Phase II Study of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: Georgetown University

 TITLE: Phase II study of Nivolumab/Ipilimumab plus Cabozantinib in patients 
with unresectable advanced melanoma 
 
NCT # NCT04091750 
 
VERSION DATE: December 13, 2021 

 
Version 2.2, December 13, 2021 
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PROTOCOL 
TITLE: 
Phase II study of Nivolumab/Ipilimumab plus 
Cabozantinib in patients with unresectable advanced 
melanoma 
 
 
VERSION NUMBER: 
2.2, December 13, 2021 
TEST PRODUCTS: 
Nivolumab 
Ipilimumab 
Cabozantinib 
 
INDICATION: 
Advanced melanoma 
PRINCIPAL 
INVESTIGATOR: 
 
 
 
 
 
Geoffrey T. Gibney, MD 
Lombardi Comprehensive Cancer Center 
Medstar George University Hospital 
3800 Reservoir Rd NW, Podium A 
Washington, DC, 20007 
Telephone:  202-444-2223 
Fax:  202-444-1229 
E-mail: geoffrey.t.gibney@gunet.georgetown.edu 
 
CO-PI: 
 
 
 
 
COLLABORATORS: 
 
 
Suthee Rapisuwon, MD 
3800 Reservoir Rd NW, Washington DC 20007 
Georgetown University Medical Center 
E-mail: sr905@georgetown.edu  
 
Michael B. Atkins, MD 
Lombardi Comprehensive Cancer Center, Georgetown 
University Medical Center, Washington, DC 
 
Kevin Chen, MD 
MedStar Franklin Square Medical Center, The Harry and 
Jeanette Weinberg Cancer Institute, Baltimore, MD 
 
Andrew Pecora MD 
John Theurer Cancer Center, Hackensack Meridian Health, 
Hackensack, NJ 
BIOSTATISTICIAN 
 
 
SPONSOR: 
Jaeil Ahn, PhD 
ja1030@georgetown.edu 
 
Georgetown University 
 
 
 

 
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TABLE OF CONTENTS 
SECTION TITLE 
PAGE 
1 
SYNOPSIS 
3 
2 
INTRODUCTION 
7 
3 
BACKGROUND INFORMATION 
8 
4 
STUDY OBJECTIVES AND ENDPOINTS 
16 
5 
STUDY DESIGN 
17 
6 
INCLUSION/EXCLUSION CRITERIA 
20 
7 
STUDY ASSESSMENTS AND PROCEDURES 
24 
8 
TREATMENT PROCEDURES 
33 
9 
CONCOMITANT MEDICATIONS AND THERAPIES 
59 
10 
SAFETY 
63 
11 
STATISTICAL CONSIDERATIONS 
66 
12 
DATA QUALITY ASSURANCE 
66 
13 
STUDY COMMITTEES 
67 
14 
ETHICAL ASPECTS 
67 
15 
CONDITIONS FOR MODIFYING THE PROTOCOL 
68 
16 
CONDITIONS FOR TERMINATING THE STUDY 
68 
17 
STUDY DOCUMENTATION AND RECORD-KEEPING 
68 
18 
MONITORING THE STUDY 
70 
19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
70 
20 
PUBLICATIONS OF DATA AND PROTECTION OF TRADE 
SECRETS 
70 
21 
REFERENCES 
71 
22. 
APPENDIX 
74 
 
 
 
 
 
 
 
 
 
 

 
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1.0 SYNOPSIS 
 
TITLE 
Phase II study of Nivolumab/Ipilimumab plus Cabozantinib in 
patients with unresectable advanced melanoma 
SHORT TITLE 
Nivolumab/Ipilimumab plus Cabozantinib in Advanced Melanoma 
PHASE  
II 
OBJECTIVES 
Primary objective: 
1. To determine progression free survival (PFS) for 
nivolumab/ipilimumab plus cabozantinib in patients with 
unresectable advanced melanoma  
Secondary objectives: 
1. To determine the response rate of nivolumab/ipilimumab 
plus cabozantinib in patients with unresectable advanced 
melanoma 
2. To determine the overall survival (OS) of patients with 
unresectable advanced melanoma treated with 
nivolumab/ipilimumab plus cabozantinib 
3. To determine the safety profile of nivolumab/ipilimumab 
plus cabozantinib in patients with unresectable advanced 
melanoma 
Exploratory objectives: 
1. To determine associations between baseline tumor 
mutational burden (TMB), angiogenesis pathways, and 
immunophenotyping with clinical activity of 
nivolumab/ipilimumab plus cabozantinib in patients with 
unresectable advanced melanoma 
2. To determine associations between baseline mutations in 
genes regulating anti-tumor immunity with tumor 
immunophenotype and  clinical activity of 
nivolumab/ipilimumab plus cabozantinib in patients with 
unresectable advanced melanoma 
3. To assess on treatment biopsy for evidence of increased 
immune infiltration, vascularization, and MHC expression 
to nivolumab/ipilimumab plus cabozantinib in patients with 
unresectable advanced melanoma 
STUDY DESIGN 
In this phase II advanced melanoma study, all patients will receive 
treatment with nivolumab/ipilimumab plus cabozantinib for a 12 
week induction period followed by nivolumab plus cabozantinib 
maintanence to complete up to 2 years of therapy unless disease 

 
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progression, dose limiting toxicity, provider/patient decision or 
patient withdrawal of consent occurs. The primary endpoint is the 
one year PFS rate. Patients will have staging scans at baseline and 
every 12 weeks during the first 2 years on study. Safety evaluations 
including labs, EKG and history and physical will occur at each 
visit. Baseline tumor sample is required and on treatment biopsy 
will be optional of superficial tumor in the skin, subcutaneous 
tissue or lymph node that is palpable.  
KEY ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
1. All patients must have unresectable stage IIIb-IIId or IV 
melanoma by AJCC 8th edition. (Note: Patients with uveal 
melanoma are excluded from this study.) 
2. Age > 18 and ECOG Performance Status of 0 or 1. 
3. Measurable disease by RECIST 1.1  
4. Baseline tumor specimen available. (Note: unless waiver is 
granted) 
5. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities 
related to any prior treatments, unless AE(s) are clinically 
nonsignificant and/or stable on supportive therapy. 
6. Adequate organ and marrow function. 
7. Capable of understanding and complying with the protocol 
requirements and must have signed the informed consent 
document. 
8. Sexually active fertile subjects and their partners must agree to 
use medically accepted methods of contraception (eg, barrier 
methods, including male condom, female condom, or 
diaphragm with spermicidal gel) during the course of the study 
and for 4 months after the last dose of study treatment.  
9. Female subjects of childbearing potential must not be pregnant 
at screening.  
 
Exclusion Criteria 
1. Prior treatment with anti-PD-1/PD-L1 therapy, anti-CTLA-4 
therapy or cabozantinib. Prior adjuvant anti-PD-1 and/or anti-
CTLA-4 therapy is allowed if relapse is greater than 6 months 
from last dose. 
2. Receipt of any type of small molecule kinase inhibitor 
(including investigational kinase inhibitor) within 2 weeks 
before first dose of study treatment. 
3. Receipt of any type of cytotoxic, biologic or other systemic 
anticancer therapy (including investigational) within 4 weeks 
before first dose of study treatment. 
4. Radiation therapy for bone metastasis or brain metastasis within 
2 weeks, any other radiation therapy within 4 weeks before first 
dose of study treatment. Systemic treatment with radionuclides 
within 6 weeks before the first dose of study treatment.  

 
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5. Known brain metastases that are >10mm or cranial epidural 
disease unless adequately treated with radiosurgery and/or 
surgery (including radiosurgery). Eligible subjects must be 
neurologically asymptomatic and without corticosteroid 
requirement. Dexamethasone < 2mg daily (or equivalent) will 
be allowed if discontinuation of corticosteroids is not feasible 
due to post-radiation effects and patient is asymptomatic. 
Patients with active, asymptomatic brain metastases that are 
<10mm and no corticosteroid requirement will be allowed 
without radiosurgery or surgery. 
6. History of active autoimmune disorder requiring 
immunosuppressive agents. Patients with autoimmune disorders 
considered low risk, such as vitiligo and thyroiditis, will be 
allowed.  
7. Concomitant anticoagulation with coumarin agents (eg, 
warfarin), direct thrombin inhibitors (e.g., dabigatran),  
betrixaban, or platelet inhibitors (eg, clopidogrel).  
Allowed anticoagulants are the following: 
a. Prophylactic use of Low-dose aspirin for cardio-
protection (per local applicable guidelines) and low-
dose low molecular weight heparins (LMWH) are 
permitted.  
b. Anticoagulation with therapeutic doses of LMWH or 
anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed in 
subjects without known brain metastases who are on a 
stable dose of the anticoagulant for at least 1 week 
before first dose of study treatment, and who have had 
no clinically significant hemorrhagic complications 
from the anticoagulation regimen or the tumor.  
8. The subject has prothrombin time (PT)/INR or partial 
thromboplastin time (PTT) test ≥ 1.3  the laboratory ULN 
within 7 days before the first dose of study treatment.  
9. The subject has uncontrolled, significant intercurrent or recent 
illness. 
10. Major surgery (eg, GI surgery, removal or biopsy of brain 
metastasis) within 8 weeks before first dose of study treatment. 
11. Corrected QT interval calculated by the Fridericia formula 
(QTcF) > 500 ms per electrocardiogram (ECG) within 28 days 
before first dose of study treatment. 
12. Pregnant or lactating females. 
13. Inability to swallow tablets. 
14. Previously identified allergy or hypersensitivity to components 
of the study treatment formulations. 
15. Diagnosis of another malignancy within 2 years before first 
dose of study treatment, except for superficial skin cancers, or 

 
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localized, low grade tumors deemed cured and not treated with 
systemic therapy. 
16. Subjects with a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days of study 
drug administration. Inhaled or topical steroids, and adrenal 
replacement doses > 10 mg daily prednisone equivalents are 
permitted in the absence of active autoimmune disease. 
STATISTICAL 
CONSIDERATIONS 
 
The primary endpoint for the study is 1 year landmark PFS rate. 
The historical control with nivo/ipi from the Checkmate 067 study 
is a 1 year PFS rate of ~50% [1]. The target for this study is 75% 
(improvement by 25%), which is deemed a clinically meaning 
improvement.  This will require a sample size of 23 for a one sided 
alpha of 0.05 and the power of 0.80. A simon two stage approach 
will be utilized. The study will be stopped if there 7 or few subjects 
out of 14 subjects progression free at 1 year. If the study meets 
criteria for continuation to the second stage, an additional 9 
subjects will be enrolled. In the final analysis, the null hypothesis 
will be rejected (i.e., accept the alternative hypothesis of improved 
efficacy with nivolumab/ipilimumab plus cabozantinib) if 16 
subjects or more are progression free at 1 year of the 23 total 
subjects.  Assuming a dropout rate of 15% during the time of study, 
up to 27 subjects will be enrolled. 
TOTAL  
NUMBER OF 
SUBJECTS 
27 enrolled subjects (23 subjects required for primary endpoint 
analysis) 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 18 months 
ESTIMATED 
STUDY DURATION  
Estimated 42 months (2 years beyond last patient enrolled) 

 
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2.0  
INTRODUCTION 
Combination immune checkpoint blockade with nivolumab and ipilimumab demonstrated 
objective responses in 58% of patients with advanced unresectable melanoma in the Checkmate 
067 study [1]. While responses and progression free survival (PFS) are superior with 
nivolumab/ipilimumab over monotherapy, not all patients have long-term benefit. Twenty four 
percent of patients had progressive disease as their best response and over 30% of patients 
progressed after initial disease control. At one year, the PFS rate was 49%. In addition, several 
patient subgroups had less clinical benefit as demonstrated by shorter progression free survival in 
patients with PD-L1 low tumors, high LDH levels, M1c disease, or greater than 3 disease sites. 
Other studies have also shown that patients with low interferon gamma gene expression scores or 
low baseline tumor immune infiltrate are less likely to have a response to standard anti-PD-1 
based therapy [2]. Therefore, further immunotherapy strategies are needed. 
 
Targeting vascular signaling in the tumor microenvironment, along with other oncogenic 
pathways, can enhance the anti-tumor activity of immune checkpoint therapies. A phase 1 study 
ipilimumab in combination with the anti-VEGF antibody bevacizumab in patients with advanced 
melanoma demonstrated an increased response rate and longer median overall survival compared 
to historical data [3]. On-treatment tumor biopsies revealed activated vessel endothelium with 
extensive CD8+ and macrophage cell infiltration. Similarly, clinical trials of combination 
therapy with the VEGFR inhibitor axitinib plus pembrolizumab and bevacizumab plus 
atezolizumab have demonstrated markedly increased anti-tumor activity in patients with 
advanced renal cell carcinoma [4, 5]. In addition to increased immune cell infiltration, targeting 
VEGF/R can enhance T-cell priming and dendritic cell maturation, as well as increased MHC 
class antigen presentation on tumor cells, which can lead to greater anti-tumor immune responses 
[6-8]. 
  
Cabozantinib, an inhibitor of c-MET, VEGFR2, and other receptor tyrosine kinases (RTKs) may 
be able to further augment immune responses in combination with nivolumab plus ipilimumab. 
In a phase II study of cabozantinib 55% of patients with advanced melanoma demonstrated 
tumor regression in the first 12 weeks [9]. Our team performed biomarker analyses on baseline 
tumor samples from this study [Gibney GT, unpublished data]. Patients with tumor regression 
and stable disease had greater tumor mutational burden (TMB) than those with disease 
progression. The high TMB status has been associated with greater neoantigen exposure and 
clinical activity with immunotherapies [2], suggesting cabozantinib also functions as an immune 
agent in addition to its direct anti-tumor and anti-angiogenic activities. Other studies with 
cabozantinib have also demonstrated immune modulatory effects by decreasing Treg populations 
in the tumor microenvironment and by increasing cytotoxic lymphocyte and decreasing 
immunosuppressive myeloid cell levels in the peripheral blood [10, 11]. A phase I study of 
nivolumab/ipilimumab plus cabozantinib in a range of genitourinary malignancies demonstrated 
clinical activity and an acceptable safety profile with only 11% of patients discontinuing therapy 
due to toxicity [12].    
 
We propose a single arm phase II study of nivolumab/ipilimumab plus cabozantinib in patients 
with advanced melanoma, along with correlative studies to assess biologic/immune activity and 
predictive biomarkers. 
 

 
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Hypotheses: 
1) Nivolumab/ipilimumab plus cabozantinib will demonstrate greater clinical activity 
compared to either nivolumab/ipilimumab or cabozantinib alone (historical data) in 
patients with unresectable advanced melanoma. 
2) Nivolumab/ipilimumab plus cabozantinib will demonstrate clinical activity in patients 
with low tumor PD-L1 and interferon (IFN) gamma gene expression profile (GEP) 
scores, particularly those who have high TMB. 
 
 
3.0  
BACKGROUND INFORMATION 
 
3.1 Anti-PD-1 monotherapy in advanced melanoma 
Nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) is a fully human monoclonal 
immunoglobulin (Ig) G4 antibody that binds to the PD-1 cell surface membrane receptor, a 
negative regulatory molecule expressed by activated T and B lymphocytes. Inhibition of the 
interaction between PD-1 and its ligands promote immune responses and antigen-specific T cell 
responses to both foreign and self antigens. PD-1 receptor blockade by nivolumab is an effective 
approach for immunotherapy of a variety of solid tumors. Results from a Phase 1/2 study 
(CA209-003) indicated that nivolumab was active in multiple tumor types including advanced 
melanoma, non-small cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC) [13]. 
Clinical activity was noted across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 
mg/kg). Among 106 subjects with advanced melanoma who received nivolumab and were 
evaluable for response, the preliminary objective response rates (ORR) were 6/17 (35%), 5/18 
(28%), 11/34 (32%), 7/17 (41%), and 4/20 (20%) for melanoma subjects treated at 0.1, 0.3, 1, 3, 
and 10 mg/kg, respectively [14]. Duration of response range from 3.6 to 11.2, 1.8 to 9.2, 1.9 to 
24.9, 9.2 to 22.4, and 17.0 to 25.7 months in the melanoma subjects treated at 0.1, 0.3, 1, 3, and 
10 mg/kg, respectively. Stable disease ≥24 weeks occurred in an additional 1/18 (6%), 4/34 
(12%), 1/17(6%) melanoma subjects at 0.3, 1, and 3 mg/kg, respectively. Finally, the PFS-24 
week was 41%, 33%, 48%, 55%, and 30% in melanoma subjects treated at 0.1, 0.3, 1, 3, and 10 
mg/kg, respectively. 
 
