Conditions: Refractory Cutaneous Melanoma
Keywords: Phase 2 Melanoma ipilimumab nivolumab cabozantinib anti-pd-1
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The primary objective of this clinical trial is to evaluate the clinical efficacy and progression free survival of the triplet combination of ipilimumab + nivolumab + cabozantinib in patients with anti-PD-1/PD-L1 refractory metastatic cutaneous melanoma.

Detailed description:
This is a phase II, single arm, single institution clinical trial. Eligible adults with anti-PD-1 refractory, unresectable/metastatic cutaneous melanoma will be treated with the triplet combination of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks for 4 cycles in addition to cabozantinib 40 mg/day. For cycles 5+, treatment will consist of nivolumab 480 mg IV every 4 weeks in combination with cabozantinib 40 mg/day. The total duration of therapy will be 24 months or until either disease progression or the occurrence of unacceptable drug-related toxicity. Regular tumor assessments should be performed to determine if PD is present.

Arms:
arm 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg IV every 3 weeks + Cabozantinib 40 mg PO daily for 4 cycles followed by Nivolumab 480 mg IV every 4 weeks + Cabozantinib 40 mg PO daily for up to 24 months.

Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Cabozantinib
Intervention descriptions: intervention 1: Ipilimumab is a fully human IgG1 kappa monoclonal antibody that binds the co-inhibitory receptor CTLA-4. Antibody binding prevents interaction with the CTLA-4 ligands CD80 and CD86. Blockade of CTLA-4 results in increased T cell activation and proliferation. Ipilimumab was the first immune checkpoint inhibitor to receive FDA approval as a cancer therapy. Treatment of patients with advanced metastatic melanoma with ipilimumab monotherapy resulted in improved overall survival. Subsequent clinical trials with ipilimumab alone and in combination with anti-PD-1 antibodies have demonstrated impressive clinical activity in patients with melanoma, renal cell carcinoma, non-small cell lung cancer and other cancers. Side effects of ipilimumab result from autoimmune attack on healthy tissues. Side effects may include dermatitis, colitis, hepatitis, hypophysitis, pneumonitis, endocrinopathies, nephritis, arthritis, neuropathies and others. intervention 2: Nivolumab is a fully human IgG4 kappa monoclonal antibody that binds the co-inhibitory receptor PD-1. Nivolumab binding to PD-1 blocks interaction with the PD-1 ligands PD-L1 and PD-L2. PD-1 blockade can lead to reinvigoration of exhausted T cells and prevent T cell exhaustion of newly activated T cells. Nivolumab has been shown to have excellent clinical efficacy in treating a wide range of cancers as monotherapy and in combination with ipilimumab. intervention 3: Cabozantinib is a potent small molecule inhibitor of multiple receptor tyrosine kinases. Cabozantinib inhibits VEGFR2, MER, KIT, and MET at single digit nanomolar IC50 concentrations. Other kinases including ROS1, RET, FLT3, RON, AXL, and TIE2 are also inhibited with nanomolar concentrations of cabozantinib. Cabozantinib has been shown to have clinical activity in a variety of solid tumors and has been approved by the FDA for treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.

Protocol document:
Prot_SAP_001.pdf: 
Page 1 of 92 
Site Protocol Number: 2021000533 
Protocol Number: XL184-IST122/CA184-605 
NCT Number: NCT05200143 
Title: A phase II, single-arm clinical trial evaluating the triplet combination of ipilimumab, nivolumab 
and cabozantinib in patients with anti-PD-1(L1) refractory cutaneous melanoma.  
Principal Investigator: 
Matthew Taylor, MD 
Co-director, Providence Melanoma Program 
Providence Cancer Institute 
4805 NE Glisan St., Portland, Oregon 97123 
Phone: 503-215-6614 
Fax: 503-215-6841 
Email: Matthew.Taylor@providence.org 
Co-Investigator(s): 
Brendan Curti, MD 
Co-director, Providence Melanoma Program 
Providence Cancer Institute 
4805 NE Glisan St., Portland, Oregon 97123 
Phone: 503-216-6259 
Fax: 503-215-6841 
Email: Brendan.Curti@providence.org 
Site(s): 
Providence Cancer Institute, Providence Portland Medical Center 
Version:  
Version 1.0 8-4-2021 
CONFIDENTIAL - Cabozantinib + Nivolimab + Ipililumab Protocol Required Elements 


 
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BACKGROUND INFORMATION 
Introduction: 
1.1 Background on the indication 
PD-1 and CTLA-4 immune checkpoint inhibitors 
Tumor antigen-specific T cells exposed to chronic antigenic stimulation develop an exhausted phenotype 
characterized by increased surface expression of various co-inhibitory checkpoint molecules (including 
PD-1, LAG-3, TIM-3, and others) and loss of effector function1. Blockade of co-inhibitory checkpoint 
molecules can reinvigorate exhausted T cells and produce dramatic anti-tumor effects2.  
Over the past decade, treatment with immune checkpoint inhibitors has revolutionized the treatment of 
patients with advanced cancer. The combination of ipilimumab plus nivolumab has been shown to be 
one of the most effective treatment regimens for patients with advanced metastatic melanoma2,3. Over 
half of patients with metastatic cutaneous melanoma treated with the combination of ipilimumab + 
nivolumab achieve at least a partial response and are alive 5 years later2. The Checkmate 511 clinical 
trial showed that treatment with a reduced dose of ipilimumab (1 mg/kg) in combination with 
nivolumab (3 mg/kg) resulted in similar progression free survival and overall survival compared with 
Ipilimumab 3 mg/kg + nivolumab 1 mg/kg. The Ipi 1 mg/kg + Nivo 3 mg/kg regimen was far better 
tolerated with significantly less toxicity4. 
Despite the success of immune checkpoint inhibitors and targeted therapeutics, melanoma continues to 
claim the lives of thousands each year. For patients with metastatic melanoma who are refractory to 
anti-PD-1 monotherapy, treatment with the combination of Ipilimumab plus nivolumab or 
pembrolizumab results in a median progression free survival of 3-5 months5-7. As such, improved 
therapy options for patients with PD-1 refractory cutaneous melanoma is a significant unmet clinical 
need. 
Vascular endothelial growth factor (VEGF) 
VEGF signaling within the tumor microenvironment results in profound local immunosuppression. VEGF 
signaling promotes tumor infiltration of regulatory T cells (Treg) and myeloid derived suppressor cells 
(MDSC) which suppress adaptive anti-tumor immune responses. VEGF signaling also inhibits dendritic 
cell maturation resulting in impaired antigen presentation and T cell activation8. Activated T cells 
upregulate VEGF cell surface receptors. VEGF signaling in activated T cells results in upregulated surface 
expression of co-inhibitory receptors as well as reduced cytotoxic activity and proliferative capacity9,10.   


