantinib) (XL184), a novel MET and 
VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.  Mol 
Cancer Ther.  10:2298-2308. 
 
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Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United 
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Zitvogel, L., Tesniere, A., and Kroemer, G.  (2006).  Cancer despite immunosurveillance:  
immunoselection and immunosubversion.  Nat Rev Immunol.  6:715-727. 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX D 
PRE-BIOPSY ASSESSMENT 
 
A pre-biopsy lesion assessment can increase trial safety and efficiency.  By agreement between 
all investigators, an attempt at biopsy will be made if the clinical trial team determines that a 
biopsy poses minimal relative risk, provides potential clinical gain to the participant, and will 
likely yield sufficient tissue for analysis.   
 
Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within the 
CTEP Medidata Rave system.  Additional information can be found in the Investigational 
Radiology SOP available at:   
https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN IR Research Biopsy SOP.pdf.  
 
Individual Patient Pre-Biopsy Assessment.  IR co-investigators are encouraged to apply this 
pre-biopsy scoring and correlation system to assist in the determination of biopsy 
appropriateness. 
 
• IR co-investigators assign a subjective score of 1-3 based on likelihood of success due to 
lesion characteristics.  
 
1.  Biopsy should not be done  
A. 
Due to safety concerns 
B. 
Due to lack of suitable lesion for biopsy 
 
2.  Uncertainty about success  
A. 
Due to access path to lesion 
B. 
Due to lesion characteristics  
 
3.  Likely successful  
 
• Lesion characteristics to be considered 
• Size (small) (<2 cm) 
• Location/path to lesion 
• Morphologic features (necrosis, sub-solid, sclerosis, ill-defined/infiltrative) 
• PET (+/-), avidity  
• Organ/site (sclerotic bone is low yield; fine needle aspiration to be used) 
 

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APPENDIX E 
PATIENT MEDICATION DIARY  
 
 
PATIENT’S MEDICATION DIARY – XL184 (cabozantinib) – For Cycles 1-4 
Today’s date:   
 
Agent:  XL184 (cabozantinib) 
Patient Name:   
(initials acceptable) Patient Study ID:   _________________  
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle. 
2. You will take your dose of XL184 (cabozantinib) at the same time each day: 
 2 (20 mg) tablets every day; (or)  1 (20 mg) tablet every day; (or)  1 (20 mg) tablet every other day. 
You should swallow the tablets as a whole.  Do not crush or chew.  You should take XL184 (cabozantinib) on an empty stomach, and at 
least 2 hours after and 1 hour before eating. 
3. Store XL184 (cabozantinib) tablets in the original bottle and not in weekly pill boxes.  Record the date, the number of tablets you took, and 
when you took them. 
4. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 12 hours of the scheduled time.  You 
should not take the  missed dose if it is within 12 hours of your next scheduled dose.  Take your next dose at the regularly scheduled time. 
5. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
6. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
7. If you have any comments or notice any side effects, please record them in the Comments column. 
8. Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
What time was dose taken? # of tablets taken 
Comments 
1. 
 
 
 
 
2. 
 
 
 
 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
6. 
 
 
 
 
7. 
 
 
 
 
8. 
 
 
 
 
9. 
 
 
 
 
10.  
 
 
 
11.  
 
 
 
12.  
 
 
 
13.  
 
 
 
14.  
 
 
 
15.  
 
 
 
16.  
 
 
 
17.  
 
 
 
18.  
 
 
 
19.  
 
 
 
20.  
 
 
 
21.  
 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
 ________________________________________________ 
2. Date patient was removed from study 
 ________________________________________________ 
3. Patient’s planned total daily dose 
 ________________________________________________ 
4. Total number of pills taken this month (each size)  ________________________________________________ 
5. Physician/Nurse/Data Manager’s Signature 
 ________________________________________________ 
 
 
Patient’s signature:   ___________________________________________________________________________ 
 
 
 
CTEP-assigned Protocol # 10315 
Local Protocol # TBD 

BATCH 
INITIALS:  
 
DATE:   
 
NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 
 
PATIENT’S MEDICATION DIARY – XL184 (cabozantinib) – For Cycles 5 and beyond 
Today’s date:   
 
Agent:  XL184 (cabozantinib) 
Patient Name:   
(initials acceptable) Patient Study ID:   _________________  
INSTRUCTIONS TO THE PATIENT: 
5. Complete one form for each cycle. 
6. You will take your dose of XL184 (cabozantinib) at the same time each day: 
 2 (20 mg) tablets every day; (or)  1 (20 mg) tablet every day; (or)  1 (20 mg) tablet every other day. 
You should swallow the tablets as a whole.  Do not crush or chew.  You should take XL184 (cabozantinib) on an empty stomach, and at 
least 2 hours after and 1 hour before eating. 
7. Store XL184 (cabozantinib) tablets in the original bottle and not in weekly pill boxes.  Record the date, the number of tablets you took, and 
when you took them. 
8. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 12 hours of the scheduled time.  You 
should not take the  missed dose if it is within 12 hours of your next scheduled dose.   Take your next dose at the regularly scheduled time. 
9. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
10. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
11. If you have any comments or notice any side effects, please record them in the Comments column. 
12. Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
What time was dose taken? # of tablets taken 
Comments 
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CTEP-assigned Protocol # 10315 
Local Protocol # TBD 

BATCH 
INITIALS:  
 
DATE:   
 
NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
INSTRUCTIONS TO THE PATIENT: 
5. Complete one form for each cycle. 
6. You will take your dose of XL184 (cabozantinib) at the same time each day: 
 2 (20 mg) tablets every day; (or)  1 (20 mg) tablet every day; (or)  1 (20 mg) tablet every other day. 
You should swallow the tablets as a whole.  Do not crush or chew.  You should take XL184 (cabozantinib) on an empty stomach, and at 
least 2 hours after and 1 hour before eating. 
7. Store XL184 (cabozantinib) tablets in the original bottle and not in weekly pill boxes.  Record the date, the number of tablets you took, and 
when you took them. 
8. If you forget to take a dose at the scheduled time, you can still take that dose as long as it is within 12 hours of the scheduled time.  You 
should not take the  missed dose if it is within 12 hours of your next scheduled dose.   Take your next dose at the regularly scheduled time. 
9. If you vomit after taking a dose, do not retake the dose.  Take the next dose at the regularly scheduled time. 
10. Notify your doctor at the first sign of poorly formed or loose stools, or an increased frequency of bowel movements.  Loperamide (Imodium) 
should be kept on hand and should be taken as recommended by your doctor. 
11. If you have any comments or notice any side effects, please record them in the Comments column. 
12. Please return the forms to your physician when you go for your next appointment. 
Day 
Date 
What time was dose taken? # of tablets taken 
Comments 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment 
 ________________________________________________ 
2. Date patient was removed from study 
 ________________________________________________ 
3. Patient’s planned total daily dose 
 ________________________________________________ 
4. Total number of pills taken this month (each size)  ________________________________________________ 
5. Physician/Nurse/Data Manager’s Signature 
 ________________________________________________ 
 
Patient’s signature:   ___________________________________________________________________________ 

NCI Protocol #:  10315 
Version Date:  November 25, 2024 
158 
APPENDIX F: 
NIVOLUMAB AND IPILIMUMAB MANAGEMENT ALGORITHMS FOR ENDOCRINOPATHY, 
GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, PULMONARY, RENAL, AND SKIN 
ADVERSE EVENTS 

NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 

NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 

NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 

NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 

NCI Protocol #:  10315 
Version Date:   June 3, 2025 
 
 
 

NCI Protocol #:  10315 
Version Date:   June 3, 2025