In a Phase 3 trial (CheckMate 066), nivolumab monotherapy demonstrated an improvement in 
overall survival (OS) versus dacarbazine in treatment-naïve patients with BRAF wild-type 
tumors [15]. Follow-up of patients in this study has shown 2-year OS rates of 58% with 
nivolumab and 27% with dacarbazine. Frontline nivolumab monotherapy has also been studied 
in the CheckMate 067, which included both BRAF wild-type and mutant melanoma [1]. The 
objective response rate was 44% with 3 year PFS and OS rates of 32% and 52% respectively.   
 
Pembrolizumab (MK-3475) is a selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. The variable region sequences of a mouse antihuman PD-1 antibody were 
attached into a human IgG immunoglobulin with a stabilizing S228P Fc alteration, where the 
IgG4 subtype does not engage Fc receptors or activate complement, therefore avoiding cytotoxic 
effects of the antibody when it binds to the T cells that are intended to activate.  Results from a 
Phase 1 study (KEYNOTE 001) demonstrated that pembrolizumab is active in patients with 
advanced melanoma [16].  In the overall population, the objective response rate was 33%, with 

 
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74% of responses ongoing at the time of data cut. For treatment naïve patients, the objective 
response rate was 45% and 12 month PFS rate was 54%. 
 
Similarly, the randomized KEYNOTE 006 study confirmed the efficacy of pembrolizumab in 
advanced melanoma patients, demonstrating superiority over ipilimumab [17]. In the treatment 
naïve population, the objective response rate was 47% by immune-related response criteria 
(irRC) and the 12-, 24-, and 36-month PFS rates were ~45%, 34%, and 31%, respectively. 
 
Overall, anti-PD-1 monotherapy with pembrolizumab and nivolumab have been well tolerated. 
The most common adverse events include fatigue, pruritus, rash, diarrhea, nausea, and 
arthralgias [1, 16]. Most are low grade events that do not require treatment interruption or 
discontinuation. Severe treatment related adverse events have been reported in up to 21% of 
patients treated with anti-PD-1 monotherapy [1].  The more common severe adverse events 
occurring in 1-4% of patients include fatigue, rash, diarrhea/colitis, and elevated transaminase 
levels/hepatitis. Refer to Table 3-1. Adverse events with anti-PD-1 and anti-CTLA-4 therapies 
are usually immune mediated events and specific treatment algorithms for management have 
been published [18]. 

 
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Table 3-1. Treatment related adverse events (occurring in more than 5% of patients) on 
CheckMate 067.
 
 
 
 
3.2. Ipilimumab monotherapy in advanced melanoma 
Ipilimumab is a fully humanized IgG1 monoclonal antibody (mAb) binding to the anti-cytotoxic 
T-cell lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for patients with 
metastatic melanoma (Yervoy® Prescribing Information, 2018) and has demonstrated improved 
overall survival as monotherapy and in combination with dacarbazine [19, 20].  
 

 
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In melanoma, the completed Phase 3 study MDX010-20 demonstrated a clinically meaningful 
and statistically significant survival benefit with ipilimumab in pre-treated advanced melanoma 
[19]. The study compared the OS of ipilimumab plus a melanoma-specific vaccine (gp100) to 
that of gp100 alone. A second comparison defined the OS of ipilimumab alone vs gp100 alone. 
Both comparisons demonstrated statistically significant improvements in OS (P = 0.0004 and 
0.0026, respectively). The 1-year survival for the two ipilimumab-containing groups, 
respectively, was 44% and 46% respectively, compared to 25% for the gp100 control group. The 
2-year survival was 22%, 24% and 14% respectively. The median survival was 10, 10.1, and 6.4 
months, for ipilimumab plus gp100, ipilimumab monotherapy, and gp100 monotherapy, 
respectively.  
 
Ipilimumab has been shown to produce prolonged survival in over 20% of patients based on 
long-term follow up on a composite analysis of 12 clinical studies with ipilimumab in advanced 
melanoma [21]. In this series, 1,257 patients were pretreated and 604 were previously untreated 
for metastatic disease. The dose of ipilimumab was 3 mg/kg for 965 patients and 10 mg/kg for 
706 patients. The median overall survival for the whole patient population was 11.4 months. 
Most importantly, the survival curve reached a plateau of 22% at 3 years, which extended to 10 
years, and it was independent of the dose. 
 
Both the KEYNOTE 006 and CheckMate 067 studies have demonstrated superior efficacy with 
anti-PD1 therapy (pembrolizumab and nivolumab) over ipilimumab [1, 17]. Hazard ratios for 
PFS and OS in treatment naïve patients with anti-PD-1 versus ipilimumab were reported to be 
0.54-0.55 and 0.65- 0.73, respectively (all statistically significant with P<0.05).  Based on this 
data, ipilimumab is now considered a second/third line agent or used in combination with anti-
PD-1 therapy (see Nivolumab/Ipilimumab section 3.3). 
 
Most common adverse reactions (≥5%) with ipilimumab as a single agent are fatigue, diarrhea, 
pruritus, rash, and colitis [YERVOY package insert, 2018]. These usually are immune-related 
toxicities based on the mechanism of action for anti-CTLA-4 therapy. Refer to package insert for 
further information on adverse reactions. Severe grade 3-4 adverse events (treatment related) 
have been reported in 23-28% patients receiving ipilimumab at 3mg/kg [1, 19]. See Table 3-1. 
 
3.3 Nivolumab plus Ipilimumab 
Combination therapy has emerged as an effective treatment option for advanced melanoma. The 
efficacy data further support the combination of nivolumab plus ipilimumab as first-line 
treatment option for patients with advanced melanoma, regardless of BRAF mutation status, 
based on the results of the CheckMate 069 and 067 studies [1, 22]. The combination of these 
immune checkpoint inhibitors was approved for the treatment of unresectable or metastatic 
melanoma in the USA in January 2016 and in the European Union in May 2016. 
 
In a Phase 2 trial of treatment-naïve patients with BRAF wild-type melanoma (CheckMate 069), 
142 patients with previously untreated advanced melanoma were randomized in a 2:1 ratio to 
either receive both ipilimumab (3mg/kg) and nivolumab (1mg/kg) every 3 weeks followed by 
nivolumab (3mg/kg), or ipilimumab (3mg/kg) and placebo every 3 weeks followed by placebo 
every 2 weeks [22]. The combination of nivolumab and ipilimumab demonstrated a statistically 
significant improvement in ORR and longer PFS compared with ipilimumab alone with an ORR 

 
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of 61% (44/72) in patients treated with the combination versus 11% (4/37) in ipilimumab 
monotherapy. Complete responses were reported in 22% (16/72) in the combination group, and 
no patients in the ipilimumab monotherapy group. With a minimum follow-up period of 11 
months, median PFS and median duration of response were not reached in the combination 
group, compared with mPFS of 4.4 months with ipilimumab monotherapy.  
 
In CheckMate 067 study, 945 patients with previously untreated advanced or metastatic 
melanoma were randomized in a 1:1:1 ratio to receive nivolumab monotherapy, nivolumab 
(1mg/kg) and ipilimumab (3mg/kg) combination therapy, or ipilimumab monotherapy [1]. The 
study was primarily powered to demonstrate efficacy differences between nivolumab versus 
ipilimumab and nivolumab/ipilimumab versus ipilimumab. The observed ORRs were 43.7% in 
nivolumab monotherapy, 57.6% in the combination group, and 19% in ipilimumab monotherapy. 
Nivolumab/ipilimumab as well as nivolumab monotherapy demonstrated superior PFS and OS 
compared to ipilimumab monotherapy. The 12 month PFS rate was 42% and 49% in the 
nivolumab monotherapy and nivolumab/ipilimumab combination groups, respectively. Longer 
follow up showed the 3 year PFS rates were 32% and 39%, respectively. Similarly, the overall 
survival at 3 years was numerically higher with nivolumab/ipilimumab versus nivolumab alone 
(58% versus 52%).  
 
While response rates are greater with nivolumab/ipilimumab combination therapy, the serious 
adverse event rates are also greater compared to monotherapies. In the CheckMate 067 study, 
59% of patients experienced a grade 3-4 treatment related adverse event with 
nivolumab/ipilimumab (see Table 3-1) [1]. The more concerning grade 3-4 events included 
diarrhea/colitis and increased transaminase levels/hepatitis, seen in up to 9% of patients each. To 
address this issue, alternative dosing for anti-PD-1/anti-CTLA-4 combination therapy in 
advanced melanoma has been investigated. The randomized, double blinded phase 3b/4 
CheckMate 511 study compared the standard nivolumab 1mg/kg plus ipilimumab 3mg/kg 
(nivo1/ipi3) dose levels to the inverse nivolumab 3mg/kg plus ipilimumab 1mg/kg (nivo3/ipi1) 
dose levels in patients with advanced melanoma [23]. Patients in both arms then continued on 
with maintenance nivolumab 480mg every 4 weeks if tolerating with disease control.  The 
primary endpoint of safety showed a significant reduction in treatment related grade 3-4 adverse 
events with nivo3/ipi1 versus nivo1/ipi3 (34% versus 48%, P=0.0059). Efficacy was similar in 
both group but still early in follow up. The 12 month PFS rate was 46-47% between the two 
groups. A separate study (KEYNOTE 029) supports the use of lower dose ipilimumab in 
combination with anti-PD-1 therapy [24]. In this study of 110 patients with advanced melanoma 
treated with pembrolizumab 2mg/kg plus ipilimumab 1mg/kg, the treatment related grade 3-4 
adverse event rate was 45% (immune-related grade 3-4 was 27%).  
 
3.4 Cabozantinib 
Cabozantinib (also known at XL184) is an oral tyrosine kinase inhibitor that targets VEGFR2, c-
MET, AXL, and other RTKs with half maximal inhibitory concentration (IC50) in the low 
nanomolar range [25]. Clinical activity with cabozantinib has been demonstrated in a range of 
tumor types, including advanced hepatocellular carcinoma, renal cell carcinoma and medullary 
thyroid cancer where the drug is now FDA approved [26-30]. The predicted terminal half life of 
cabozantinib at the approved dose of 60mg daily in RCC patients was 99hrs [Investigator’s 

 
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Brochure version 14]. Of note, different pharmacokinetics was observed in medullary thyroid 
cancer patients. Cabozantinib is also highly protein bound in human plasma (≥ 99.7%).   
 
Cabozantinib has previously been studied in melanoma patients as cohort in a larger phase 2 
randomized discontinuation trial (RDT) [9]. A total of 77 patients with advanced melanoma 
(62% cutaneous melanoma) were treated with cabozantinib at 100mg daily for a 12 week lead in 
period. Patients with stable disease after 12 weeks were randomized to either continue on 
cabozantinib or discontinue and evaluate for progression free survival (those patients with partial 
or complete responses would stay on drug). At week 12, the ORR was 5%; however 55% of 
patients with evaluable disease demonstrated some tumor regression (refer to Figure 3-1). Of the 
26 patients with stable disease and randomized to stay on treatment or discontinue, the median 
PFS was 4.1 months versus 2.8 months (HR 0.59, P=0.284). The median overall survival of the 
entire cohort was 9.4 months.  
 
 
Figure 3-1. Best change in tumor response (RECIST) at week 12 from baseline on the Phase 2 
RDT of cabozantinib in patients with advanced melanoma. N=64 for evaluable patients. 
 
The most common adverse events (> 25%) reported for cabozantinib are diarrhea, fatigue, 
nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, 
vomiting, weight decreased, and constipation (Cabozantinib package insert, 2018). At the 
continuous 60mg daily dosing of cabozantinib in patients with advanced RCC, the treatment 
emergent grade 3-4 adverse event rate was 68% [27]. Dose reductions occurred in 60% of 
patients and drug discontinuation due to adverse event occurred in 9% of patients. In the phase 2 
RDT of cabozantinib (100mg daily) in patients with advanced melanoma, safety data was 
reported on the 12 week lead in period [9].  During this window, dose reduction occurred in 29% 
of patients and drug discontinuation due to adverse event occurred in 8% of patients. The most 
common treatment emergent grade 3-4 events were fatigue (14%), hypertension (10%), and 
abdominal pain (8%) (see Table 3-2).   
 
 
 

 
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Table 3-2. Most frequently reported adverse events during the lead in stage regardless of 
causality on the phase II RDT of cabozantinib in patients with advanced melanoma. 
 
 
 
3.5 Nivolumab/Ipilimumab plus Cabozanitinib 
The triple combination of nivolumab/ipilimumab plus cabozantinib has been evaluated in a 
metastatic urothelial cancer and other genitourinary malignancies (non-clear cell RCC) [12]. In 
this phase 1 study, nivolumab/ipilimumab plus cabozantinib was studied in part 2, after 
nivolumab plus cabozantinib was cleared. Primary endpoint was to define maximum tolerated 
dose and the recommended phase 2 dose. Three dose levels of the triple combination were 
planned: cohort 5 – cabozantinib 40mg PO daily + nivo1/ipi1, cohort 6 - cabozantinib 40mg PO 
daily + nivo3/ipi1, and cohort 7 – cabozantinib 60mg PO daily + nivo3/ipi1. Data was presented 
on 18 subjects with a median follow up of 12.8 months. All grade adverse events were seen in 
16/18 subjects (89%) and grade 3-4 adverse events were seen in 13/18 subjects (72%) (this was 
similar to the adverse event data for nivolumab/cabozantinib). Treatment related adverse events 
leading to drug discontinuation occurred in 2/18 (11.1%) during the maintenance phase with 

 
Version 2.2, December 13, 2021 
15 
nivolumab plus cabozantinib (colitis and hepatitis). Dose holds for nivolumab and cabozantinib 
occurred in 7/18 (39%) and 12/18 (67%) of subjects, respectively. Cabozantinib was dose 
reduced in 6/18 (33%) of subjects. Treatment related grade 3-4 adverse events occurring in 2 or 
more patients included fatigue, hypertension, lymphopenia, hypophosphatemia, hyponatremia, 
elevated ALT level, and elevated lipase level. Only 1 case each of grade 3-4 immune colitis and 
hepatitis were reported.  Refer to tables 3-3 and 3-4 for adverse event summaries for the triple 
combinations. Of the 18 subjects treated with nivolumab/ipilimumab plus cabozantinib, 4 (22%) 
demonstrated an objective response, which included patients with advanced/metastatic penile 
cancer (n=1), sarcomatoid RCC (n=1), and urothelial carcinoma of the bladder (n=2). The 
recommended phase 2 dose was cabozantinib 40mg PO daily plus nivolumab 3mg/kg and 
ipilimumab 1mg/kg.  
 
Table  3-3. Select clinical treatment related adverse events: any grade ≥ 20% of patients and any 
irAE from the phase 1 study of Cabozantinib plus Nivolumab/Ipilimumab. 
 
  
 
 
 
 
 
 
 
 
 

 
Version 2.2, December 13, 2021 
16 
 
Table 3-4. Laboratory abnormalities: any grade ≥ 20% of patients and any irAE from the phase 1 
study of Cabozantinib plus Nivolumab/Ipilimumab. 
 