 
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Given that VEGF signaling has multiple pro-tumorigenic and immunosuppressive effects in cancer 
progression – there is a strong rationale for combining VEGF inhibition with immune checkpoint 
inhibition. Several recent clinical trials have demonstrated improved anti-tumor activity with 
combination therapies blocking VEGF and PD-1/PD-L1 signaling. We recently published the results of our 
phase Ib/II clinical trial with the combination of lenvatinib + pembrolizumab11. This clinical trial showed 
impressive anti-tumor activity in heavily pre-treated patients including those with metastatic renal cell 
carcinoma and endometrial cancer12. 
1.2 Background on the compounds 
Ipilimumab 
Ipilimumab is a fully human IgG1 kappa monoclonal antibody that binds the co-inhibitory receptor CTLA-
4. Antibody binding prevents interaction with the CTLA-4 ligands CD80 and CD8613. Blockade of CTLA-4 
results in increased T cell activation and proliferation. Ipilimumab was the first immune checkpoint 
inhibitor to receive FDA approval as a cancer therapy. Treatment of patients with advanced metastatic 
melanoma with ipilimumab monotherapy resulted in improved overall survival14. Subsequent clinical 
trials with ipilimumab alone and in combination with anti-PD-1 antibodies have demonstrated 
impressive clinical activity in patients with melanoma, renal cell carcinoma, non-small cell lung cancer 
and other cancers2,15,16. Side effects of ipilimumab result from autoimmune attack on healthy tissues. 
Side effects may include dermatitis, colitis, hepatitis, hypophysitis, pneumonitis, endocrinopathies, 
nephritis, arthritis, neuropathies and others. 
Nivolumab 
T cell activation results in upregulation of counter regulatory co-inhibitory receptors including PD-1 and 
CTLA-4. Ligation of these co-inhibitory receptors with their corresponding ligands results in diminished 
cytotoxicity and proliferative capacity. These regulatory mechanisms serve to prevent excessive immune 
activation and autoimmune disease. However, in some diseases such as cancer and chronic viral 
infections, chronic antigenic stimulation of T cells results in high expression of co-inhibitory checkpoint 
receptors which leads to T cell exhaustion. Nivolumab is a fully human IgG4 kappa monoclonal antibody 
that binds the co-inhibitory receptor PD-1. Nivolumab binding to PD-1 blocks interaction with the PD-1 
ligands PD-L1 and PD-L2. PD-1 blockade can lead to reinvigoration of exhausted T cells and prevent T cell 
exhaustion of newly activated T cells. Nivolumab has been shown to have excellent clinical efficacy in 
treating a wide range of cancers as monotherapy and in combination with ipilimumab2,15,16. 


 
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Cabozantinib 
Cabozantinib is a potent small molecule inhibitor of multiple receptor tyrosine kinases. Cabozantinib 
inhibits VEGFR2, MER, KIT, and MET at single digit nanomolar IC50 concentrations. Other kinases 
including ROS1, RET, FLT3, RON, AXL, and TIE2 are also inhibited with nanomolar concentrations of 
cabozantinib.  Cabozantinib has been shown to have clinical activity in a variety of solid tumors and has 
been approved by the FDA for treatment of medullary thyroid cancer, renal cell carcinoma and 
hepatocellular carcinoma17-19. 
1.3 Rationale for the proposed study 
In this clinical trial, we will evaluate the clinical efficacy and safety of the combination of VEGF inhibition 
(cabozantinib 40 mg/day) with immune checkpoint inhibition (ipilimumab 1 mg/kg + nivolumab 3 mg/kg) 
for patients with metastatic cutaneous melanoma who are refractory to anti-PD-1/PD-L1 therapy. The 
hypothesis is that concurrent blockade of distinct and inter-related signaling pathways (VEGF and co-
inhibitory immune checkpoint pathways), will result in improved anti-tumor immune reactivity and 
clinical efficacy. Inhibition of VEGF signaling in the tumor microenvironment will increase CD8+ T cell 
infiltration, reduce infiltration of Treg and MDSC populations, and block the direct immunosuppressive 
effects of VEGF on activated T cells. Blockade of PD-1 and CTLA-4 immune checkpoint pathways will 
facilitate reinvigoration of exhausted T cells and allow expansion and activation of a broader repertoire 
of tumor antigen-specific T cells.  
 
 STUDY OBJECTIVES AND ENDPOINTS 
Recent clinical trials have demonstrated median PFS as high as 5 months with the combination of low 
dose ipilimumab (1 mg/kg IV every 3 weeks) in combination with anti-PD-1 therapies in patients with 
anti-PD1 refractory cutaneous melanoma. As such, we will use the 5 month mPFS as the benchmark for 
the design of this clinical trial. In order to show a 4 month improvement in mPFS (with a power of 0.8 
and a one-sided test given a type I error rate of 0.05), a total of 41 subjects would need to be enrolled.  
This signal seeking pilot study will initially enroll 25 subjects at our site (single institution) in less than 2 
years. If this treatment combination results in a mPFS of at least 8 months or an ORR of 45% or higher, 
we will review these results with BMS and Exelixis and propose protocol and budget amendments to 
add 1-2 additional sites to expedite enrollment to a total of at least 41 subjects. 
 


 
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Primary Objective 
The primary objective of this clinical trial is to evaluate the clinical efficacy and progression free survival 
of the triplet combination of ipilimumab + nivolumab + cabozantinib in patients with anti-PD-1/PD-L1 
refractory metastatic cutaneous melanoma. 
Secondary Objectives: 
 
Safety/Tolerability (CTCAE v5.0) 
 
Objective response rate (iRECIST) 
 
Overall survival 
 
Correlative translational studies (paired pre-treatment and day #15 on-treatment tumor 
biopsies for characterization of tumor infiltrating immune cell profiling and gene expression 
changes) 
Primary endpoint:  
Progression free survival will be defined as the time between the date of enrollment and the first date of 
documented progression (per iRECIST), as determined by the investigator, or death due to any cause, 
whichever occurs first. Cumulative incidence functions will be displayed and summarized for the median 
time to progression as well as percentage of patients without disease progression at 12, 18, and 24 
months.  
Secondary endpoints:  
1. Objective response rate (iRECIST) 
2. Duration of response 
3. 6, 12 and 24 month progression free survival 
4. 12 month overall survival 
5. Incidence of grade ≥3 treatment related adverse events (CTCAE v5.0) 
6. Correlative molecular profiling 
 
STUDY DESIGN: This is a phase II, single arm, single institution clinical trial. Adults (age ≥18 years-old) 
with anti-PD-1 refractory, unresectable/metastatic cutaneous melanoma will be evaluated for eligibility. 
Eligible participants will be treated with the triplet combination of ipilimumab 1 mg/kg + nivolumab 3 
mg/kg every 3 weeks for 4 cycles in addition to cabozantinib 40 mg/day. For cycles 5+, treatment will 


 
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consist of nivolumab 480 mg IV every 4 weeks in combination with cabozantinib 40 mg/day. The total 
duration of therapy will be 24 months. 
 
Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg IV every 3 weeks + Cabozantinib 40 mg PO daily for 4 
cycles followed by: 
 
Nivolumab 480 mg IV every 4 weeks + Cabozantinib 40 mg PO daily for up to 24 months  
 
 
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 requires 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 Section 5.4. 
 
Necessity for treatment with other anticancer treatment prohibited by protocol. 
 
Sexually active subjects who refuse to use medically accepted barrier methods of contraception 
(e.g., male condom, female condom) during the study and for 4 months after the last dose of 
cabozantinib and 3 months after the last dose of ipilimumab and 5 months after the last dose of 
nivolumab.  
 
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. 
 
Necessity for interrupting all study treatment for greater than 12 weeks for study-treatment-
related AEs unless approved by the Principal Investigator. 


 
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 
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. Patients who continue study treatment beyond progression must be 
reconsented into the study. 
 
Subject participation in another clinical study using an investigational agent, investigational 
medical device, or other intervention. 
 
Subject request to discontinue all study treatments (with or without concurrent withdrawal of 
informed consent). 
 
INCLUSION/EXCLUSION CRITERIA 
3.1 
Inclusion Criteria 
To be eligible for the study, the subject must meet all of the inclusion and none of the exclusion criteria: 
1. Histologically (or cytologically) confirmed diagnosis of metastatic cutaneous melanoma.  
2. Prior therapy: 
a. 
Must have been treated previously with an immune checkpoint inhibitor targeting 
PD-1 or PD-L1. 
b. 
Disease progression following treatment with prior anti-PD-1/PD-L1 therapy must 
be confirmed at least 4 weeks after the first imaging showing disease progression 
to rule out pseudoprogression. 
c. 
Prior therapy with BRAF/MEK inhibitors (before or after anti-PD-1(L1) therapy) is 
allowed but not required. 
d. 
Patients who develop unresectable/metastatic disease while receiving or following 
completion of adjuvant systemic anti-PD-1/PD-L1 therapy are eligible. 
3. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, 
unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. 
4. Men and women, aged ≥ 18 years 
 
5. Measurable disease meeting the following iRECIST criteria: 
a. At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or >1.5 cm in the 
short-axis diameter for a lymph node metastasis that is serially measurable according to 


 
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iRECIST using computed tomography/magnetic resonance imaging (CT/MRI). 
b. Lesions that have had external beam radiotherapy must show evidence of disease 
progression to qualify as a target lesion. 
6. ECOG performance status ≤ 1 
7. Adequate cardiac function, as defined by:  
a. Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition 
(MUGA) scan or echocardiogram, 
b. Baseline QTc interval ≤ 480 ms 
8. 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/µL without granulocyte colony-stimulating factor 
support. 
b. White blood cell count ≥ 2500/µL. 
c. Platelets ≥ 100, 000/µL without transfusion. 
d. Hemoglobin ≥ 9 g/dL (≥ 90 g/L). 
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline 
phosphatase (ALP) ≤ 3x upper limit of normal (ULN). ALP ≤ 5x ULN with documented bone 
metastases. 
f. 
Total bilirubin < 1.5 x ULN. Note: Individuals who have a total bilirubin level >1.5 X ULN 
will be allowed if their indirect bilirubin level is < 1.5 x ULN  (i.e., participants with 
suspected or known diagnosis of Gilbert’s Syndrome) 
g. Serum albumin ≥ 2.8 g/dl. 
h. (PT)/INR or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN 
i. 
Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min 
(≥ 0.675mL/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 
j. 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine 
protein ≤ 1 g. 
9. Capable of understanding and complying with the protocol requirements and must have signed 
the informed consent document.  
10. Sexually active fertile subjects and their partners must agree to use medically accepted methods 
of contraception (e.g., 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 


 
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cabozantinib and 3 months after the last dose of ipilimumab and 5 months after the last dose of 
nivolumab. 
11. Participants of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at 
screening, within 24 hours prior to receiving the first dose of study medication, and then every 4 
weeks while on treatment. 
12.  Participants of child-bearing potential agree to use highly effective methods of contraception 
starting with the first dose of assigned study intervention through 5 months after the last dose 
of study therapy. Participants of childbearing potential are those who are not proven 
postmenopausal. Postmenopausal is defined as any of the following:  
a. Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments  
b. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-
menopausal range for women under 50   
c. Radiation-induced oophorectomy with last menses >1 year ago    
d. Chemotherapy-induced menopause with >1 year interval since last menses    
e. Surgical sterilisation (bilateral oophorectomy or hysterectomy 
 
3.2 
Exclusion Criteria 
1. Prior therapy: 
a) 
 
b) 
Prior therapy with a VEGF(R) inhibitor alone or in combination with immune checkpoint 
inhibitor(s).  
c) 
Prior therapy with an anti-CTLA-4 antibody 
2. Participants with active, known, or suspected autoimmune disease.  Participants with type I diabetes 
mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment 
are permitted to enroll. 
3. Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids are permitted in the absence of active autoimmune 
disease. 
4. History of allergy or hypersensitivity to any monoclonal antibody 
5. Previous or concurrent malignancy within 3 years of study entry, with the following exceptions:  
a) 
adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate 
intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent 
malignancy; OR 
b) 
other solid tumors treated curatively in which the expected rate of recurrence within 5 years is 
< 5%.  


 
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6. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the 
following: 
a) 
History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to 
screening, 
b) 
Symptomatic congestive heart failure (i.e. Grade 2 or higher), history or current evidence of 
clinically significant cardiac arrhythmia and/or conduction abnormality <6 months prior to 
screening. Exceptions include asymptomatic/well-controlled atrial fibrillation/flutter or 
paroxysmal supraventricular tachycardia;  
c) 
Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 140 
mmHg or diastolic blood pressure ≥ 90 mmHg, despite medical therapy 
7. History of thromboembolic or cerebrovascular events ≤ 6 months prior to the first dose of study 
treatment.  Examples include transient ischemic attacks, cerebrovascular accidents, 
hemodynamically significant (i.e., massive or sub-massive) deep vein thrombosis or pulmonary 
emboli.  
Note: Individuals with either deep vein thrombosis or pulmonary emboli that does not result in 
hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants 
for at least 4 weeks.  
Note: Individuals with thromboembolic events related to indwelling catheters or other procedures 
may be enrolled. 
8. Impaired gastrointestinal function or disease that may significantly alter the absorption of 
cabozantinib (e.g., uncontrolled vomiting or malabsorption syndrome) 
9. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular 
atrophy) 
10. Any other condition that would, in the Investigator’s judgment, contraindicate an individual’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, 
social/ psychological issues, etc. 
11. Participants who have undergone major surgery (e.g., intracranial, intrathoracic, or intra-abdominal 
surgery) ≤ 3 weeks prior to starting study drug, minor surgery < 10 days prior to starting study drug 
or who have not recovered from side effects of such procedure. Subjects must have complete 
wound healing from major surgery or minor surgery before first dose of study treatment. 
12. Participants that are pregnant or nursing (lactating) 
13. Prisoners or individuals who are involuntarily incarcerated 
14. Medical, psychiatric, cognitive or other conditions that may compromise the participant’s ability to 
understand the patient information, give informed consent, comply with the study protocol or 
complete the study 
15. Patients with leptomeningeal involvement by melanoma 
16. Participants with CNS metastases or leptomeningeal carcinomatosis are not eligible unless: 