 
 
4.0 STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
To determine PFS for nivolumab/ipilimumab 
plus cabozantinib in patients with 
unresectable advanced melanoma 
To determine the 1 year PFS rate for 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma using imRECIST 
Secondary Objectives 
Secondary Endpoints 
To determine the response rate of 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma 
To determine the ORR by imRECIST of 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma 
To determine the OS of patients with 
unresectable advanced melanoma treated with 
nivolumab/ipilimumab plus cabozantinib  
To determine the median and 3 year OS rate 
of patients with unresectable advanced 
melanoma treated with nivolumab/ipilimumab 
plus cabozantinib  
To determine the safety profile of 
nivolumab/ipilimumab plus cabozantinib in 
To determine the rate of all grade and grade 
3-5 adverse events (treatment emergent and 
treatment related) 

 
Version 2.2, December 13, 2021 
17 
patients with unresectable advanced 
melanoma 
To determine the tolerability of 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma 
To determine the rate of discontinuation of 
study drug(s) due to adverse events 
Exploratory Objectives 
 
To determine associations between baseline 
tumor mutational burden (TMB), 
angiogenesis pathways, and 
immunophenotyping with clinical activity of 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma 
To analyze molecular profiles based on whole 
exome sequencing (WES), PD-L1 
immunohistochemistry and RNAseq from 
baseline tumors and correlate to ORR, PFS, 
and OS in patients with unresectable 
advanced melanoma treated with 
nivolumab/ipilimumab plus cabozantinib 
To determine associations between baseline 
mutations in genes regulating anti-tumor 
immunity with tumor immunophenotype and  
clinical activity of nivolumab/ipilimumab 
plus cabozantinib in patients with 
unresectable advanced melanoma 
To determine if loss of critical immune genes 
(such as IFN receptor and MHC) are 
associated with a low IFN gamma gene 
expression profile and impact on baseline 
tumors and correlate to ORR, PFS, and OS in 
patients with unresectable advanced 
melanoma treated with nivolumab/ipilimumab 
plus cabozantinib 
To assess on treatment biopsy for evidence of 
increased immune infiltration, 
vascularization, and MHC expression to 
nivolumab/ipilimumab plus cabozantinib in 
patients with unresectable advanced 
melanoma 
To determine change in immune cell 
populations, CD31 vascularization, and MHC 
class I expression by multiplex 
immunofluorescense (IF) between baseline 
and on treatment tumor specimens  
 
 
5.0 STUDY DESIGN 
 
5.1 Overall Schema 
Subjects with unresectable advanced melanoma meeting eligibility criteria (refer to Section 6.0) 
will be screened for participation on the protocol. The screening phase will include obtaining 
baseline imaging studies, labs, history & physical, EKG, and collection of a fresh tumor biopsy 
or archived tumor specimen (refer to Table 7-1). Once meeting eligibility criteria and enrolled on 
study, subjects will begin treatment with nivolumab/ipilimumab and cabozantinib starting on day 
1 of cycle 1.The treatment schedule and follow up is outlined further in the schema Figure 5-1 
and Table 7-1. Patients who attain confirmed response or stable disease and are able to tolerate 
study drugs will continue treatment for up to 2 years. Discontinuation after 1 year but prior to 2 
years will be permitted at the discretion of the treating investigator in patients with disease 
control achieving either a complete or partial response. 
 
 
 

 
Version 2.2, December 13, 2021 
18 
 
 
 
 
 
 
 
Figure 5-1. Treatment Schema 
 
5.2 Study Drug Dosing 
 
Induction phase: 
 
Nivolumab 3mg/kg IV plus Ipilimumab 1mg/kg IV every 3 weeks x 4 cycles (12 week period) 
 
Cabozantinib 40mg PO daily for 12 weeks 
 
When nivolumab and ipilimumab are to be administered on the same day during the induction 
phase, nivolumab is to be administered first over 30 minutes. Nivolumab infusion must be 
promptly followed by a saline flush to clear the line of nivolumab before starting the ipilimumab 
infusion. The second infusion will be the ipilimumab over 30 minutes and will start after the 
infusion line has been flushed, filters changed, and participant has been observed to ensure no 
infusion reaction has occurred. The time in between infusions is expected to be approximately 30 
minutes but may be more or less depending on the situation. Infusion window of -5 minutes/+ 10 
minutes for each study drug.  
 
Cabozantinib is an oral tablet taken by the patient daily. Participant is to self administer at the 
same time every day +/- 1 hour window. Participant is not to eat for at least 2 hours before and at 
least 1 hour after taking the medication. 
 
A window of ± 3 days may be applied to all study visits. 

 
Version 2.2, December 13, 2021 
19 
 
Maintenance phase: 
 
Nivolumab 480mg IV every 4 weeks for up to 92 weeks 
 
Cabozantinib 40mg PO daily for up to 92 weeks 
 
Maintenance therapy will continue for up to 92 weeks to complete 2 years total of treatment if 
tolerating therapy well and disease is controlled.  
 
Nivolumab is administered over a 30 minute infusion without any premedication unless there is a 
prior history of infusion reaction.  Nivolumab infusion must be promptly followed by a saline 
flush to clear the line of nivolumab. Participant is to be observed following infusion to ensure no 
infusion reaction has occurred.  
 
Cabozantinib is an oral tablet taken by the patient daily. Participant is to self administer at the 
same time every day +/- 1 hour window. Participant is not to eat for at least 2 hours before and at 
least 1 hour after taking the medication. 
 
A window of ± 3 days may be applied to all study visits. 
 
5.3 Biospecimen collection 
 
Baseline tumor collection 
Prior cycle 1 of study, all patients must have either an archived tumor specimen available or a 
fresh biopsy for confirmation of disease and correlative studies. Fresh tumor biopsies may be 
core needle, punch, or incisional/excisional biopsy. Patients without a safe site of biopsy (as 
assessed by treating provider) or archived specimen will be exempt from this requirement and 
may obtain a waiver from the principal investigator after discussion. Refer to lab manual for 
specific details on handling, processing and storage. 
  
On treatment tumor collection 
Fresh tumor collection at week 13 (refer to Table 7-1) will be optional in patients with a palpable 
superficial tumor in the skin, subcutaneous tissue or lymph node. This can be a core needle 
biopsy, punch biopsy, or incisional/excisional biopsy. Patients without a safe site of biopsy (as 
assessed by treating provider) will not be considered eligible for the optional biopsy. Refer to 
lab manual for specific details on handling, processing and storage. 
 
At progression tumor collection 
Fresh tumor collection at time of progression (refer to Table 7-1) will be optional. This can be a 
core needle biopsy, punch biopsy, or incisional/excisional biopsy. Refer to lab manual for 
specific details on handling, processing and storage. 
 
Peripheral blood biospecimen collection 
Blood samples for study of serum, peripheral blood mononuclear cells (PBMCs), and other 
components will be collected. Samples will be processed using standard protocols and stored at -

 
Version 2.2, December 13, 2021 
20 
80 degrees Celsius for future analyses.  Refer to lab manual for specific details on handling, 
processing and storage. 
 
Stool biospecimen collection 
Baseline stool samples will be collected from patients at the start of treatment. Patients will be 
given a stool kit (Omnigene®-Gut tube, and collection materials including a toilet hat and tool 
for stool transfer). Patients will need to provide the sample on day 1 of the first cycle (+/- 7 day 
window). Refer to lab manual for specific details on handling, processing and storage. 
 
 
5.4 Study Treatment Discontinuation 
Subjects may discontinue study treatment or withdraw their consent to participate in the study at 
any time without prejudice. The investigator may withdraw a subject from study treatment or 
from the study if, in his or her clinical judgment, it is in the best interest of the subject or if the 
subject cannot comply with the protocol.  
 
In addition, any of the following conditions require discontinuation of the subject from study 
treatment: 
• An AE or intercurrent illness that in the opinion of the investigator warrants the subject’s 
withdrawal from study treatment; 
• The investigator believes it is not in the best interest of the subject to continue on study 
• Specific conditions described in the Management of Adverse Events Sections 8.2.4.1; 
• Necessity for treatment with other anticancer treatment prohibited by protocol; 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, male condom, female condom) during the course of the study and for 
4 months after discontinuation of study treatment; 
• Women who become pregnant or are breastfeeding; 
• If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 
weeks, the subject will have study treatment discontinued unless there is unequivocal 
evidence that the subject is benefitting. In this situation, a subject may be able to restart 
therapy with a dose reduction upon resolution of the toxicity and with agreement of the 
principal investigator / Sponsor; 
• Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol; 
• Significant noncompliance with the protocol schedule in the opinion of the investigator; 
• Subjects who cannot tolerate the minimum protocol-specified dose of study treatment 
will have study treatment discontinued; 
• Progressive disease (PD) or the subject no longer experiences clinical benefit as 
determined by the investigator 
 
 
6.0 INCLUSION/EXCLUSION CRITERIA 
To be eligible for the study the subject must meet all of the inclusion and none of the exclusion 
criteria: 

 
Version 2.2, December 13, 2021 
21 
 
Inclusion Criteria 
1. All patients must have unresectable stage IIIb-IIId or IV melanoma by AJCC 8th edition. 
Note: Patients with uveal melanoma are excluded from this study. 
2. Age > 18 and ECOG Performance Status of 0 or 1. 
3. Measurable disease by imRECIST. 
4. Baseline tumor specimen available – either archived tumor specimen collection within the 
past year and no intervening treatment or fresh tumor collection (A waiver may be 
considered for the baseline biopsy requirement after discussion with study principal 
investigator). 
5. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, 
unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. 
6. Adequate organ and marrow function, based upon meeting all of the following laboratory 
criteria within 14 days before first dose of study treatment: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-
stimulating factor support. 
b. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L). 
c. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion. 
d. Hemoglobin ≥ 9 g/dL (≥ 90 g/L). 
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline 
phosphatase (ALP) ≤ 3  upper limit of normal (ULN). ALP ≤ 5  ULN with 
documented bone metastases. 
f. Total bilirubin ≤ 1.5  ULN (for subjects with Gilbert’s disease ≤ 3  ULN). 
g. Serum albumin ≥ 2.8 g/dl. 
h. Serum creatinine ≤ 2.0  ULN or calculated creatinine clearance ≥ 30 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault equation: 
Males: (140 – age) x weight (kg)/(serum creatinine [mg/dL] × 72) 
Females: [(140 – age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 
i. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol). 
7. Capable of understanding and complying with the protocol requirements and must have 
signed the informed consent document.  
8. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (eg, barrier methods, including male condom, female condom, or 
diaphragm with spermicidal gel) during the course of the study and for 4 months after the last 
dose of study treatment.  
9. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming pregnant 
(ie, females who have had any evidence of menses in the past 12 months, with the exception 
of those who had prior hysterectomy). However, women who have been amenorrheic for 
12 or more months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or 
other reasons.  

 
Version 2.2, December 13, 2021 
22 
 
Exclusion Criteria 
1. Prior treatment with anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy or cabozantinib. Prior 
adjuvant anti-PD-1 and/or anti-CTLA-4 therapy is allowed if relapse is greater than 6 months 
from last dose. 
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks before first dose of study treatment. 
3. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including 
investigational) within 4 weeks before first dose of study treatment. 
4. Radiation therapy for bone metastasis or brain metastasis within 2 weeks, any other radiation 
therapy within 4 weeks before first dose of study treatment. Systemic treatment with 
radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically 
relevant ongoing complications from prior radiation therapy are not eligible. 
5. Known brain metastases that are >10mm or cranial epidural disease unless adequately treated 
with radiosurgery and/or surgery. Patients with treated brain metastases need to be 
asymptomatic (no neurologic symptoms or stable neurologic deficit) and off corticosteroids 
prior to start of treatment. If discontinuation of corticosteroids is not feasible due to post-
radiation effects, asymptomatic patients on a stable dose of dexamethasone < 2mg daily (or 
equivalent) for > 1 week prior to start of treatment will be permitted. Patients with active, 
asymptomatic brain metastases that are <10mm and no corticosteroid requirement will be 
permitted without radiosurgery or surgery based on nivo/ipi brain metastasis response data 
from Checkmate 204 [31]. Patients with active untreated brain metastases who are enrolled 
will require more frequent brain monitoring while on protocol. Refer to study schedule Table 
7-1. 
6. History of active autoimmune disorder requiring immunosuppressive agents. Patients with 
autoimmune disorders considered low risk, such as vitiligo and thyroiditis, will be allowed.  
7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors 
(e.g. dabigatran), betrixaban, or platelet inhibitors (eg, clopidogrel).  
Allowed anticoagulants are the following: 
a. Prophylactic use of Low-dose aspirin for cardio-protection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH) are permitted.  
b. Anticoagulation with therapeutic doses of LMWH or anticoagulation with direct 
factor Xa inhibitors rivaroxaban, edoxaban, or apixaban is allowed in 
subjects without known brain metastases who are on a stable dose of anticoagulant 
for at least 1week before first dose of study treatment, and who have had no clinically 
significant hemorrhagic complications from the anticoagulation regimen or the 
tumor.  
8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3  
the laboratory ULN within 7 days before the first dose of study treatment.  
9. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions:  
a. Cardiovascular disorders: 
i. Congestive heart failure New York Heart Association Class 3 or 4, unstable 
angina pectoris, serious cardiac arrhythmias.  

 
Version 2.2, December 13, 2021 
23 
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) 
> 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment. 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction 
(MI), or other ischemic event, or thromboembolic event (eg, deep venous 
thrombosis, pulmonary embolism) within 6 months before first dose.  
b. Gastrointestinal (GI) disorders including those associated with a high risk of 
perforation or fistula formation:  
i. The subject has evidence of tumor invading the GI tract, active peptic ulcer 
disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, 
acute obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction. 
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed 
before first dose. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 
ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) 
within 12 weeks before first dose. 
d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease 
manifestation. 
e. Lesions invading or encasing any major blood vessels. 
f. Other clinically significant disorders that would preclude safe study participation. 
i. Serious non-healing wound/ulcer/bone fracture.  
ii. Uncompensated/symptomatic hypothyroidism. 
iii. Moderate to severe hepatic impairment (Child-Pugh B or C). 
10. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before 
first dose of study treatment. Complete wound healing from major surgery must have 
occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth 
extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible. 
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 28 days before first dose of study treatment [32]. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs 
at intervals of approximately 3 min must be performed within 30 min after the initial ECG, 
and the average of these three consecutive results for QTcF will be used to determine 
eligibility.  
12. Pregnant or lactating females. 
13. Inability to swallow tablets. 
14. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations. 
15. Diagnosis of another malignancy within 2 years before first dose of study treatment, except 
for superficial skin cancers, or localized, low grade tumors deemed cured and not treated 
with systemic therapy. 

 
Version 2.2, December 13, 2021 
24 
16. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 
 
 
7.0 STUDY ASSESSMENTS AND PROCEDURES 
 
7.1 Pre-Treatment Period 
During the Pre-Treatment Period, subjects are consented and qualified (screened) for the study. 
Informed consent must be obtained before initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for this study. Evaluations performed 
as part of routine care before informed consent can be considered as screening evaluations if 
done within the defined screening period, and if permitted by the site’s institutional review board 
(IRB)/ethics committee (EC) policies.  
 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening and on Study Day 1 before study treatment administration. The following 
assessments will be conducted before subjects receiving their first dose of study drugs on this 
protocol: 
• History and Physical Exam 
• Concurrent medication review 
• Baseline laboratory assessment 
• Baseline EKG 
• Staging CT scan chest/abdomen/pelvis (+/- neck) and MRI brain 
 
For each subject, the Pre-Treatment Period ends upon receipt of the first dose of study treatment 
or final determination that the subject is ineligible for the study. 
 
7.2 Treatment Period  
During the Treatment Period subjects will receive nivolumab, ipilimumab and cabozantinib until 
either disease progression, the occurrence of unacceptable drug-related toxicity or for other 
reason(s) for subject withdrawal as described in Section 5.2. Treatment will continue for up to 2 
years unless there is disease progression, drug intolerance or other reason for discontinuation 
discussed with the principal investigator (PI). Patients with ongoing complete or partial response 
may discontinue therapy after 1 year on treatment at the discretion of the treating investigator. 
Subjects should be instructed to immediately inform the PI/sub-I of any AEs. Subjects 
experiencing seizures, dizziness, sleepiness, or other symptoms that could influence alertness or 
coordination should be advised not to drive or operate other heavy machinery. 
 
The following schedule of assessments applies to all subjects ( 
 
 

 
Version 2.2, December 13, 2021 
25 
Table 7-1). More frequent assessments should be obtained if clinically indicated. 
 