 
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16.1. 
CNS metastases have been treated and remained stable by radiographic evaluation at 
least 4 weeks after CNS directed therapy and/or: 
16.2. 
There are ≤5 asymptomatic untreated CNS metastases measuring no larger than 10 mm 
each. 
16.3. 
Eligible subjects must be neurologically asymptomatic and without corticosteroid 
treatment at the time of first dose of study treatment.”  
17. Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 
weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study 
treatment; ongoing clinically relevant complications from prior radiation therapy are not 
eligible 
18. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin 
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., 
clopidogrel). Allowed anticoagulants are the following: 
18.1. 
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH). 
18.2. 
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban 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 without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor. 
19. Administration of a live, attenuated vaccine within 30 days prior to first dose of study 
treatment 
20. Evidence of tumor invading the GI tract, active peptic ulcer disease, IBD, diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction 
of pancreatic duct or common bile duct, or gastric outlet obstruction 
21. Abdominal fistula, GI perforation, bowel obstruction or intra-abdominal abscess within 6 
months before first dose of study treatment. Complete healing of intra-abdominal abscess 
must be confirmed before first dose of study treatment 
22. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) of red 
blood, or other history of significant bleeding within 12 weeks before first dose of study 
treatment 
23. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease 
manifestation 
24. Lesions invading or encasing any major blood vessels.  
25. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, 
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. 
26. Serious non-healing wound/ulcer/bone fracture. 
27. Moderate to severe hepatic impairment (Child-Pugh B or C). 
28. Requirement for hemodialysis or peritoneal dialysis. 
29. History of solid organ or allogenic stem cell transplant. 


 
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30. QTcF > 500 msec within 14 days before first dose of study treatment (Note: Could also be 
listed in Inclusion as ≤ 500 msec) 
 
 
STUDY ASSESSMENTS AND PROCEDURES 
 
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 receive their first dose of treatment on this protocol: 
 
Screening Procedures 
Pre-treatment 
Period 
Day -28 through  
initiation of 
treatment 
 
Instructions 
Informed Consent 
X 
 
Medical History 
X 
All medical history relevant to the disease under study 
including smoking history, alcohol use, AJCC M stage, 
recreational drug use 
Adverse Event Collection 
X 
 
Concomitant Medications 
X 
Complete review of current medications with patient 
including herbal and dietary supplements, and over the 
counter (OTC) 
Comprehensive Physical 
Exam 
X 
To include basic body systems 


 
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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. 
 
Clinical Safety Laboratory Assessments  
Clinical Safety Laboratory Assessments
Hematology – CBC with Hemoglobin, Hematocrit, Total leukocyte count, including differential and 
Platelet count 
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT) 
Total bilirubin 
Alkaline phosphatase (ALP) 
Albumin
Sodium 
Potassium 
Chloride 
Vital Signs 
X 
Height, weight, blood pressure, pulse, 02 saturation, 
respiration 
ECOG Performance Status 
X 
 
Disease Assessment 
X 
Contrast enhanced CT of the chest, abdomen, pelvis Or 
MRI abdomen,w/wo gadolinium contrast including non 
contrast CT are acceptable for patients with iodine 
contrast allergies. 
Cardiac Assessment 
X 
ECHO and ECG 
Biopsy 
X 
Optional biopsy prior to initiation of treatment. In 
patients who do not consent then archival tissue will be 
requested. 
Laboratory Assessments 
X 
See Clinical Safety Laboratory Assessments.
 
Tumor Markers 
X 
LDH 
Specimen Collection or 
Optional Specimen Banking 
X 
Serum for banking ( 4ml lavender top and 4ml red top ) 


 
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Lactate dehydrogenase (LDH)
Creatinine 
Blood Urea Nitrogen (BUN) or serum UREA 
Glucose 
Bicarbonate 
Total Protein 
Calcium
Phosphorus 
CK 
GGT- screening 
Magnesium-screening 
Troponin - screening 
TSH, and free T4 - screening 
TSH, with reflexive fT4 if TSH is 
abnormal - on treatment 
Lipase and /or amylase 
PT/INR/PTT, and drug adherence checks  
Serology
Hepatitis B/C, (HBV sAG, HCV antibody or HCV RNA), - screening only
(Testing for HIV-1 and HIV-2 must be performed where mandated by local requirements) 
Other Analyses
Serum Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG).
Follicle stimulating hormone (FSH) screening -only required to confirm menopause in women < age 
55) 
Urinalysis with UPCR (urine protein creatinine ratio) - screening and at each study visit
 
 
Treatment Period 
During the Treatment Period subjects will receive treatment for up to 24 months or until either disease 
progression, the occurrence of unacceptable drug-related toxicity or for other reason(s) for subject 
withdrawal as described in Section 2.1. Subjects should be instructed to immediately inform the 
Investigator of any AEs. Subjects experiencing dizziness, sleepiness, or other symptoms that could 
influence alertness or coordination should be advised not to drive or operate other heavy machinery.  
 
Abnormalities in clinical laboratory tests that lead to a change in subject management (e.g., dose 
delayed [withheld] or reduced, requirement for additional medication, treatment or monitoring) are 
considered clinically significant and should be documented. If laboratory values constitute part of an 


 
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event that meets criteria defining it as serious, the event (and associated laboratory values) must be 
reported as an SAE.  
 
Regular tumor assessments should be performed to determine if PD is present. Tumor assessments 
should continue on the protocol-defined schedule, relative to the date of first dose of study 
treatment, regardless of whether study treatment is given, reduced, held or discontinued. The 
same imaging modalities used at screening will be used for subsequent tumor assessments 
after first dose.  
 
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 (e.g., clinic closure, personal emergency, inclement weather, 
vacation), the assessment should be performed as close as possible to the required schedule.  
 
The Treatment Period ends when a subject receives his or her last dose of study treatment; the subject 
then enters the Post-Treatment Period. 
 
The following schedule of assessments applies to all subjects. More frequent assessments should be 
obtained if clinically indicated. 
Study Assessments 
Study Day/Visit Day 
Cycles 1-4 
( 21 days) 
Day 1 
( +/- 4 days) 
Cycles 5 + 
Day 1 
( +/- 4 days)
 
 
Instructions 
Adverse Event Assessment
X
X
Concomitant Medications 
X 
X 
Review of prohibited medications prior to 
each study drug dosing 
Physical Exam
X
X
Vital Signs 
X 
X 
Weight, blood pressure, pulse, 02 saturation, 
respirations at each visit  
ECOG Performance Status 
X 
X 
Questionnaire(s)
X
X
FACT-M (Version 4)
Cabozantinib
40 mg PO daily 
Continuous 
X 
X 


 
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Ipilimumab 1 mg/kg IV
Day 1 Every 3 weeks 
(cycles 1-4 ) 
X 
 
Nivolumab 3mg/kg IV
Day 1 Every 3 weeks 
(cycles 1-4  ) 
X 
 
Nivolumab 480mg IV
Day 1 every 4 weeks 
 
X 
Disease Assessment 
Refer to 
instructions for 
interval 
Refer to 
instructions 
for interval 
Contrast enhanced CT of the chest, 
abdomen, pelvis.      
Restaging will occur every 12 weeks ( +/- 1 
week) 
Cardiac Assessment 
X 
 
ECG/EKG – day 1 of cycles 1-4 only 
Specimen Collection or 
Optional Specimen Banking 
X 
X 
Serum for banking ( 4ml lavender top and 
4ml red top ) 
Biopsy 
x 
 
(prior to treatment start and on treatment 
for 10 patients)  prestudy and on day 15 for 
consenting patients  
Complete Blood Count (CBC) 
X* 
X 
See Clinical Safety Laboratory Assessments. 
 *Repeat CBC/CMP on D14 of cycles 1-4. 
Blood Chemistry 
X* 
X 
See Clinical Safety Laboratory Assessments. 
*Repeat CBC/CMP on D14 of cycles 1-4. 
Thyroid Function Tests 
X 
X 
See Clinical Safety Laboratory Assessments. 
TSH with reflex to free T4 day 1 of odd 
numbered cycles  
Tumor Markers 
 
 
LDH 
Immune Parameters 
X 
X 
Immune parameters assessment. Refer to 
Section 4.4  
Study Labs Serum Sample 
Pharmacokinetics (PK) 
 
 
Please see PK section of the protocol. 
Section 4.4  
Urinalysis  UPCR 
X 
X 
UA to evaluate for proteinuria 
Pregnancy Test (HCG) 
X 
X 
For WOCBP


 
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Post-Treatment Period 
Subjects will return to the study site approximately 30 days after their last dose of treatment to 
complete end-of-study assessments. Patients will be followed for residual toxicity for 100 days post last 
day of treatment even if they start a new anticancer therapy. Patients who are removed from study 
early will be followed for residual toxicity for 100 days post last day of treatment even if they start a new 
anticancer therapy.   
 
Laboratory and physical examinations will be performed. Remaining study drug 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.  
Study Day/Visit Day 
30 days (+/- 7 
days) last study 
treatment 
12 weeks after 
last study 
treatment 
(+/- 14 days ) 
Instructions 
Adverse Event Assessment
X
X
Concomitant medications
X 
X 
Physical Exam
X 
X 
Vital Signs
X
X
ECOG Performance Status
X
X
Disease Assessment
 
 
Contrast enhanced CT of the 
chest, abdomen, pelvis.  
 
Restaging will occur every  
12 weeks (+/- 14 days) through 
3 years from the start of 
treatment and then every 6 
months until 5 years from start 
of treatment.  


 
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Complete Blood Count (CBC)
X 
X 
See Clinical Safety Laboratory 
Assessments. 
Blood Chemistry
X 
X 
See Clinical Safety Laboratory 
Assessments. 
Thyroid Function Tests
X 
X 
See Clinical Safety Laboratory 
Assessments.  
Tumor Markers
X
X
LDH 
 
 
 
4.4  
         Correlative Studies  
Translational studies will be performed on fresh tumor biopsies and peripheral blood specimens and 
correlated with clinical response to therapy.  
 
Paired tumor biopsies (pre-treatment and day #15) on 10 subjects with accessible tumors 
amenable to safe biopsy.  
 
PBMCs and serum will be collected pre-treatment and on day 1 of each cycle for the first 6 
cycles. 
 
Analysis may include multiplex immunofluorescent tissue staining for characterization of tumor 
infiltrating immune profile, RNAseq to evaluate global gene expression changes within tumor 
resulting from treatment, and characterization of peripheral blood immune cell profiles, T cell 
activation status, and cytokine analysis. Scope of work and budgets will be negotiated with BMS 
and Exelixis separate from this clinical trial protocol. 
4.5 
     Research Participant Registration and Subject Number Assignment Procedures 
Research Participant Registration 
Patients must meet all of the eligibility requirements and undergo all screening procedures. If a patient 
enrolls in the study, but does not receive study therapy, the patient’s enrollment may be canceled. 
Reasons for cancellation will be documented in writing. Any patient whose enrollment was canceled 
before receiving study therapy will be replaced. 


 
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Assignment of Subject Numbers 
 
Subject numbers will be assigned at enrollment based on order of enrollment. For example: 
o MFH is the 4th patient enrolled to study. Subject number INC– 04 
 
o B-A is 9th patient enrolled to study. Subject number INC – 09 
 
All case report forms, study reports, and laboratory samples for research tests, including immune  
parameters or pharmacokinetics, will be labeled with the full patient subject number. 
 
Each Consented participant will be assigned only 1 identification number. Numbers must not be  
reused for different participants. Any participant who is screened multiple times will retain their  
original identification number. 
 
 
TREATMENT PROCEDURES 
 
Composition, Formulation, and Storage 
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. Please refer to the most up to date Investigator Brochure in regards to storage 
conditions, handling, and preparation specifications for all study agents. 
 
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. Cabozantinib 
20-mg tablets are round. Doses of 40 mg will comprise two 20-mg tablets. The components of the 
tablets are listed below.  


 
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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. 
 
Nivolumab 
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy 
chains and 2 identical light chains. Nivolumab is produced from cell culture using a CHO cell line. 
The physical and chemical properties of nivolumab drug substance are provided below:  
 
Physical and Chemical Properties of Nivolumab Drug Substance 
BMS Number BMS-936558-01 
Other Names nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
Molecular Weight 146,221 daltons (143,619.17 daltons, protein portion) 
Appearance Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may be present 
Solution pH 5.5 to 6.5 
Refer to the Pharmacy Manual for details on storage and handling of nivolumab. 
 