 
 

 
Version 2.2, December 13, 2021 
26 
Table 7-1: Study Assessments 
 
 
 
 
 
 
Schedule 
 
 
Nivo-Ipi-Cabo combination treatment 
Nivo-Cabo 
treatment 
Off 
treatment 
but not 
progressed9 
At progression 
Cycle Week 
Baseline 
Screening 
1 
1 
4 
4 
7 
7 
10 
10 
13 
Q4weeks 
(weeks 
17-105) 
Q12 weeks 
(+/- 4 
weeks) 
30 day follow up 
visit 
Day of cycle 
(+/- 3 days) 
-14 to 0 
1 
8 
1 
8 
1 
8 
1 
8 
1 
1 
1 
1 
Nivolumab 
dosing 
q3weeks 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Ipilimumab 
dosing 
q3weeks 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Cabozantinib 
dosing 
continuous 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Medication 
compliance 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Prior and 
concomitant 
medications 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Baseline tissue 
collection1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline stool 
collection 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Labs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
test3 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
12 Lead EKG 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Tumor 
imaging 
assessments4 
X4 
 
 
 
 
 
 
 
 
X 
X6 
X6 
 
Adverse event 
assessment 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Tumor biopsy5 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Research 
blood 
collection8 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
1. Baseline tumor collection can be archived specimen if no intervening systemic therapy or 
fresh biopsy (core needle biopsy, punch biopsy or incisional/excisional biopsy).  
2. Labs for Day 1 of each Cycle Week include CBCa, comprehensive metabolic panela, free 
T3, free T4, TSH, INR/PT, PTT, urinalysis, spot UPCR and Creatine Kinase (CK) with 
Troponin I if CK is abnormal. Labs for Day 8 of each Cycle Week include only liver 

 
Version 2.2, December 13, 2021 
27 
function tests (ALT, AST, alkaline phosphatase, GGT, total protein, albumin, and total 
bilirubin).  
3. Only required for premenopausal female subjects. Urine or blood HCG. 
4. CT scan of the chest, abdomen and pelvis. Tumor Imaging Assessments are to be 
performed within 4 weeks of Cycle 1 Day 1 for the Baseline Screening Assessment. 
Patients with primary or metastatic disease involving the head or neck areas will require 
CT scan of the neck as well. MRI brain will be performed at baseline and per discretion 
of the treating investigator during the treatment period. In patients with a history of a 
prior brain metastasis, MRI brain will be performed at each reassessment. In patients with 
active, untreated brain metastases, MRI of the brain should be performed every 6 weeks 
through week 25 on protocol. Brain imaging with CT scan with IV contrast can be 
performed in place of MRI brain if there is a contraindication for MRI. 
5. Optional core needle biopsy or punch biopsy of superficial tumor in the skin, 
subcutaneous tissue or lymph node that is palpable on treatment and at progression.  
6. Scans every 12 weeks. Scans should occur prior to the visit. A window of -7 to +3 days is 
acceptable. 
7. Patients will need to provide the sample on day 1 of the first cycle (+/- 7 day window). 
8. Research blood collection should occur based on the calendar whenever possible and are 
not required to be redrawn due to treatment delays or interruptions. 
9. Follow up off treatment will continue for 2 years after treatment is discontinued. Beyond 
this time point, progression free survival and overall survival would be assessed every 6 
months via chart review or phone contact. 
 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; PT/INR, prothrombin 
time/International Normalized Ratio; PTT, partial prothrombin time; UPCR, urine 
protein/creatinine ratio 
a Laboratory tests should include a standard hematology panel (CBC, differential, platelets) and 
chemistry panel (albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, bilirubin, 
blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, lipase, 
magnesium, phosphorus, potassium, sodium, total protein) 
 
If the subject is unable to have a study assessment taken within the defined time window due to 
an event outside of his or her control (eg, clinic closure, personal emergency, inclement weather, 
vacation), the assessment should be performed as close as possible to the required schedule.  
Regular tumor assessments should be performed in accordance to the guidelines in [Section 7.4] 
to determine if PD is present.  
 
The Treatment Period ends when a subject receives his or her last dose of study treatment; the 
subject then enters the Post-Treatment Period. 
 
7.3 Post-Treatment Period 
Subjects will return to the study site approximately 30 days after their last dose of study drug to 
complete end-of-study assessments if they progressed on study while still on active treatment. If 
the subject is already off treatment at the time of disease progression, by either scan or exam, 
then the end of study assessments may occur anytime within 30 days of documented disease 
progression. Laboratory and physical examinations will be performed. Remaining study 

 
Version 2.2, December 13, 2021 
28 
treatment will be returned by the subject, and treatment compliance will be documented. 
Additional follow-up will occur for subjects with AEs related to study treatment that are ongoing 
at the time of this visit, and for subjects with SAEs related to study treatment that occur after the 
time of this visit. Patients who complete treatment will be followed as in schedule Table 7-1. 
Patients who are beyond 2 years from last treatment on study will be monitored for progression 
free survival and overall survival every 6 months via chart view or phone contact for total of 5 
years from starting the study treatment. Management including but not limited to laboratory 
assessment, history/physical examination, imaging studies will be at the discretion of the treating 
provider. 
 
Patients who come off treatment for progression should be followed for overall survival for up to 
5 years from the start of study treatment. Follow up contact for survival should be performed 
every 6 months by chart review or phone call, unless the patient has withdrawn consent from the 
trial.  
 

 
Version 2.2, December 13, 2021 
29 
7.4 Laboratory Assessments 
Laboratory panels are composed of the following:  
Hematology 
• WBC count with 
differential 
(including at 
minimum: 
neutrophils, 
basophils, 
eosinophils, 
lymphocytes, 
monocytes) 
• hematocrit 
• platelet count 
• RBC count 
• hemoglobin 
 
 
Serum chemistry 
• albumin 
• ALP 
• amylase 
• ALT 
• AST 
• bicarbonate 
• BUN 
• chloride 
• creatinine 
• GGT 
• Glucose 
• calcium 
• lactate 
dehydrogenase  
• lipase 
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin 
• total protein 
 
Urinalysis 
• appearance 
• color 
• pH 
• specific gravity 
• ketones 
• protein 
• UPCR 
• glucose 
• bilirubin 
• nitrite 
• creatinine 
• urobilinogen 
 
• occult blood 
(microscopic 
examination of 
sediment will be 
performed only if 
the results of the 
urinalysis dipstick 
evaluation are 
positive or not 
available) 
Other 
• TSH, Free T4 
• Pregnancy test 
(urine or serum) for 
women of child-
bearing potential 
• Creatine Kinase 
(CK), if CK is 
abnormal then 
Troponin-I must be 
drawn 
 
• PT/INR or PTT 
• 24 hour urine 
collection for 
protein if elevated 
UPCR >1mg/mg 
(>113.1mg/mmol; 
refer to Table 8-7)  
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate ; GGT, -glutamyltransferase; 

 
Version 2.2, December 13, 2021 
30 
INR, International Normalized Ratio; PT, prothrombin time; PTT partial thromboplastin time; 
RBC, red blood cell; TSH, thyroid stimulating hormone; UPCR, urine protein/creatinine ratio; 
WBC, white blood cell. 
 
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, dose 
delayed [withheld] or reduced, requirement for additional medication, treatment or monitoring) 
are considered clinically significant for the purposes of this study, and will be recorded on the 
Adverse Events Case Report Form (CRF). If laboratory values constitute part of an event that 
meets criteria defining it as serious, the event (and associated laboratory values) must be reported 
as an SAE. 
 
7.5 
Treatment Response Assessment 
Only those subjects who have measurable disease present at baseline, have received at least one 
dose nivolumab, ipilimumab and cabozantinib, and had one on-treatment scan or progressed 
clinically will be considered evaluable for response. These subjects will have their response 
classified according to the definitions stated below. Those subjects that are not evaluable for 
response will be replaced. Immune-Modified Response Evaluation Criteria in Solid Tumors 
(imRECIST) will be used for the primary response assessment and for progression free survival 
determination [33]. Best overall response rate will be reported. Start of treatment will define the 
start date for calculations of PFS and OS. 
 
7.5.1 Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
(NOTE: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the site investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol). 
 
7.5.2 Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
7.5.3 Non-measurable lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. Non-measurable also includes lesions that are < 20 mm 
by chest x-ray. NOTE: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases 
can be considered as measurable lesions, if they meet the definition of measurability described 

 
Version 2.2, December 13, 2021 
31 
above. However, if non-cystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
 
7.5.4 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. Evaluation of target lesions as per Table 7-2. 
 
7.5.5 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. Non-target lesion 
progression does not define progression of disease. It can only contribute to defining complete 
response (complete disappearance required). 
 
7.5.6 New Lesions 
In contrast to RECIST v1.1, new lesions that develop during treatment are not automatically 
captured as progressive disease in the overall response assessment with imRECIST. New 
measurable lesions are incorporated into the total tumor burden using the criteria in sections 
7.5.1 and 7.5.2. Non-measurable new lesions preclude complete response, but are not added to 
the sum of diameters calculations for response evaluation. 
 
7.5.7 Evaluation of Target Lesions 
Table 7-2 summarizes the response evaluation by serial imaging using imRECIST.  In patients 
with progressive disease, particularly on the first scan, it is recommended to confirm disease 
progression with a subsequent scan at least 4 weeks later. If the subsequent scan shows no 
progressive disease (lack of confirmation), patient would not be captured as having a progressive 
event and may continue on therapy per protocol. In patients with unequivocal disease 
progression as determined by the treating investigator, a confirmatory scan will not be required. 
In this situation, patient would discontinue therapy on study and be captured as a progressive 
event. 
 
 
 
 
 

 
Version 2.2, December 13, 2021 
32 
 
 
 
Table 7-2. Response evaluation by imRECIST: 
 
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. To be assigned a status of complete response, changes in 
tumor measurements must be confirmed by a repeat assessment 
performed no less than six weeks after the criteria for response is 
met. This can be performed at the next scheduled scans per protocol. 
Patients must also have complete disappearance or normalization of 
lymph nodes/other non-target tumor sites (e.g. resolution of a malignant 
pleural effusion), and no new non-measurable lesions. 
Partial 
Response 
(PR) 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters, as well as the addition 
of new measurable lesions. To be assigned a status of partial 
response, changes in tumor measurements must be confirmed by a 
repeat assessment performed no less than six weeks after the 
criteria for response is met. This can be performed at the next 
scheduled scans per protocol. Patients must also not have unequivocal 
progression in non-target lesions and new lesions. 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the baseline tumor assessment. New measurable 
lesions will be added to the total sum of diameters calculation 
(numerator). This will be used for assessment of best overall response. In 
patients with tumor burden decrease followed by tumor burden increase, 
the nadir sum of diameters will be used for assessment of progression 
(i.e. the new denominator). If this occurs, an increase of 20% from nadir 
will used for determination of progression. The sum must also 
demonstrate an absolute increase of at least 5 mm. Subjects with 
equivocal disease progression (e.g. a new lesion in the setting of 
major disease regression and the absence of or improvement in 
disease related symptoms) should have a scan confirming disease 
progression a t  l e a s t  4 weeks following the initial scan showing 
imRECIST defined PD. Subjects may continue on protocol therapy 
until repeat scan confirms PD. If repeat scan does not confirm PD, 
subjects should proceed with treatment and evaluation as directed by 
the protocol. 

 
Version 2.2, December 13, 2021 
33 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. NOTE: a change of 20% or more that does not 
increase the sum of the diameters by 5 mm or more is coded as stable 
disease). To be assigned a status of stable disease, response must be 
confirmed on a subsequent scan. 
 
 
The  best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence or non-protocol therapy (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria. Table 7-3 summarizes potential outcomes. 
 
Table 7-3. Summary of potential response outcomes by imRECIST 
 
Target Lesions and New 
Measurable Lesions 
Non-Target Lesions 
New Lesions 
(Non-measurable) 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
Yes or No 
PR 
PR 
Non-PD 
Yes or No 
PR 
SD 
Non-PD 
Yes or No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD (unequivocal) 
Yes or No 
PD 
 
 
7.6  
Correlative studies  
 
7.6.1 Biomarkers 
A variety of factors impact the immunomodulatory properties and efficacy of immune 
checkpoint therapy, including nivolumab and ipilimumab, in patients with advanced melanoma. 
Baseline variables and changes that occur during treatment can be used to predict anti-tumor 
immune responses and to correlate with mechanisms of action of agents with immune 
modulatory properties, such as the RTK inhibitor cabozantinib. These include tumor specific 
factors such as tumor mutational burden, PD-L1 expression, MHC antigen presentation, 
interferon gamma related gene expression profiles [2, 34]. Host factors such as baseline 
peripheral lymphocyte counts, inhibitor immune cell levels (such as Tregs), HLA variants and 
dynamic changes during treatment have also been associated with responses to immune 
checkpoint therapy responses. Recent data on the gut microbiome indicates this may play a large 

 
Version 2.2, December 13, 2021 
34 
role in anti-tumor immunity as well [35].  In addition, anti-VEGF/R and anti-c-MET therapies 
have the ability to enhance T-cell priming and dendritic cell maturation, increase MHC antigen 
presentation on tumor cells, reduce immune suppressive Treg and myeloid cell populations, and 
activate vessel endothelium that can lead to augmented CD8+ T-cell and macrophage cell 
infiltration [4-8, 10, 11].  
 
Assessment of baseline and on treatment molecular and cellular variables will serve the purpose 
of establishing predictive biomarkers for nivolumab/ipilimumab plus cabozantinib in patients 
with advanced melanoma. Exploratory analyses and comparisons to efficacy endpoints – ORR, 
PFS, and OS will be performed. In particular, this data will allow identification of sub-
populations where clinical benefit is most often observed. We hope to show that patients 
typically predicted to have a low probability of response (e.g. PD-L1 IHC <1%, interferon 
gamma GEP low) will have substantial clinical benefit with the immunotherapy strategy 
investigated in this protocol. This will lead to future studies of nivolumab/ipilimumab plus 
cabozantinib in biomarker selected advanced melanoma patients.  
 
Collection time points of biospecimens on protocol is outlined in Table 7-1. Refer to lab manual 
for specific details on handling, processing, and storage of biospecimen samples. Future assays 
planned for tumor specimen biomarker analyses include targeted exome sequencing (or whole 
exome sequencing), RNA gene expression, PD-L1 immunohistochemistry, and multiplex 
immunofluorescence for assessment of immune cell populations and immune markers. 
Peripheral blood will be analyzed by flow cytometry to characterize dynamic changes in immune 
cell populations, along with assessment of cytokines and other variables. Stool microbiome will 
be analyzed by 16s rRNA sequencing or equivalent approach. Additional biomarker analyses 
may be considered based on emerging data. 
 
Samples remaining after initial protocol specific testing is completed will be banked for future 
unspecified cancer related research. Permission from subjects will be obtained during the 
consenting process. Samples that are collected will be identified by a subject’s sequence ID 
number assigned at the time of registration to the trial. Any material issued to collaborating 
researchers will be anonymized and only identified by the subject’s study number. 
 
 
8 
TREATMENT PROCEDURES 
 
8.1 
Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the appropriate prescribing 
information for that country (if applicable) or the pharmacy manual and inventoried in 
accordance with applicable state and federal regulations. 
 
8.2  
Investigational Treatment: Cabozantinib 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, 
hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate 
and Opadry® yellow. The 20-mg tablets are round. Doses of 40 mg will comprise two 20-mg 
tablets. The components of the tablets are listed in Table 8-1.  

 
Version 2.2, December 13, 2021 
35 
 
Table 8-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/wa 
Cabozantinib Drug Substance (25% drug load as free base) 
Active 
Ingredient 
31.68 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose Anhydrous (60M) 
Filler 
19.42 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.00 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
6.00 
Colloidal Silicon Dioxide 
Glidant 
0.30 
Magnesium Stearate 
Lubricant 
0.75 
Opadry® yellow film coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron 
oxide yellow 
Film 
Coating 
4.00 
a weight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose 
Refer to the Pharmacy Manual for details on storage and handling of cabozantinib. 
 
8.2.1 Cabozantinib Administration 
Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily.  
Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to eat for at 
least 2 hours before and at least 1 hour after taking cabozantinib.  Subjects should be instructed 
to take their cabozantinib dose at approximately the same time every day.  If a subject 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.   
 
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 subjects taking cabozantinib. 
 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 8.3 below. 
 
8.2.2 Cabozantinib Dose Modifications, Interruptions, and Discontinuation 
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 cabozantinib is 40 mg/day. 1 dose reduction level of 
cabozantinib is permitted (see Table 8-2). If cabozantinib is not tolerated at the first dose 
reduction level, it will then be discontinued. 
• Dose modification criteria for cabozantinib are shown in Table 8-3 and 8-10. Dose 
interruptions and/or reductions should be implemented for unacceptable toxicity. Doses may 
be modified at any time while a subject is on treatment. 

 
Version 2.2, December 13, 2021 
36 
• Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined in Table 8-3, if the investigator feels it is in the interest of a subject’s safety and will 
optimize drug tolerability. 
• Interruption of cabozantinib treatment for cabozantinib-related AEs may occur at any time 
per investigator discretion. If treatment is interrupted due to related AEs for more than 
6 weeks, cabozantinib should be discontinued unless there is unequivocal evidence that the 
subject is benefitting. In this situation, a subject may be able to restart therapy with a dose 
reduction upon resolution of the toxicity per the discretion of the investigator. 
• Dose interruptions for reason(s) other than related AEs (eg, surgical procedures) can be 
longer than 6 weeks per the discretion of the investigator. 
Guidelines for the management of specific AEs are provided in Section 8.2.4.  
 
Table 8-2: 
Dose Reductions of Cabozantinib 
Assigned Dose 
First Dose Level Reduction 
Second Dose Level 
Reduction 
40-mg cabozantinib oral qd 
20-mg cabozantinib oral qd 
No dose reduction permitted 
qd, once daily 
Cabozantinib will be discontinued if a qd dose of 20-mg cabozantinib (minimum dose) is not 
tolerated 
 

 
Version 2.2, December 13, 2021 
37 
Table 8-3: 
Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.4.0 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib 
treatment at the current dose level if AE is manageable and 
tolerable. 
Grade 2 AEs which are 
tolerable and are easily 
managed 
 
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed  
Continue cabozantinib treatment at the current dose level with 
supportive care. 
 
At the discretion of the investigator, cabozantinib should be dose 
reduced or interrupted. 
Note: It is recommended that dose holds be as brief as possible.  
Grade 3 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction and optimal medical care.  
Note: It is recommended that dose holds be as brief as possible. 
Grade 4 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Subjects should have cabozantinib interrupted immediately.  
Discontinue cabozantinib unless the following criteria are met:  
• Subject is deriving clear clinical benefit as determined by 
the investigator 
• Toxicity can be managed with a dose reduction following 
recovery to Grade 1 (or baseline) and optimal medical care  
AE, adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided in 
Section 8.2.4 . For re-treatment criteria of study treatment after a dose hold see Section 8.2.3. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to 
cabozantinib treatment or had an unclear relationship to cabozantinib treatment. 
 
8.2.3 Cabozantinib Dose Reinstitution and Reescalation 
If the subject recovers from his or her toxicities to CTCAE v.4.0 Grade  1 or to the baseline 
value (or lower) and the toxicity was unrelated to study treatment, then study treatment may be 
restarted with no change in dose.  
 
If the subject recovers from his or her toxicities to Grade  1 or to the baseline value (or lower) 
the toxicity was deemed possibly related to study treatment, then study treatment may be 
restarted at a reduced dose (see Table 8-2 for the schedule of dose reductions).  
Subjects receiving a daily dose of 20 mg may be restarted at the same dose if deemed safe at the 
discretion of the investigator. Subjects unable to tolerate a daily dose of 20 mg should 
discontinue study treatment. 
 
Re-escalation to the previous dose, (but not higher than 40 mg/day) may be allowed at the 
discretion of the investigator for AEs which have resolved or recovered to Grade 1 (or baseline 
value) and deemed tolerable and easily managed by optimized supportive treatment. Dose 
re-escalation is not allowed for a drug-related dose reduction triggered by Grade 4 hematologic 
toxicities or by Grade 4 AEs affecting major organs (eg, central nervous system, cardiac, hepatic, 
renal). 
 

 
Version 2.2, December 13, 2021 
38 
8.2.4 Guidelines for Management of Potential Adverse Events associated with 
Cabozantinib 
Subjects will be monitored for AEs from the time of signing informed consent through their last 
follow-up visit (30 days after the date of the last dose of cabozantinib treatment.) Subjects 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 v.4.0.  
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption for cabozantinib.  
 
8.2.4.1 Cabozantinib Adverse Events 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, weight 
decreased, PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and 
dyspnea. For a full description of the safety profile of cabozantinib, refer to the Cabozantinib 
Investigator’s Brochure. 
 
Other medically important but less frequent AEs including arterial thrombotic AEs (eg, transient 
ischemic attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs (eg, deep 
vein thrombosis [DVT] and pulmonary embolism), 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 subjects treated 
with 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 
cabozantinib, as cabozantinib 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. Adverse events 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 (Section 8.2.2). 
 
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. 
 

 
Version 2.2, December 13, 2021 
39 
8.2.4.1.1 Gastrointestinal Disorders 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After starting 
treatment with 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 (Turnage and Badgwell 2016) are present. Discontinue 
cabozantinib and initiate appropriate management in subjects who have been diagnosed with GI 
perforation or fistula. 
 
Diarrhea: Subjects 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. Guidelines for the 
evaluation and management of diarrhea are shown in Table 8-4. Patients and treating providers 
need to be aware that diarrhea may occur as a non-immune mediated event with cabozantinib or 
as an immune mediated event with nivolumab/ipilimumab. Directions outlined here refer to non-
immune mediated diarrhea. Administration of antidiarrheal/antimotility agents is recommended 
at the first sign of diarrhea as initial management. Some subjects may require concomitant 
treatment with more than one antidiarrheal agent. When therapy with antidiarrheal agents does 
not control the diarrhea to tolerable levels, cabozantinib should be temporarily interrupted or 
dose reduced. When the diarrhea is controlled, retreatment with cabozantinib may be acceptable 
per investigator decision. In addition, general supportive measures should be implemented such 
as continuous oral isotonic hydration, correction of fluid and electrolyte abnormalities, small 
frequent meals, and stopping lactose-containing products, high-fat meals, and alcohol. 
 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever diarrhea 
has occurred during treatment with cabozantinib. Infections of the perianal region should be 
treated per local guidelines. 

 
Version 2.2, December 13, 2021 
40 
Table 8-4:  
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• Continue with study treatment and consider dose reduction 
• Initiate treatment with an antidiarrheal agent (eg, loperamide 4 
mg followed by 2 mg after each episode of diarrhea [maximum: 
16 mg loperamide per day]) 
• Dietary modifications (eg, small lactose-free meals, bananas 
and rice) 
• Intake of isotonic fluids (1-1.5 L/day) 
• Re-assess after 24 hours: 
o Diarrhea resolving to baseline bowel habits: gradually 
add solid foods and discontinue or decrease antidiarrheal 
treatment after 12 h diarrhea-free interval 
o Diarrhea not resolving: Continue/resume antidiarrheal 
treatment  
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• Interrupt study treatment 
• Ask subject to attend clinic 
• Rule out infection (eg, stool sample for culture) 
o Administer antibiotics as needed (eg, if fever or Grade 
3-4 neutropenia persists > 24 h) 
• Administer fluids (1-1.5 L/day orally or IV, as appropriate) for 
hydration or to correct electrolyte abnormalities 
• For Grade 3-4 or complicated lower grade diarrhea consider 
hospitalization and IV hydration 
• Re-assess after 24 h 
o Diarrhea resolving to baseline bowel habits or Grade 
≤ 1: consider restarting study treatment at reduced dose 
o Diarrhea not resolving: Start and or continue 
antidiarrheal treatment (eg, loperamide 4 mg followed 
by 2 mg after each episode of diarrhea [maximum: 16 
mg loperamide per day]). Consider starting second line 
antidiarrheal or referral to gastroenterologist 
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment 
or prophylaxis of nausea and vomiting, along with supportive care. Dehydration and electrolyte 
abnormalities may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. Antiemetic medications should be assessed for 
potential drug interactions (refer to Section 9.3 for further details). 
 
8.2.4.1.2 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 
subjects undergoing treatment with VEGF pathway inhibitors. 
Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with a non-GI fistula. 

 
Version 2.2, December 13, 2021 
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8.2.4.1.3 Hemorrhage 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be monitored for bleeding events with serial complete blood 
counts and physical examination while on study.  
 
Risk factors for hemorrhagic events may include (but may not be limited to) the following: 
• Tumor of the lung with cavitary lesions or tumor lesions which invade or encase major 
blood vessels. NSCLC with squamous cell differentiation is known for significant lung 
cavitations and centrally located tumors that may invade major blood vessels. Thus, the 
anatomic location and characteristics of tumor as well as the medical history should be 
carefully reviewed in the selection of subjects for treatment with cabozantinib. 
• Recent or concurrent radiation to the thoracic cavity.  
• Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease and 
ulcerative colitis. 
• Underlying medical conditions which affect normal hemostasis (eg, deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia). 
• Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis. 
• History of clinically significant hemoptysis, hematemesis, or hematuria. 
 
The risk of hemorrhage in cabozantinib-treated subjects with brain metastases has not been 
thoroughly analyzed. Though the incidence of CNS hemorrhage events in a study of subjects 
with glioblastoma was higher than observed in general population of subjects with cancer treated 
with cabozantinib, it is not clear how the risk of hemorrhage in glioblastoma translates to a risk 
of hemorrhage for subjects with brain metastases. Currently, brain metastases of carcinomas are 
not contraindications to the use of cabozantinib, but subjects with brain metastases should be 
monitored with a high index of suspicion if symptoms that could be due to a CNS hemorrhage 
occur.  
 
Complete healing from radiation-induced side effects should have occurred before initiating 
cabozantinib treatment, and cabozantinib should be discontinued in subjects with serious and 
life-threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood). 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 2.5 mL of red blood). 
 
8.2.4.1.4 Thromboembolic events  
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in 
clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary 
embolism and/or DVT should have study treatment interrupted until therapeutic anticoagulation 
is established. Treatment with cabozantinib may be resumed in subjects with pulmonary 
embolism or DVT if it is determined that the event is uncomplicated and that the subject is 
deriving clinical benefit from 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. Therapeutic doses of Low molecular weight 

 
Version 2.2, December 13, 2021 
42 
heparins (LMWH) or the direct factor Xa oral inhibitors rivaroxaban, edoxaban, or apixaban are 
allowed for management of thrombotic events. Other oral anticoagulants including coumarin 
agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor 
betrixaban, platelet inhibitors (e.g., clopidogrel), and chronic use of aspirin above low dose 
levels for cardioprotection per local applicable guidelines are not allowed, until 4 weeks after 
cabozantinib has been permanently discontinued.. 
 
Arterial thrombotic events (eg, TIA, MI) have been observed in studies with cabozantinib. 
Further treatment with cabozantinib should be discontinued in subjects who develop an acute MI, 
cerebral infarction, or any other clinically significant arterial thromboembolic complication. 
 
8.2.4.1.5 Hypertension 
Table 8-5 provides treatment guidelines for hypertension deemed related to cabozantinib. Blood 
pressure should be monitored in a constant position visit to visit, either sitting or supine in a 
relaxed setting. Decisions to reduce or interrupt the dose of study treatment 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.  
 
Cabozantinib should be discontinued in subjects with hypertensive emergency. 

 
Version 2.2, December 13, 2021 
43 
Table 8-5: 
Management of Hypertension Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic)a and < 160 
mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 
mm Hg 
 
• 
Optimize antihypertensive medications by adding 
new or additional antihypertensive medications 
and/or increase dose of existing medications. 
• 
Reduce cabozantinib treatment by one dose level 
if optimal antihypertensive therapy (usually to 
include 3 agents) does not result in BP <150 mm 
Hg systolic or <100 mm Hg diastolic 
• If subject is symptomatic interrupt cabozantinib 
treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or 
interrupt cabozantinib treatment per investigator 
discretion 
• 
Add new or additional anti-hypertensive 
medications and/or increase dose of existing 
medications and monitor subject closely for 
hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not 
result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic, cabozantinib treatment 
should be dose reduced further or interrupted 
• 
Cabozantinib treatment should be dose interrupted 
if upper limits of systolic BP (≥ 160 mm Hg) are 
sustained and not adequately manageable or if 
systolic BP is > 180 mm Hg or diastolic BP > 110 
mm Hg, or if subject is symptomatic 
• Re-start cabozantinib treatment at the most 
tolerable dose and re-escalate only if BP falls to 
and is sustained at < 150 mm Hg systolic and 
< 100 mm Hg diastolic 
Hypertensive emergencyc 
• 
Discontinue cabozantinib treatment 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower 
threshold than systolic BP >150 or diastolic BP >100 based on their clinical judgment and 
assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols. 
c Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of 
progressive or impending end-organ damage (eg, myocardial infarction/ischemia, intracranial 
hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, kidney damage). 
 
8.2.4.1.6 Stomatitis and Mucositis 
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before study treatment is initiated. Appropriate correction of 
local factors should be instituted as indicated, such as modification of ill-fitting dentures and 

 
Version 2.2, December 13, 2021 
44 
appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and 
standard local treatments such as non-traumatic and non-irritating cleansing, and oral rinses 
(eg, with a weak solution of salt and baking soda) should be maintained. Lips should be kept 
moisturized with lip balm. The use of lipstick, lip-gloss, and Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as clinically indicated.  
 
8.2.4.1.7 Skin and Subcutaneous Tissue Disorders 
Wound healing and surgery: Cabozantinib has the potential to cause wound healing 
complications and wound dehiscence which may even occur long after a wound has been 
considered healed. Therefore, surgical and traumatic wounds must not only be completely healed 
prior to starting cabozantinib treatment but must also be monitored for wound dehiscence, wound 
infection and other signs of impaired wound healing while the subject is being treated with 
cabozantinib. If dehiscence occurs, cabozantinib treatment should not be restarted until complete 
healing has taken place.  
 
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery. The 
decision to resume treatment with cabozantinib after surgery should be based on clinical 
judgment of adequate wound healing. 
 
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot syndrome), skin 
rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported with cabozantinib. All subjects on study should be 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. 
 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment recommendations in response to PPES are summarized in Table 8-6. 

 
Version 2.2, December 13, 2021 
45 
Table 8-6: 
Management of Hand-Foot Syndrome (PPES) Associated with Cabozantinib 
CTCAE v.4.0 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if 
PPES is clinically insignificant and tolerable. Otherwise, 
cabozantinib should be reduced to the next lower dose level.a Start 
urea 20% cream twice daily AND clobetasol 0.05% cream once 
daily. Reassess at least weekly; if PPES worsens at any time or does 
not improve after 2 weeks, proceed to the intervention guidelines 
for Grade 2. 
Grade 2  
Cabozantinib treatment may be continued if PPES is tolerated. 
Cabozantinib should be dose reduced or interrupted if PPES is 
intolerable. Continue urea 20% cream twice daily AND high 
potency steroid cream (eg, clobetasol 0.05%) once daily and add 
analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPES worsens or 
affects self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 
or 0. Continue treatment of skin reaction with high potency steroid 
cream (eg, clobetasol 0.05%) twice daily AND analgesics. Resume 
study drug at a reduced dose if PPES recovers to Grade ≤ 1. 
Discontinue subject from study treatment if PPES does not improve 
within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-
inflammatory drug; PPES, palmar plantar erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
 
8.2.4.1.8 Osteonecrosis 
Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors 
include use of bisphosphonates and denosumab, chemotherapy and anti-angiogenic drugs, use of 
corticosteroids, local radiotherapy, and dental or orofacial surgery procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, 
tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain 
or slow healing of the mouth or jaw after dental surgery may also be manifestations of 
osteonecrosis. 
 
Advise subjects regarding oral hygiene practice and to quickly report symptoms to investigator. 
Caution should be used in subjects receiving bisphosphonates. 
 
Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be interrupted for at least 4 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a 
protracted time. 
 
8.2.4.1.9 Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring 
UPCR. Table 8-7 provides treatment guidelines for proteinuria deemed related to cabozantinib.  

 
Version 2.2, December 13, 2021 
46 
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria 
> 3.5 grams per day in combination with low blood protein levels, high cholesterol levels, high 
triglyceride levels, and edema).  
 