 
Ipililumab 
Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1 consisting of 4 polypeptide chains; 
2 identical heavy chains primarily consisting of 447 amino acids each with 2 identical kappa light 
chains consisting of 215 amino acids each linked through inter-chain disulfide bonds. Ipilimumab 
is produced from cell culture using a Chinese Hamster Ovary (CHO) cell line. The physical and 
chemical properties of the ipilimumab drug substance are provided below:   
 
Physical and Chemical Properties of Ipilimumab Drug Substance 
BMS Number BMS-734016-01 or BMS-734016 
Other Names/Laboratory Codes Yervoy, MDX-010, MDX-CTLA-4 
Molecular Weight 147,991 Daltons 


 
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Appearance Clear to slightly opalescent, colorless to pale yellow liquid, may contain particles 
Solution pH 7.0 
pI The isoelectric focusing analysis generates a banding pattern in the pI range of 8.5 to 8.8, with the 
major isoform at an approximate pI of 8.7 
Abbreviations: pI = isoelectric point. 
Refer to the Pharmacy Manual for details on storage and handling of nivolumab. 
 
 
STUDY TREATMENT ADMINISTRATION 
 
Cabozantinib Administration 
Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily.  
 
Cabozantinib tablets should only be taken whole by mouth and should not be cut, chewed, or crushed 
for dissolving in liquid or administered through other routes including percutaneous endoscopic 
gastrostomy (PEG) tubes. Cabozantinib tablets should not be administered to subjects who do not have 
adequate swallowing capacity. Cabozantinib should not be taken with food (subjects should not eat for 
at least 2 h before and at least 1 h after taking cabozantinib) and should be taken with a full glass (at 
least 8 ounces or 240 mL) of water. If a dose is missed, the missed dose should not be taken less than 12 
h before the next dose. Cabozantinib tablets should be stored at controlled room temperature and 
inventoried according to applicable regulations 
 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 5.4 below. 
 
IO Therapy Administration 
Participants will be treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks for 4 cycles . 
For cycles 5+, treatment will consist of nivolumab 480 mg IV every 4 weeks. The total duration of 
therapy will be 24 months. 
 
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 


 
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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 unused study treatment will be reconciled 
and destroyed according to applicable state, federal, and local regulations. 
 
Drug accountability records will be maintained by the Providence Health & Services Oregon Region 
Investigational Drug Services pharmacy.  
Unused investigational drug will be returned or destroyed at study close or when drug expires as per the 
site’s policy.  
 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply study drug 
(Nivolumab and Ipilimumab) to subjects/investigators unless the Sponsor-Investigator chooses to extend 
their study. The investigator is responsible to ensure that the subject receives appropriate standard of 
care or other appropriate treatment in the independent medical judgement of the Investigator to treat 
the condition under study.” 
 
All investigational drug accountability records, physical inventory and other supporting documents (such 
as temperature monitoring logs) will be made available to the monitor and applicable regulatory 
agencies for auditing and monitoring purposes. 
 
Study Treatment Dose Modifications, Interruptions, and Discontinuation 
The following should be taken into consideration in decisions regarding management for treatment-
related side effects: cabozantinib and IO agents have class-specific safety profiles based on their 
mechanisms of action but may also cause AEs that overlap. In the case of AEs clearly attributed to 
cabozantinib or the IO agent, independent dose modification for either agent is allowed. 
 
 
Examples of VEGFR TKI associated AEs caused by cabozantinib are hypertension and hand-foot 
syndrome. 
 
Examples of irAEs caused by IO agents are pneumonitis and endocrinopathies. 
 
Examples of overlapping AEs are diarrhea and elevations in liver function tests. 
 


 
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As a general approach all AEs should be managed with supportive care including both pharmacological 
and non-pharmacological treatments according to consensus management guidelines at the earliest 
signs of toxicity considered related to study treatment.   
 
Study treatment may be continued for mild AEs if appropriate supportive care has been initiated to 
ameliorate symptoms. Should this be ineffective and toxicities become unacceptable, dose 
modifications of study treatment should be considered to prevent worsening of toxicity. Moderate to 
severe AEs usually require dose modifications including dose reductions and/or interruptions.   
 
Dose interruptions of cabozantinib or IO agents for AEs may occur independent of the other agent at the 
discretion of the Investigator. If all study treatment is interrupted for more than 12 weeks, treatment 
should be discontinued unless approved by the Principal Investigator.  
 
Management of AEs Associated with Cabozantinib 
The following should be taken into consideration in decisions regarding dose modifications (reductions 
or interruption): 
 
As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity considered related to the study treatment. Should this be ineffective, dose interruptions 
and/or reductions should be considered to prevent worsening of toxicity.  
 
The assigned starting dose for cabozantinib is 40 mg/day. Two dose reduction levels of 
cabozantinib are permitted (see “Dose Reductions of Cabozantinib” table). 
 
Dose modification criteria for cabozantinib are shown in the “Dose Reductions of Cabozantinib” 
table. Dose interruptions and/or reductions should be implemented for unacceptable toxicity. 
Doses may be modified at any time while a subject is on treatment. 
 
Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined in the “Dose Modifications of Cabozantinib for Treatment-Related AEs” table, 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 12 weeks, 
cabozantinib should be discontinued unless there is unequivocal evidence that the subject is 


 
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benefitting. In this situation, a subject may be able to restart therapy with a dose reduction 
upon resolution of the toxicity, with approval from the Principal Investigator. 
 
Dose interruptions for reason(s) other than related AEs (e.g., surgical procedures) can be longer 
than 12 weeks per the discretion of the Investigator. 
 
Guidelines for the management of specific AEs of cabozantinib such as GI disorders, non-GI 
fistula formation, hemorrhage, thromboembolic events, hypertension, stomatitis and mucositis, 
skin disorders, osteonecrosis, proteinuria, nervous system disorders, infections and infestations, 
blood system disorders, fatigue, weight loss, QTc prolongation, electrolyte disorders, endocrine 
disorders, respiratory disorders and hepatic adverse events begin in Section 5.4.1.2. 
Dose Reductions of Cabozantinib 
Assigned Dose 
First Dose Level Reduction 
Second Dose Level 
Reduction 
Third Dose Level 
Reduction 
40 mg daily (qd) 
20 mg daily (qd) 
20 mg every other day 
(qod)  
No dose reduction 
permitted 
Cabozantinib will be discontinued if a  dose of 20-mg cabozantinib every other day (minimum dose) is not tolerated 
 
Dose Modifications of Cabozantinib for Treatment-Related AEs 
Event 
Management 
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 
Continue cabozantinib treatment at the current dose level with supportive care. 
 
  
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed 
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, and 
approved by the Principal Investigator. 
 
Toxicity can be managed with a dose reduction following recovery to Grade 1 
(or baseline) and optimal medical care . 
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 5.4.1.2. 


 
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Cabozantinib Dose Reinstitution and Reescalation 
If the subject recovers from his or her toxicities to CTCAE v.5.0 Grade  1 or to the baseline value (or 
lower) and the toxicity was unrelated to cabozantinib, then cabozantinib 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 cabozantinib, then cabozantinib may be restarted at a reduced 
dose.  
 
Subjects who initiated treatment with cabozantinib at 40 mg and experience a possibly related AE of 
Grade 1 or 2 severity may be restarted with no dose change after recovery of the toxicities to ≤ Grade 1 
or to the baseline value (or lower) if appropriate supportive care can prevent or minimize the risk 
of the AE. 
 
Subjects receiving a dose of 20 mg qod may be restarted at the same dose if deemed safe at the 
discretion of the investigator. Subjects unable to tolerate a dose of 20 mg qod should discontinue 
cabozantinib.  
 
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. A minimum two-week interval is 
needed between resuming study treatment and the escalation to the next higher dose level. 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 (e.g., central nervous system, cardiac, hepatic, renal). 
 
Guidelines for Management of Potential Adverse Events Associated with Cabozantinib Treatment 
Subjects will be monitored for AEs from the time of 1st treatment through their last follow-up visit (100 
days after the date of the last dose of study 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.5.0.  


 
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Management of severe or intolerable adverse reactions may require temporary dose reduction and/or 
interruption for cabozantinib.  
 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in descending order 
of frequency were diarrhea, fatigue, decreased appetite, nausea, palmar-plantar erythodysesthesia 
syndrome (PPES), vomiting, weight decreased, hypertension, PPES, vomiting, constipation, 
hypertension, dysgeusia, dysphonia, and asthenia. For a full description of the safety profile of 
cabozantinib, refer to the cabozantinib Investigator’s Brochure. 
Subjects may also experience other medically important but less frequent AEs including arterial and 
venous thrombotic AEs (e.g., deep vein thrombosis [DVT], pulmonary embolism, transient ischemic 
attack [TIA], and myocardial infarction [MI]), severe hemorrhagic events, proteinuria, wound healing 
complications, GI perforation, abscesses including intra-abdominal and pelvic abscess, GI and non-GI 
fistulae formation, osteonecrosis, and 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, 
LDH increased, lipase increased, neutropenia, ALP increased, hyponatremia, and leukopenia.  
 
Many AEs can occur early (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. In 
addition, earlier onset for events of dehydration was observed in subjects with castrate-resistant 
prostate cancer (CRPC) when compared with subjects with other tumor types. 
 
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. Cabozantinib should be discontinued for the following 
AEs: visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic 


 
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events, nephrotic syndrome, hypertensive emergency, persistent uncontrolled hypertension despite 
optimal medical management, and reversible posterior leukoencephalopathy syndrome (RPLS).  
 
A population pharmacokinetics analysis of cancer subjects with RCC, HCC, MTC, glioblastoma, and other 
solid tumors predicted a terminal half-life of approximately 99 h for cabozantinib when administered as 
repeated once-daily doses. Thus, as described above, it will take most subjects 2 to 3 weeks (5 half-lives) 
to reach steady state with daily dosing after initiating therapy with cabozantinib. AEs attributable to 
cabozantinib may be expected to occur by the time maximum plasma concentrations are reached, and 
therefore early intervention with dose modifications within the first 15-21 days of daily dosing may be 
justified. 
 
Gastrointestinal Events 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess:  
Prior to initiation of treatment with cabozantinib, subjects should be carefully evaluated for potential 
risk factors including (but not limited to) the following: 
 
Tumors invading GI or respiratory tracts. 
 
Active peptic ulcer disease, inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease), 
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis. 
 
History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess. 
 
Ongoing visceral complications from prior radiation therapy. 
 
Prior GI surgery (particularly when associated with delayed or incomplete healing). 
  
Complete healing following abdominal surgery and radiation therapy and/or resolution of intra 
abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.  
 
After starting cabozantinib, subjects should be monitored for early signs of GI perforation such as 
abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for developing 
GI perforation or fistula20  are present.  
 
Discontinue cabozantinib and initiate appropriate management in subjects who have been diagnosed 
with GI perforation or fistula. 
 


 
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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 below.  
 
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. 


 
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Management of Diarrhea Associated with Cabozantinib 
Event 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
 
Continue with study treatment and consider dose reduction. 
 
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg followed by 2 
mg after each episode of diarrhea [maximum: 16 mg loperamide per day]). 
 
Dietary modifications (e.g., 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 (e.g., stool sample for culture). 
o 
Administer antibiotics as needed (e.g., 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 
(e.g., 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 6 for further details). 
 
 
Hepatic Events 
See section 5.4.3 for guidance regarding both cabozantinib and IO agent. 


 
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Non-Gastrointestinal Fistula 
Radiation therapy (in certain areas of the body) has been identified as a possible predisposing risk factor 
for fistula formation in subjects undergoing treatment with cabozantinib. 
 
Subjects with any clinically relevant ongoing complications from prior radiation therapy (e.g., radiation 
esophagitis or other inflammation of the viscera) should not be treated with cabozantinib until these 
complications have resolved. 
 
Radiation therapy to the thoracic cavity (including mediastinum) should be avoided within 4 weeks of 
starting treatment with cabozantinib (excluding local radiation for bone metastases). Fistula should be 
ruled out as appropriate in cases of onset of severe mucositis or difficulty swallowing after start of 
therapy. Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with a non GI fistula. 
 
Hemorrhage 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be evaluated for potential bleeding risk factors prior to initiating 
cabozantinib treatment and 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 (e.g., deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia). 
 
Concomitant medication with anticoagulants or other drugs which affect normal hemostasis. 


 
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 
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). 
 
Vascular Disorders 
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 
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 


 
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applicable guidelines are not allowed, until 4 weeks after cabozantinib has been permanently 
discontinued. See Section 6.2 for additional restrictions on anticoagulation therapy.  
 
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with cabozantinib. Subjects 
should be evaluated for pre-existing risk factors for arterial thrombotic events such as diabetes mellitus, 
hyperlipidemia, hypertension, coronary artery disease, history of tobacco use, and cardiac and/or 
thromboembolic events that occurred prior to initiation of study treatment. Further treatment with 
cabozantinib should be discontinued in subjects who develop an acute MI, cerebral infarction, or any 
other clinically significant arterial thromboembolic complication. 
Hypertension 
The below table provides treatment guidelines for hypertension deemed related to cabozantinib. 
Subjects with known hypertension should be optimally managed prior to entry into clinical trials with 
cabozantinib according to entry criteria of specific protocols. 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. 


 
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Management of Hypertension Associated with Cabozantinib 
Event 
Management 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic)a and < 160 
mm Hg 
 
OR 
 
> 90 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 <140 mm Hg systolic or <90 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 < 140 mm Hg systolic or < 90 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 < 140 mm Hg systolic 
and < 90 mm Hg diastolic. 
Hypertensive emergencyc 
 Discontinue cabozantinib treatment. 
a Permitted dose levels are defined by individual protocols. 
b Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending end-
organ damage (e.g., myocardial infarction/ischemia, intracranial haemorrhage, cerebral ischemia, pulmonary edema, 
encephalopathy, kidney damage). 
 
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 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 (e.g., with a weak solution of salt and baking 
soda) should be maintained. Lips should be kept moisturized with lip balm. The use of lipstick, lip-gloss, 
and Vaseline should be avoided. 