Table 8-7: 
Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
 
 
• 
Consider confirming with a 24-h protein assessment within 7 
days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 
mg/mg or urine protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 
mg/mg on repeat UPCR testing or urine protein > 2 g/24 h on 
24-h urine collection. Continue cabozantinib on a reduced dose 
if UPCR decreases to < 2 mg/mg. Consider interrupting 
cabozantinib treatment if UPCR remains > 2 mg/mg despite a 
dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose 
interruption. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 
mg/mg on 2 consecutive readings, UPCR monitoring can 
revert to protocol-specific times. (Second reading is 
confirmatory and can be done within 1 week of first reading.) 
If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is 
determined to be stable (< 20% change) for 1 month, check 
urine protein/creatinine per protocol or as clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR within 
7 days and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt 
cabozantinib treatment and check UPCR every 7 days. If 
UPCR decreases to < 2 mg/mg, restart cabozantinib treatment 
at a reduced dose and monitoring of urine protein/creatinine 
should continue weekly until the UPCR decreases to < 1 
mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg for 
1 month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine per protocol or as 
clinically indicated. 
Nephrotic syndrome 
• 
Discontinue cabozantinib treatment 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 
 
8.2.4.1.10 Nervous System Disorders 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on 
nonclinical Good Laboratory Practice (GLP)-compliant toxicology studies. Dysphonia, 
dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory impairment, 

 
Version 2.2, December 13, 2021 
47 
hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed 
in clinical studies with cabozantinib. The development of any new or progressive, unexplained 
neurological symptoms should be assessed for underlying causes.  
 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, 
headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment 
should be discontinued in subjects with RPLS. 
 
As neuritis, encephalitis, meningitis and other neurologic disorders have been observed with 
nivolumab and ipilimumab, management beyond cabozantinib drug hold may be necessary. 
 
8.2.4.1.11 Hepatocellular Toxicity 
Elevation of aminotransferases (ALT and AST): Evaluation of subjects with elevated 
transaminases or bilirubin should be individualized and guided by the presence of specific risk 
factors such as liver conditions (eg, liver cirrhosis, metastases to the liver, thrombosis of portal or 
hepatic vein, hepatocellular carcinoma, hepatitis), concomitant hepatotoxic medication, alcohol 
consumption, and cancer related causes.  
 
As immune hepatitis has been observed with nivolumab and ipilimumab, management beyond 
cabozantinib drug hold may be necessary. If ALT or AST elevations are grade 2 or greater, 
immune checkpoint therapy may need to be held/discontinued and patient initiated on 
corticosteroids. Refer to specific guidance in section 8.5 for management of liver toxicity 
suspected to be potentially from cabozantinib and immune checkpoint therapy. 
 
8.2.4.1.12 Infections and Infestations 
Infections are commonly observed in cancer subjects. Predisposing risk factor include a 
decreased immune status (eg, after myelosuppressive anticancer therapies, splenectomy), 
destructive growth of the underlying malignancy including bone marrow infiltration with 
suppression of normal hematopoiesis, as well as the presence of IV devices.  
 
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until adequate healing has taken place. 
 
8.2.4.1.13 Blood and Lymphatic System Disorders 
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Subjects with hematologic toxicities may require additional 
or more frequent laboratory tests according to institutional guidelines. 
Dose reductions or dose interruptions for hematological toxicities are not mandated but can be 
applied as clinically indicated. Supportive care for thrombocytopenia or anemia, such as 
transfusions, may be managed according to institutional guidelines. The use of colony-
stimulating growth factors should be considered, but need to be used with caution in the presence 
of concurrent immune checkpoint therapy. Febrile neutropenia or evidence of infection 
associated with neutropenia must be assessed immediately and treated appropriately and in a 
timely manner according to institutional guidelines. 
 

 
Version 2.2, December 13, 2021 
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8.2.4.1.14 Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression 
and/or anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be 
ruled out and treated according to standard of care. Pharmacological management should be 
considered after disease specific morbidities have been excluded when not prohibited.  
 
8.2.4.1.15 Weight Loss 
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy should be considered for appetite enhancement when 
not prohibited by a particular protocol. 
 
8.2.4.1.16 Corrected QT Prolongation 
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a 
placebo-controlled study in subjects with MTC. A mean increase in QTcF of 10-15 ms was 
observed after 4 weeks after initiating cabozantinib treatment. A concentration-QTc relationship 
could not be definitively established. Changes in cardiac wave form morphology or new rhythms 
were not observed. No cabozantinib-treated subjects in this study had a QTcF > 500 ms. Review 
of the larger safety database (~5000 subjects exposed to cabozantinib in clinical trials and in 
post-marketing experience) confirmed the absence of safety concerns associated with QT 
prolongation. There were no events of torsades de pointes reported. 
 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.  
 
If at any time on study there is an increase in QTcF to an absolute value > 500 ms, two additional 
ECGs must be performed with intervals not less than 3 min apart within 30 min after the initial 
ECG. 
 
If the average QTcF from the three ECGs is > 500 ms, the following actions must be taken: 
• Interrupt cabozantinib treatment 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• Consider cardiology consultation for asymptomatic subjects 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 ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert. 
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Cabozantinib treatment may be restarted 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 ms is not confirmed  

 
Version 2.2, December 13, 2021 
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• Cabozantinib treatment has been interrupted through a minimum of 1 week following the 
return of the QTcF to ≤ 500 ms. 
• QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
Cabozantinib treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced dose 
 
8.2.4.1.17 Electrolyte Disorders 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with cabozantinib, and serum electrolyte 
levels should be monitored frequently while receiving cabozantinib. Clinically relevant 
electrolyte disorders should be managed according to the dose modification guidelines as 
outlined in Section 8.2.2 or as clinically indicated. Standard clinical practice guidelines should be 
used for management of electrolyte disorders and may include oral or intravenous replacement.  
 
8.2.4.1.18 
Endocrine Disorders 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed with 
cabozantinib treatment. Currently available data are insufficient to determine the mechanism of 
thyroid function test alterations and its clinical relevance. Management of thyroid dysfunction 
(eg, symptomatic hypothyroidism) should follow accepted clinical practice guidelines. 
 
8.2.4.1.19 
Angioedema 
Angioedema should be managed according to standard practice. The subject should be observed 
until symptoms resolve, with particular attention to maintaining an open airway.  
 
 
8.3 
Nivolumab  
Opdivo, BMS-936558, MDX1106, anti-PD-1 
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical 
heavy chains and 2 identical light chains. Molecular Wt 146,221 daltons (143,619.17 daltons, 
protein portion).  
 
8.3.1 Supplier/How Supplied 
Standard of care nivolumab will be utilized and provided by local pharmacy. The cost of 
nivolumab will not be covered by the protocol. The site investigators and pharmacies will be 
responsible for maintenance of appropriate records and ensure appropriate supply, storage, 
handling, distribution, and usage of the product in accordance with the protocol and any 
applicable laws and regulations. 
 
8.3.2 Preparation  
Refer to current nivolumab package insert. Nivolumab Injection: 40 mg/4 mL, 100 mg/10 mL, 
and 240 mg/24 mL solution in a single-dose vial.  

 
Version 2.2, December 13, 2021 
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Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the 
vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a 
few translucent-to-white, proteinaceous particles. Do not shake the vial. 
 
During induction phase, nivolumab dosing is 3mg/kg IV every 3 weeks x 4 cycles (concurrent 
with ipilimumab and cabozantinib). During the maintenance phase, nivolumab dosing is 480mg 
IV every 4 weeks (concurrent with cabozantinib).  
• Withdraw the required volume of nivolumab and transfer into an intravenous container.  
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 
10 mg/mL. The total volume of infusion must not exceed 160 mL.  
• For adult and pediatric patients with body weights less than 40 kg, the total volume of 
infusion must not exceed 4 mL/kg of body weight.  
• Mix diluted solution by gentle inversion. Do not shake.  
• Discard partially used vials or empty vials of nivolumab.  
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micro 
pore size, low-protein binding in-line filter at the protocol-specified doses and infusion times. It 
is not to be administered as an IV push or bolus injection.  
 
8.3.3 Storage and Stability 
The product does not contain a preservative.  
After preparation, store the nivolumab infusion either:  
• at room temperature for no more than 8 hours from the time of preparation. This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion or  
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of infusion preparation.  
Do not freeze. 
 
8.3.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
8.3.5 Administration 
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-
pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).  
• 
Do not coadminister other drugs through the same intravenous line.  
• 
Flush the intravenous line at end of infusion.  
• 
When administered in combination with ipilimumab, infuse nivolumab first followed 
by ipilimumab on the same day. Use separate infusion bags and filters for each 
infusion. 
 

 
Version 2.2, December 13, 2021 
51 
8.3.6 Adverse Events and Management 
Please see the package insert for a complete list of possible adverse events and guidance on 
adverse event management. Refer to Table 8-8 and ASCO/NCCN guidelines [18]. Also refer to 
section 8.5 for management guidance on potential overlapping adverse events from nivolumab, 
ipilimumab and cabozantinib.   
 
Most common adverse reactions (≥20%) in patients were:  
• Nivolumab as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, 
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, 
upper respiratory tract infection, pyrexia, headache, and abdominal pain.  
• Nivolumab in combination with ipilimumab are fatigue, rash, diarrhea, nausea, pyrexia, 
musculoskeletal pain, pruritus, abdominal pain, vomiting, cough, arthralgia, decreased 
appetite, dyspnea.  
 
No dose reductions are permitted. Interrupt or slow the rate of infusion in patients with mild or 
moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion 
reactions. 
 
Grade 2 and above immune related adverse events (irAEs) may/will require drug 
hold/discontinuation and administration of high dose corticosteroids (1-2mg/kg/day of 
prednisone or equivalent) tapered off over a 4-6 week period. Patient are to be completely off 
prednisone unless used for adrenal replacement purposes prior to resuming any immunotherapy, 
unless discussed with the Principal Investigator, Dr. Gibney. Additional immune modulatory 
agents may be required for treatment of irAEs that are refractory to corticosteroids, such as 
infliximab for immune colitis and mycophenylate for immune hepatitis. Refer to guidance below 
in Table 8-8 and ASCO/NCCN guidelines. After recovery from irAE during the 
nivolumab/ipilimumab induction phase, patients will be permitted to receive maintenance 
nivolumab if the irAE was most likely due to ipilimumab (e.g. immune colitis or hepatitis) and 
patient is receiving clinical benefit with the therapy.  
 
During the Induction Period (Nivo-Ipi-Cabo treatment), the subject should stay on schedule and 
follow procedures as outlined. Drug dosing may be omitted based on toxicity guidance per 
protocol. If Nivolumab is restarted in the induction phase, the dose will remain at 3mg/kg for the 
duration of the induction phase. 
 
During the induction phase, if an Adverse Event requires all drug to be held, and the toxicity has 
recovered to Grade 1 or baseline prior to the next scheduled treatment visit and the patient is 
eligible for Nivolumab and/or Ipilimumab, please consult study chair for approval to restart prior 
to the next scheduled treatment visit. If a subject is eligible to restart Nivolumab and Ipilimumab 
after a delay, then all subsequent visits/procedures may be shifted, including the scans, in order 
to complete all 4 induction cycles. The scans may be done earlier, at the investigator’s discretion.  
  
During the Maintenance phase (Nivo+Cabo treatment), starting at cycle week 13, 
treatment/assessment cycle date may be shifted to account for recovery from immunotherapy 
related toxicity. The one exception is that scans should remain every 12 weeks according to 
calendar days. 

 
Version 2.2, December 13, 2021 
52 
 
Table 8-8 Adverse event management for nivolumab [Package Insert, 2018].
 
 

 
Version 2.2, December 13, 2021 
53 
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events. Version 4.0 (NCI CTCAE v4).  
a Resume treatment when adverse reaction improves to Grade 0 or 1.  
b HCC: hepatocellular carcinoma.  
c Resume treatment when AST/ALT returns to baseline. 
 
8.4 
Ipilimumab 
YERVOY, BMS-734016, MDX-010, anti-CTLA-4 
Ipilimumab is a recombinant, human monoclonal antibody that binds to the CTLA-4. Ipilimumab 
is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. 
Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. 
 
8.4.1 Supplier/How Supplied 
Standard of care ipilimumab will be utilized and provided by local pharmacy. The cost of 
nivolumab will not be covered by the protocol. The site investigators and pharmacies will be 
responsible for maintenance of appropriate records and ensure appropriate supply, storage, 
handling, distribution, and usage of the product in accordance with the protocol and any 
applicable laws and regulations. 
 
 
8.4.2 Preparation 
Refer to current ipilimumab package insert. Ipilimumab Injection: 50 mg/10 mL (5 mg/mL) and 
200 mg/40 mL (5 mg/mL) in a single-use vial. 
 
Do not shake product. 
 
• Inspect parenteral drug products visually for particulate matter and discoloration prior 
to administration. Discard vial if solution is cloudy, there is pronounced discoloration 
(solution may have pale-yellow color), or there is foreign particulate matter other than 
translucent-to-white, amorphous particles. 
 
Preparation of Solution 
• Allow the vials to stand at room temperature for approximately 5 minutes prior to 
preparation of infusion. 
• Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. 
Mix diluted solution by gentle inversion. 
• Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). 
• Discard partially used vials or empty vials of ipilimumab. 
 
8.4.3 Storage and Stability 
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials 
from light 
 
 

 
Version 2.2, December 13, 2021 
54 
8.4.5 Handling and Disposal 
Ipilimumab injection is available as follows: 
Carton Contents 
NDC 
 
One 50 mg vial (5 mg/mL), single-use vial  
 
NDC 0003-2327-11 
One 200 mg vial (5 mg/mL), single-use vial 
NDC 0003-2328-22 
 
Store ipilimumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect ipilimumab from light 
by storing in the original carton until time of use. Do not freeze or shake. 
 
8.4.6 Administration 
Administration Instructions 
• Do not mix ipilimumab with, or administer as an infusion with, other medicinal 
products. 
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP after each dose. 
• Administer diluted solution over 30 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low-protein-binding in-line filter. 
 
When administered in combination with nivolumab, infuse nivolumab first followed by 
Ipilimumab on the same day. Use separate infusion bags and filters for each infusion. 
 
8.4.6 Adverse Events 
Please see the package insert for a complete list of possible adverse events and guidance on 
adverse event management. Refer to Table 8-9 and ASCO/NCCN guidelines [18]. Also refer to 
section 8.5 for management guidance on potential overlapping adverse events from nivolumab, 
ipilimumab and cabozantinib.   
 
Most common adverse reactions (≥5%) with ipilimumab as a single agent are fatigue, diarrhea, 
pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (≥5%) 
include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia.  
 
Most common adverse reactions (≥20%) with ipilimumab in combination with nivolumab are 
fatigue, rash, diarrhea, nausea, pyrexia, musculoskeletal pain, pruritus, abdominal pain, 
vomiting, cough, arthralgia, decreased appetite, dyspnea. 
 
No dose reductions are permitted. Interrupt or slow the rate of infusion in patients with mild or 
moderate infusion reactions. Discontinue in patients with severe or life-threatening infusion 
reactions. 
 
Grade 2 and above immune related adverse events (irAEs) may/will require drug 
hold/discontinuation and administration of high dose corticosteroids (0.5-2mg/kg/day of 
prednisone or equivalent) tapered off over a 4-6 week period. Patient are to be completely off 
prednisone unless used for adrenal replacement purposes prior to resuming any immunotherapy, 
unless discussed with the Study Chair. Additional immune modulatory agents may be required 

 
Version 2.2, December 13, 2021 
55 
for treatment of irAEs that are refractory to corticosteroids, such as infliximab for immune colitis 
and mycophenylate for immune hepatitis. Refer to guidance below in Table 8-9 and 
ASCO/NCCN guidelines. 
 
During the Induction Period (Nivo-Ipi-Cabo treatment), the subject should stay on schedule and 
follow procedures as outlined. Drug dosing may be omitted based on toxicity guidance per 
protocol. If Nivolumab is restarted in the induction phase, the dose will remain at 3mg/kg for the 
duration of the induction phase. 
 
During the induction phase, if an Adverse Event requires all drug to be held, and the toxicity has 
recovered to Grade 1 or baseline prior to the next scheduled treatment visit and the patient is 
eligible for Nivolumab and/or Ipilimumab, please consult study chair for approval to restart prior 
to the next scheduled treatment visit. If a subject is eligible to restart Nivolumab and Ipilimumab 
after a delay, then all subsequent visits/procedures may be shifted, including the scans, in order 
to complete all 4 induction cycles. The scans may be done earlier, at the investigator’s discretion. 
  
During the Maintenance phase (Nivo+Cabo treatment), starting at cycle week 13, 
treatment/assessment cycle date may be shifted to account for recovery from immunotherapy 
related toxicity. The one exception is that scans should remain every 12 weeks according to 
calendar days. 
 
Table 8-9 Adverse event management for ipilimumab [Package Insert, 2018]. 

 
Version 2.2, December 13, 2021 
56 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Version 2.2, December 13, 2021 
57 
8.5  
Overlapping adverse event management guidance 
Many adverse events overlap between nivolumab/ipilimumab and cabozantinib. However, the 
mechanisms of action of the adverse events are likely different between these two classes of 
therapies and they require separate management plans. For example grade 3 diarrhea attributed to 
ipilimumab requires drug discontinuation, a course of high dose corticosteroids and supportive 
care, whereas grade 3 diarrhea attributed to cabozantinib requires temporary drug hold and 
supportive care alone. For adverse events that are most likely to occur with one class of therapy, 
the adverse event management should follow for that agent. An example is a grade 3-4 
electrolyte abnormality, which is more common with cabozantinib. In this case, all three drugs 
should be temporarily held, but no corticosteroids given as this is likely not an immune related 
event.  However, in patients with life threatening events (grade 4) or no improvement with drug 
hold after 5 days, then corticosteroids should be considered as it may be a rare irAE. In situations 
where a grade 3-4 adverse event could be due to either class of therapy, all drugs will need to be 
held and high dose corticosteroids administered if recommended by standard nivolumab or 
ipilimumab guidelines.  After recovery of adverse event to grade 1 or baseline, cabozantinib can 
be reinitiated even if the corticosteroid taper has not been completed. The cabozantinib may need 
to be dose reduced if indicated by the included dosing guidelines. For some situations, such as 
grade 2 elevated transaminase levels, it may be appropriate to hold all study drugs, but monitor 
for improvement prior initiation of corticosteroids. In patients where nivolumab/ipilimumab or 
nivolumab cannot be restarted, cabozantinib would continue alone as outlined in the protocol 
treatment schema unless permanent discontinuation indicated (section 8.2). Similarly, in patients 
where cabozantinib cannot be restarted, nivolumab/ipilimumab or nivolumab alone may be 
continued as outlined in the protocol treatment schema if not meeting discontinuation rules and 
adverse event(s) has recovered to grade 1 or baseline and patient has successfully tapered of 
corticosteroids (and other immune modulatory agents). An exception is grade 2 endocrine 
disorders that can be treated with hormone replacement. When it is unclear how to manage the 
adverse event, hold drugs and consult the principal investigator. 
 
During the Induction Period (Nivo-Ipi-Cabo treatment), the subject should stay on schedule and 
follow procedures as outlined. Drug dosing may be omitted based on toxicity guidance per 
protocol. If Nivolumab is restarted in the induction phase, the dose will remain at 3mg/kg for the 
duration of the induction phase. 
 
During the induction phase, if an Adverse Event requires all drug to be held, and the toxicity has 
recovered to Grade 1 or baseline prior to the next scheduled treatment visit and the patient is 
eligible for Nivolumab and/or Ipilimumab, please consult study chair for approval to restart prior 
to the next scheduled treatment visit. If a subject is eligible to restart Nivolumab and Ipilimumab 
after a delay, then all subsequent visits/procedures may be shifted, including the scans, in order 
to complete all 4 induction cycles. The scans may be done earlier, at the investigator’s discretion. 
  
During the Maintenance phase (Nivo+Cabo treatment), starting at cycle week 13, 
treatment/assessment cycle date may be shifted to account for recovery from immunotherapy 
related toxicity. The one exception is that scans should remain every 12 weeks according to 
calendar days. 

 
Version 2.2, December 13, 2021 
58 
 
Management of Hepatocellular Toxicity Associated with Cabozantinib and 
Nivolumab/Ipilimumab or Nivolumab 
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib.  It is recommended that subjects with elevation of ALT, AST, 
and/or bilirubin have more frequent laboratory monitoring of these parameters.  If possible, 
hepatotoxic concomitant medications should be discontinued in subjects who develop increased 
values of ALT, AST, or bilirubin, and other causes (eg, cancer-related, infection) should 
be evaluated.  
  
The following conditions require discontinuation of cabozantinib:  
• Drug-related ALT or AST > 3 × ULN in combination with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with drug-induced liver injury (DILI).  
• Drug-related ALT or AST > 8 x ULN. 
 
Elevations of aminotransferases when hepatic metastases are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than a doubling) 
and if there are no progressive elevations in serum bilirubin concentration or coagulation factors.  
Table 8-108-10 provides suggested guidance on management of hepatotoxicity related to 
cabozantinib and/or nivolumab/ipilimumab or nivolumab.  However, if Grade 2 or higher 
abnormalities of both a serum transaminase (ALT and/or AST) and serum bilirubin are 
documented, all study treatment must be discontinued.  Dose holds should not alter the timing of 
other study assessments, including but not limited to tumor imaging scheduled based on W1D1 
(≤ 3 days after start of treatment).  
Table 8-10: Management of Hepatotoxicity Associated with Study Treatment 
Severity of LFT 
Elevations by 
CTCAE v4 
Dose Modification Guidance 
Management/Follow-up Guidance 
Grade 1 
AST or ALT > ULN 
to 3.0 x ULN and/or 
total bili > ULN to 
1.5 x ULN 
• Cabozantinib: 
− Continue cabozantinib per 
protocol 
• Nivolumab/Ipilimumab or 
Nivolumab: 
− Continue therapy per protocol 
• Monitor LFTs per protocol 
• Discontinue concomitant hepatotoxic 
medications, if possible 

 
Version 2.2, December 13, 2021 
59 
Grade 2 
AST or ALT > 3.0 x 
ULN to ≤ 5 x ULN 
or total bili > 1.5 x 
ULN to ≤ 3 x ULN 
• Cabozantinib:  
− Interrupt cabozantinib dosing.  
− If LFTs return to baseline 
grade, resume cabozantinib at a 
reduced dose.   
• Nivolumab/Ipilimumab or 
Nivolumab:  
− Hold therapy per protocol.  
− If LFTs return to baseline grade, 
resume therapy per protocol 
  
• 
Monitor LFTs twice weekly or more 
frequently as deemed clinically necessary.  
• 
If tapering off steroid therapy, monitor 
LFTs once weekly or more often per 
clinical judgment 
• 
If LFTs return to baseline grade, resume 
with routine monitoring 
• 
If LFT elevations persist > 7 days or 
worsen:  
− 
Administer 0.5-1 mg/kg/day methyl-
prednisolone or oral equivalent 
− 
When LFTs return to baseline grade or 
CTCAE Grade ≤1, taper steroids over at 
least 4 weeks 
− 
Add prophylactic antibiotics for 
opportunistic infections if on immune 
suppression > 1 month or prior to 
1month per investigator decision. 
Grade 3-4 
AST or ALT 
> 5 x ULN or  
total bili > 3 x ULN 
or as otherwise 
specified 
• Cabozantinib:  
− Discontinue cabozantinib if:  
1) ALT or AST > 3 × ULN 
AND total bilirubin > 2 × ULN 
AND no radiographic evidence 
of biliary obstruction, or  
2) ALT or AST > 8 x ULN.  
− Otherwise interrupt 
cabozantinib dosing and resume 
at a reduced dose after LFTs 
return to baseline grade (Study 
Principal Investigator approval 
required) 
•  Nivolumab /Ipilimumab or 
Nivolumab:  
− Discontinue combination or 
monotherapy therapy 
− Exception: Can resume 
nivolumab after LFTs return to 
baseline grade if grade 3 event 
occurred while receiving 
Nivolumab/Ipilimumab (Study 
Principal Investigator approval 
required) 
 
• Monitor LFTs twice weekly or more 
frequently as deemed clinically necessary  
• During steroid taper, monitor LFTs once 
weekly or more often per clinical judgment 
• For Grade 3:  
− Administer 1.0-2.0 mg/kg/day 
methylprednisolone IV or PO equivalent  
• For Grade 4: 
− Administer 2.0 mg/kg/day 
methylprednisolone IV  
• Add prophylactic antibiotics for 
opportunistic infections if on immune 
suppression > 1 month or prior to 1month 
per investigator decision. 
• When LFTs return to baseline grade or 
Grade 2, convert to oral prednisone (if not 
already on it) and taper steroids over at least 
4 weeks 
• If LFT elevations do not improve in > 3-5 
days, worsen or rebound: 
− Add mycophenolate mofetil 1g BID 
− If no response within an additional 3-5 
days, consider other immune-
suppressants per local guidelines and 
hepatology consultation. Taper off 
steroid first over at least 4 weeks and 
then taper off mycophenolate (decrease 
total 24hr dose by 500mg after every 7 
days). 

 
Version 2.2, December 13, 2021 
60 
 
 
9 
CONCOMITANT MEDICATIONS AND THERAPIES 
 
9.1 
Allowed Therapy 
• Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, ASCO or ESMO guidelines).  
• Bisphosphonates can be used to control bone loss or hypocalcemia if the benefit outweighs 
the risk per the investigator’s discretion. 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates (Section 
8.3.1.3.8). Oral examinations are recommended at screening to determine eligibility and 
periodically during the study. In addition, subjects should be advised regarding oral hygiene 
practice and to quickly report symptoms to the investigator. Frequent monitoring for 
potentially overlapping toxicities with study treatment is recommended.  
• Transfusions and hormone replacement should be utilized as indicated by standard clinical 
practice. 
• Individualized anticoagulation therapy with heparin or direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and effectively 
under the following circumstances:  
o Low dose low molecular weight heparins (LMWH) for prophylactic use are allowed if 
clinically indicated and the benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of LMWH or the direct factor Xa rivaroxaban, edoxaban, or 
apixaban at the time of the first dose of study treatment are allowed if the subject has 
no evidence of brain metastasis, has been on a stable dose of anticoagulant for at least 
1 week, and has had no clinically significant hemorrhagic complications form the 
anticoagulation regimen or the tumor.  
o Low dose LMWH for prophylactic use after first dose of study treatment are allowed if 
clinically indicated and the benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of LMWH or direct factor Xa inhibitors rivaroxaban, edoxaban, or 
apixaban after first dose of study treatment are allowed if clinically indicated (eg, for 
the treatment of deep venous thrombosis), and the benefit outweighs the risk per the 
investigator’s discretion. For management of thromboembolic complications while on 
study, refer to Section 8.3.1.3.4.  
o Accepted clinical guidelines regarding appropriate management while receiving any 
kind of anticoagulation therapy must be followed. This includes, but is not limited to, 
subject education regarding potential adverse drug reactions, monitoring laboratory 
parameters, dose adjustments (eg, due to kidney dysfunction). Caution is warranted in 
settings associated with an increased risk for bleeding such as gastrointestinal 
cancers, urothelial cancers, gastrointestinal mucosal abnormality (e.g., mucositis), 
renal or hepatic impairment, thrombocytopenia, arterial hypertension, or prior history 
of gastrointestinal bleed. For direct factor Xa inhibitors, the potential for drug-drug 
interaction with other concomitant medications, as well as gastrointestinal absorption, 
should be considered. Aspirin and other nonsteroidal anti-inflammatory drugs 
(NSAIDs) should not be used concomitantly with heparin or factor Xa inhibitors due 

 
Version 2.2, December 13, 2021 
61 
to the increased risk for bleeding complications. The risks and benefits of the use of 
anticoagulants should be reassessed on a regular basis. For more information 
regarding the use of anticoagulants, refer to the prescribing information of the 
anticoagulant and accepted clinical practice guidelines 
o For restrictions on oral anticoagulants see Section 9.2. 
Potential drug interactions with cabozantinib are summarized in Section 9.3.1. 
 
9.2  
Prohibited or Restricted Therapy 
The following therapies are prohibited until study treatment has been permanently discontinued: 
• Any investigational agent or investigational medical device. 
• Oral anticoagulants with coumarin agents (eg, warfarin), direct thrombin inhibitor (e.g., 
dabigatran), direct factor Xa inhibitor betrixaban, antiplatelet agents such as clopidogrel, or 
chronic use of aspirin above low dose levels for cardioprotection (per local applicable 
guidelines) until 4 weeks after cabozantinib has been permanently discontinued. 
• Any nonprotocol systemic anticancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer under 
investigation). 
• Systemic corticosteroids above adrenal gland cortisol replacement levels (e.g. > prednisone 
7.5 daily or equivalent) at study entry are not permitted. Use of corticosteroids above this 
level while on study may be required for management of immune related adverse events. 
Nivolumab and ipilimumab are held/discontinued while patients are on high dose 
corticosteroids and subsequent taper. Once steroid taper completed, patients may restart 
nivolumab and/or ipilimumab based on management guidelines in section 8.4. Patients may 
restart cabozantinib during steroid taper if adverse event is improved to grade 1 or better and 
management guidelines in section 8.3 are followed. 
 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Local anticancer treatment including palliative radiation, ablation, embolization, or surgery 
with impact on tumor lesions should not be performed until radiographic progression per 
imRECIST 1.1 has been established.  
• Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin (Wright et al 2007). 
• Concomitant medications that are known to prolong the QTc interval should be avoided in 
subjects who receive cabozantinib until they have permanently discontinued cabozantinib 
treatment (refer to http://www.qtdrugs.org for a list of drugs which have the potential to 
prolong the QTc interval). 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
significantly increase the exposure to cabozantinib.  

 
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62 
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations and should be 
avoided. Grapefruit, star fruit, and Seville oranges may also increase plasma concentrations 
of cabozantinib and should be avoided. 
 
Additional information on potential drug interactions with cabozantinib is provided in Section 
9.3.1. 
 
9.3 
Potential Drug Interactions 
 
9.3.1 Potential Drug Interactions with Cabozantinib 
Currently available data suggest that cabozantinib: (1) is not anticipated to markedly induce or 
inhibit CYP enzymes at clinically-relevant plasma concentrations; (2) is a substrate for CYP3A4; 
(3) may have the potential to inhibit the P-gp transport activity but is not a substrate of P-gp; and 
(4) is a substrate of drug transporter MRP2. 
 
Cytochrome P450: Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but 
not a CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate. Co-administration of 
cabozantinib with strong inducers of the CYP3A4 family (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) may significantly decrease 
cabozantinib concentrations. The chronic use of strong CYP3A4 inducers should be avoided. 
Other drugs that induce CYP3A4 should be used with caution because these drugs have the 
potential to decrease exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme induction potential is recommended. Caution 
must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has 
been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the 
exposure to cabozantinib. 
 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g.,  
ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, rand ritonavir) may 
increase cabozantinib plasma concentrations. Grapefruit and Seville oranges may also increase 
plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors and other drugs that inhibit 
CYP3A4 should be avoided. 
 
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm).  
 
Protein Binding: Cabozantinib is highly bound (approximately 99.9%) to human plasma 
proteins. Therefore, highly protein bound drugs (e.g., diazepam, furosemide, dicloxacillin, and 
propranolol) should be used with caution with cabozantinib because there is a potential 
displacement interaction that could increase free concentrations of cabozantinib and/or a co-

 
Version 2.2, December 13, 2021 
63 
administered highly protein bound drug (and a corresponding increase in pharmacologic effect). 
Factors that influence plasma protein binding may affect individual tolerance to cabozantinib. A 
case of a drug-drug interaction between cabozantinib and warfarin that may involve 
displacement of plasma protein bound drug has been reported in the literature (Foxx-Lupo et al. 
2016). Because warfarin is a highly protein bound drug with a low therapeutic index, 
administration of warfarin at therapeutic doses is not allowed in subjects receiving cabozantinib 
due to the potential for a protein binding displacement interaction. 
 
Food Effects: As food increases exposure levels of cabozantinib, subjects should fast (with the 
exception of water) for at least 2 hours before taking their dose of cabozantinib. After the 2 hour 
fast, subjects are to take cabozantinib with a full glass of water (minimum of 8 oz. or 240 mL) 
with no more food intake for one hour post-dose.   
 
Other Interactions: In vitro data suggest that cabozantinib is unlikely to be a substrate for 
P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein transport 
activity. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-
administered substrates of P-glycoprotein. Subjects should be cautioned regarding taking a P-gp 
substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, 
maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving 
cabozantinib. Additional details related to these overall conclusions can be found in the 
investigator brochure. 
 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of 
gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib. Additional details regarding potential drug 
interactions with cabozantinib can be found in the investigator brochure. 
 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g., cyclosporine, delaviridine, 
efavirenz, emtricitabine) should be approached with caution, and subjects taking MRP2 
inhibitors should be monitored for AEs. 
 
9.3.2 Potential Drug Interactions with Nivolumab and Ipilimumab 
There are no specific drug-drug interactions with nivolumab and ipilimumab and other drugs. 
Based on the mechanism of action, these agents are usually held during courses of high dose 
corticosteroids and patients requiring immune suppression for organ transplant, autoimmune 
disorders and other disease are not permitted to participate on this protocol.  
 
9.4 
Study Treatment Accountability 
The investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding the date, lot 
number, and how much study treatment is dispensed and used by each subject in the study. 
Reasons for deviation from the expected dispensing regimen must also be recorded. At 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 

 
Version 2.2, December 13, 2021 
64 
unused study treatment will be reconciled and destroyed according to applicable state, federal, 
and local regulations. 
 
10 SAFETY 
 
10.1 
Adverse Events and Laboratory Abnormalities 
 
10.1.1 Adverse Events (AEs) 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. An adverse event can arise 
from any use of the drug (e.g. off-label use, use in combination with another drug) and with any 
route of administration, formulation, or dose, including an overdose. This definition also includes 
AEs associated with medication errors and uses of the investigational product outside what is in 
the protocol, including misuse and abuse. Pre-existing medical conditions that worsen during the 
study should be recorded as AEs. Abnormal laboratory values, ECG findings, or vital signs are to 
be recorded as AEs if they meet the criteria described in this protocol. All untoward events that 
occur after informed consent through 30 days after the decision to discontinue study treatment 
(or the date the subject is deemed to be a screen failure) are to be recorded by the investigational 
site. This requirement includes AEs from unscheduled as well as scheduled visits and includes 
the new onset of or increase in pain during this period. 
 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade, and relationship to 
study treatment will be assessed by the investigator. Severity grade will be defined by the current 
version of the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse 
Events (CTCAE). 
 
10.1.2 
Serious Adverse Events (SAEs) 
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Topic E2A. 
 
An SAE is defined as any untoward medical occurrence that at any dose:  
• Result in death; 
• Is life-threatening (i.e., in the opinion of the investigator, the AE places the subject at risk 
of death; it does not include an event that, had it occurred in a more severe form, might 
have caused death); 
• Requires inpatient hospitalization or results in prolongation of an existing hospitalization; 
o Note: While most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or previously 
scheduled surgeries or procedures for pre-existing conditions that have not 
worsened after initiation of treatment (e.g., a previously scheduled ventral hernia 
repair); pre-specified study hospitalizations for observation; or events that result 

 
Version 2.2, December 13, 2021 
65 
in hospital stays of fewer than 24 hours and that do not require admission (e.g., an 
ER visit for hematuria that results in a diagnosis of cystitis and discharge home on 
oral antibiotics).  SAEs must, however, be reported for any surgical complication 
resulting in prolongation of the hospitalization. 
• Results in persistent or significant disability or incapacity: 
o Note: The term “disability” refers to events that result in a substantial disruption 
of a subject’s ability to conduct normal life function. 
• Is a congenital anomaly or birth defect; 
• Is an important medical event (IME):  
o Note: The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, may not be immediately life-threatening or result 
in death or hospitalization, but may jeopardize the subject or require intervention 
to prevent one of the other serious outcomes listed. Examples of IMEs include 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of product dependency or product abuse. 
 
10.1.3 
Relationship to Study Treatment 
Assessment of the relationship of the AE to the study treatment by the investigator is based on 
the following two definitions: 
• Not Related: A not-related AE is defined as an AE that is not associated with the study 
treatment and is attributable to another cause or there is no evidence to support a causal 
relationship; 
• Related: A related AE is defined as an AE where a causal relationship between the event 
and the study treatment is a reasonable possibility. A reasonable causal relationship is 
meant to convey that there are facts (e.g., evidence such as dechallenge/rechallenge) or 
other clinical arguments to suggest a causal relationship between the AE and study 
treatment. Possibly and probably related AEs should be documented as related. 
 
10.1.4 Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
must be documented on an SAE Report Form or in an electronic database and include the 
following: (i) all SAEs that occur after starting cabozantinib and through 30 days after the 
decision to discontinue study treatment and (ii) any SAEs assessed as related to study treatment 
or study procedures, from the time of informed consent, even if the SAE occurs more than 30 
days after the decision to discontinue study treatment. 
 
All SAEs and all pregnancy/lactation reports regardless of outcome must be sent to Exelixis 
within one (1) business day of the PI’s knowledge of the event. The reports must be sent to 
drugsafety@exelixis.com or fax 650-837-7392. 
• The PI will perform adequate due diligence with regard to obtaining follow-up 
information on incomplete reports. All follow-up information must be sent to Exelixis 
within one (1) business day of the PI’s receipt of the new information. Upon Exelixis 
request, the PI will query for follow-up information. 
 

 
Version 2.2, December 13, 2021 
66 
Serious adverse events will also be reported, and all supporting documentation sent (emailed) to 
the Multicenter Project Manager(s) and to the study PI, Dr. Gibney, within 24 hours. 
 
10.1.5 Regulatory Reporting 
The Investigator will assess the expectedness of each related SAE. The current cabozantinib 
Reference Safety Information (Appendix K of the most recent approved Investigator Brochure) 
will be used as the reference document for assessing the expectedness of the event with regard to 
cabozantinib. Current package inserts for nivolumab and ipilimumab should be referenced as 
well. All serious unexpected adverse drug reactions (unexpected related SAEs) must be reported 
to all appropriate regulatory authorities and Ethics Committees by the investigator as required by 
21 CFR 312.32 or by Directive 2011/20/EC: 
• These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) or a 
CIOMS-1 form; 
• Exelixis reserves the right to upgrade the Investigator assessment of an SAE based on 
Exelixis assessment. 
• Institutions and PIs shall promptly provide all information requested by Exelixis 
regarding all adverse events occurring during the conduct of the study.  
• The PI is responsible for complying with all regulatory authority reporting requirements 
for the study that are applicable to the sponsor of a clinical trial. The PI shall provide a 
copy of all responses to regulatory agency requests, periodic reports, and final study 
reports to Exelixis within one (1) business day of the submission.   
• Exelixis will provide relevant product safety updates and notifications, as necessary. In 
the case of multi-center studies, it is the responsibility of the sponsoring PI/Institution to 
disseminate these updates to participating PIs. 
 
10.2 
Other Safety Considerations 
 
10.2.1 Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should be 
reviewed. Any abnormal value that leads to a change in subject management (e.g., dose 
reduction or delay or requirement for additional medication or monitoring) or that is considered 
to be of clinical significance by the investigator should be reported as an AE or SAE as 
appropriate. 
 
10.2.2 Pregnancy/Lactation Exposure 
If a subject becomes pregnant during the study, she will be taken off study treatment and will be 
followed through the end of her pregnancy. Pregnancy (in subject or partner) or lactation 
exposure, although not an SAE, should be reported to Exelixis. Forms will be provided to the 
study sites upon request. The outcome of a pregnancy (for a subject or for the partner of a 
subject) and the medical condition of any resultant offspring must be reported to Exelixis. Any 
birth defect or congenital anomaly must be reported as an SAE, and any other untoward events 
occurring during the pregnancy must be reported as AEs or SAEs, as appropriate. 
 
10.2.3 Medication Errors/Overdose 
Any overdose, or study drug administration error that results in an AE, even if it does not meet 
the definition of serious, requires reporting within one (1) business day to Exelixis. 

 
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10.2.4 Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after 
the decision to discontinue study treatment must be followed until either resolution of the event 
or determination by the investigator that the event has become stable or irreversible. This follow-
up guidance also applies to related SAEs that occur more than 30 days after the decision to 
discontinue study treatment. The status of all other continuing AEs will be documented as of 30 
days after the decision to discontinue study treatment. 
 
11 STATISTICAL CONSIDERATIONS 
Simon’s Two-Stage Design will be used in hypothesis testing for the primary endpoint of a 1 
year PFS rate. Based on the Checkmate 067 data [1], a 1 year PFS rate in the historical control is 
assumed to be 50% (H0: PFS rate=50%). In this trial, a target 1 year PFS rate will be 75% 
(improvement by 25%, H1: PFS rate >/=75%), which is deemed a clinical meaningful 
improvement. This will require a sample size of 23 for a one sided alpha of 0.05 and the power 
of 0.80. In the futility stage with the first 14 subjects, the study will be stopped if there are 7 or 
fewer subjects progression free at 1 year. In the final analysis, the null hypothesis will be rejected 
if 16 subjects or more are progression free at 1 year of the 23 total subjects. Assuming a dropout 
rate of 15% during the time of study, up to 27 subjects will be enrolled.  
 
In the event of unplanned interim analyses are needed due to slow accrual or any other reasons, 
we will use the curtailing based SCPRT approach for statistical analysis [36]. 
 
The PFS rate in the final analysis will be calculated and a 2-sided Clopper–Pearson 95% 
confidence interval (CI) will be calculated. PFS and OS will be analyzed using Kaplan–Meier 
product-limit estimates. Median PFS and OS and the cumulative probability of PFS and OS will 
be presented with two-sided 95% CI if estimable. 
 
Remaining analyses will be descriptive and exploratory in nature. TMB will be evaluated as a 
continuous variable and dichotomous breakdowns including previously reported high vs low 
status using a 21 nonsynonymous variants/MB cutoff [37]. PD-L1 status will use high/low 
cutoffs of 1% and 5% positive IHC rates [1]. Other variables will be analyzed based on 
published data or optimization of cutoffs. Statistical comparisons will be performed with SAS/R 
and looking to determine associations with biomarkers and clinical outcomes.     
 
 
12 DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and crosscheck of the CRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug–dispensing log by the investigator and/or pharmacy. 
 

 
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13 STUDY COMMITTEES 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Georgetown-Lombardi Comprehensive 
Cancer Center’s DSMP.  
 
Oversight activities include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to The Georgetown-Lombardi Comprehensive Cancer Center’s DSMP. 
 
13.2 
The Georgetown-Lombardi Comprehensive Cancer Center Data Safety Monitoring 
Committee 
The Georgetown-Lombardi Comprehensive Cancer Center DSMC will review: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the 
data and safety monitoring of this trial. As this study is an investigator initiated Phase II study 
using FDA approved agents it is considered a moderate risk study which requires real-time 
monitoring by the PI and study team and semi-annual reviews by the LCCC Data and Safety 
Monitoring Committee (DSMC). Documentation of DSMC reviews will be provided to principal 
investigator and sponsor.  Issues of immediate concern by the DSMC will be brought to the 
attention of the sponsor-investigator and other regulatory bodies as appropriate.  The sponsor and 
principal investigator will work to address the DSMC’s concerns. 
 
 
14 ETHICAL ASPECTS 
 
14.1 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct 
of the study complies with the basic principles of GCP as outlined in the current version of 
21 Code of Federal Regulations, subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators” Part 50, “Protection of Human Subjects” and Part 56, “Institutional Review 
Boards.” 
 
14.2 
Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject participating in this study after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study. In the case where 

 
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the subject is unable to read, an impartial witness should be present during the entire informed 
consent discussion. After the subject has orally consented to participation in the trial, the 
witness’s signature on the form will attest that the information in the consent form was 
accurately explained and understood. 
 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated as necessary. All subjects (including those already 
being treated) should be informed of the new information, should be given a copy of the revised 
form, and should give their consent to continue in the study. 
 
14.3 
Institutional Review Board/Ethics Committee  
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The investigator will 
send a letter or certificate of IRB/EC approval to Exelixis (or designee) before subject enrollment 
and whenever subsequent modifications to the protocol are made. 
 
 
15 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications (including protocol amendments) may be made and will be prepared, 
reviewed, and approved by representatives of the investigator. Protocol modifications or 
amendments must be reviewed and approved by Exelixis prior to implementation. 
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (eg, change in monitor or change of telephone number). 
 
 
16 CONDITIONS FOR TERMINATING THE STUDY 
At any time, the study may be terminated by the study sponsor, the sponsoring institution, or by 
Exelixis. Should this be necessary, Exelixis and the investigator will arrange the procedures on 
an individual study basis after review and consultation. In terminating the study, Exelixis and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. Upon study termination, the investigator(s) shall cease enrolling subjects into the study, 
and shall discontinue conduct of the study as soon as is medically practicable. 
 
 
17 STUDY DOCUMENTATION AND RECORD-KEEPING 
 
17.1 
Investigator’s Files and Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) the investigator’s study file, and 
(2) subjects’ clinical source documents. 

 
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The investigator’s study file will contain the protocol and protocol amendments, CRFs, query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, any other records required under the 
Protocol, and other appropriate documents and correspondence. 
 
Subjects’ clinical source documents include the subjects’ hospital/clinic records; physicians’ and 
nurses’ notes; the appointment book; original laboratory, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports; signed informed consent forms; consultant letters; and 
subject screening and enrollment logs.  
 
The investigator must keep these two categories of documents on file for at least the latest of 
(a) 2 years following the marketing application approval date for the study treatment in the 
indication being investigated, or (b) 2 years after the investigation is completed or discontinued, 
or (c) for a period of time consistent with local regulatory requirements, whichever is longest. 
After that period, the documents may be destroyed subject to local regulations with prior written 
permission from Exelixis. If the investigator wants to assign the study records to another party or 
move them to another location, Exelixis must be notified in advance. 
 
17.2 
Source Documents and Background Data 
Upon request, the investigator will supply its licensees and collaborators with any required 
background data from the study documentation or clinic records. This is particularly important 
when CRFs are illegible or when errors in data transcription are suspected. In case of special 
problems or governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that subject confidentiality is protected. 
 
17.3 
Audits and Inspections 
The investigator should understand that source documents for this study must be made available, 
after appropriate notification, to qualified personnel from the Exelixis Quality Assurance Unit 
(or designee) or to health authority inspectors. The verification of the CRF data must be by direct 
inspection of source documents. 
 
17.4 
Case Report Forms  
For enrolled subjects, all and only data from the procedures and assessments specified in this 
protocol and required by the CRFs should be entered on the appropriate CRF. Additional 
procedures and assessments may be performed as part of the investigator’s institution or medical 
practice standard of care and may not be required for CRF entry.  
 
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI 
or authorized delegate from the study staff. 
 
All paper forms should be typed or filled out using indelible ink and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed and 
dated by the investigator or his or her authorized delegate.  
 

 
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The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
in the CRFs and in all required reports. 
 
 
18 MONITORING THE STUDY 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
study to verify both adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor should have access to laboratory test reports and 
other subject records needed to verify the entries on the CRF. The investigator (or designee) 
must agree to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 
 
 
19 CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents, subjects should be 
identified by identification codes and not by their names. The investigator should keep a subject 
enrollment log showing codes, names, and addresses. The investigator should maintain 
documents (eg, subjects’ written consent forms) in strict confidence. 
 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review. 
 
 
20 PUBLICATIONS OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide Exelixis with a copy of any proposed publication 
or release: (a) for abstracts, slide presentations or posters, at least five (5) business day prior to 
submission (in the case of abstracts) or first public presentation (in the case of slide presentations 
and posters); and (b) at least thirty (30) days in advance of first submission and each subsequent 
submission in the case of manuscripts and also comply with any provisions regarding publication 
that are agreed to between the PI’s institution (eg, institution name.) and Exelixis, Inc. in the 
Clinical Trial Agreement related to this study.  

 
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22. 
APPENDIX