 
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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.  
 
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 3 weeks prior to elective surgery. Do not 
administer cabozantinib for at least 2 weeks after major surgery and until complete 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.  


 
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Management of Hand-Foot Syndrome (PPES) Associated with Cabozantinib 
Event 
Management 
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 (e.g., clobetasol 0.05%) once daily and add analgesics 
(e.g., 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 (e.g., clobetasol 0.05%) twice 
daily AND analgesics. Resume cabozantinib at a reduced dose if PPES recovers to Grade ≤ 1. 
Discontinue subject from cabozantinib if PPES does not improve within 6 weeks. 
a Permitted dose levels are defined by individual protocols. 
 
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.  
 
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. 
 
Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib 
treatment. Advise subjects regarding oral hygiene practice and to quickly report symptoms to 
Investigator. Caution should be used in subjects receiving bisphosphonates. 
 


 
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Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be interrupted for at least 3 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a protracted time.  
 
Withhold cabozantinib for development of ONJ until complete resolution. 
 Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring UPCR. 
The below table provides treatment guidelines for proteinuria deemed related to cabozantinib. 
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).  


 
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Management of Proteinuria Associated with Cabozantinib 
Event 
Management 
UPCR ≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
 
No change in cabozantinib treatment or monitoring. 
UPCR  > 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. 
 
UPCR  ≥ 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 hold 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. 
 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, 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. 


 
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 Infections and Infestations 
Infections are commonly observed in cancer subjects. Predisposing risk factors include a decreased 
immune status (e.g., 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 complete healing has taken place. 
 Blood and Lymphatic System Disorders 
Hematological toxicities (i.e., neutropenia, thrombocytopenia, and anemia) 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. 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. 
 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.  
 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. 


 
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 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 
(including post marketing data) confirmed the absence of safety concerns associated with QT 
prolongation. There were no events of torsades de pointes reported. 
 
Unless otherwise specified, only subjects with a baseline QTcF ≤ 500 msec are eligible for cabozantinib 
research studies. Cabozantinib should be used with caution in subjects with QT prolongation risk, a 
history of QT interval prolongation, or who are taking antiarrhythmics or drugs known to prolong the QT 
interval. Concomitant treatment with strong CYP3A4 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 or an increase of > 60 
ms above baseline, 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 or increased by > 60 ms above baseline, the 
following actions must be taken: 
 
Interrupt cabozantinib treatment. 
 
Hospitalize symptomatic subjects (e.g., 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). 


 
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 
Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms and the average increase is ≤ 60 
ms above baseline, 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. 
 
Cabozantinib treatment has been interrupted through a minimum of 1 week following the 
return of the QTcF to ≤ 500 ms or return to ≤ 60 ms above baseline. 
 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved. 
 
Principal Investigator has reviewed all available information and has agreed to the continuation 
of study treatment 
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. 


 
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 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. Routine monitoring of thyroid function and 
assessments for signs and symptoms associated with thyroid dysfunction is recommended before 
initiation and during treatment with cabozantinib. Management of thyroid dysfunction 
(e.g., symptomatic hypothyroidism) should follow accepted clinical practice guidelines. 
 Musculoskeletal and Connective Tissue Disorders 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on nonclinical 
GLP-compliant toxicology studies. The development of new or progressive, unexplained musculoskeletal 
symptoms such as pain or weakness should be assessed for underlying causes. 
Rhabdomyolysis has been reported. Cabozantinib should be discontinued in subjects with serious and 
life-threatening rhabdomyolysis and interrupted if less severe forms occur when there are no other clear 
causes. Reinitiation of cabozantinib treatment must be discussed with and approved by the Principal 
Investigator. Therapy of rhabdomyolysis should include supportive care and standard medical 
intervention. 
 Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea has been reported in clinical studies with cabozantinib. Symptoms should be managed 
according to locally accepted clinical practice including an assessment for underlying causes. Pulmonary 
embolism should be considered as possible cause of new onset dyspnea given the risk of thrombosis 
associated with inhibition of VEGF signaling. Furthermore, fistula formation and pneumonia have been 
reported in subjects treated with cabozantinib and should be considered as clinically indicated in 
subjects presenting with pulmonary symptoms.  
 
 
 


 
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 Electrolyte Abnormalities 
Electrolyte abnormalities, including hypocalcemia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been noted in subjects treated with cabozantinib. In some cases these have 
been Grade 3 or 4 and/or serious. These laboratory values should be evaluated routinely. Deficits should 
be corrected when an electrolyte abnormality is noted in order to avoid worsening. Correction of 
electrolyte abnormalities should be accompanied by increased frequency of monitoring. 
 
Management of AEs Associated with Nivolumab and Ipililumab 
The assigned dose for Nivolumab 3 mg/kg IV every 3 weeks followed by 480mg every 4 weeks. 
The assigned dose for Ipilimumab 1 mg/kg for a maximum of up to 4 doses.  
Dose reductions are not allowed for the IO agents. AEs associated with the IO agents are managed with 
dose delays. 
For more detailed guidance on management of non-hepatocellular AEs associated with IO agents please 
see Appendix A. For recommendations on management of hepatocellular toxicity and dose 
modifications of both cabozantinib and IO agents, see Section 5.4.3. 
 
Dose Delay Criteria for the Nivolumab and Ipililumab  
Administration of the Nivolumab and Ipililumab should be delayed, for any of the following: 
 
Any Grade 2 non-skin, drug-related AE, with the exception of fatigue 
 
Grade 2 drug-related creatinine, AST, ALT, and/or total bilirubin abnormalities 
 
Any Grade 3 skin, drug-related AE 
 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions: 
o Grade 3 lymphopenia does not require dose delay 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay.  
o Grade 3 AST, ALT or total bilirubin may require dose discontinuation. (See Section 5.4.3) 
 
Grade 4 amylase or lipase value necessitates dose delay for the anti-PD-(L)1 and anti-CTLA-4 and 
abdominal imaging to rule out pancreatitis regardless of presence or absence of symptoms.  If the 
diagnostic radiology scan shows no evidence of pancreatitis, the anti-PD-(L)1 and anti-CTLA-4 may 


 
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be resumed once the amylase and lipase values return to Grade 3 or lower as long as the subject 
remains asymptomatic.  
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
warrants delaying the dose of study medication. 
Immuno-oncology agents are associated with AEs that differ in severity and duration from AEs caused by 
other therapeutic classes. Early recognition and management of AEs associated with immuno-oncology 
agents may mitigate severe toxicity. Management algorithms or tables (Section 5.4.3 and Appendix A) 
have been developed to assist investigators in assessing and managing the following groups of AEs: 
 
Gastrointestinal 
 
Renal 
 
Pulmonary 
 
Hepatic 
 
Endocrinopathy 
 
Skin 
 
Neurological 
 
Myocarditis 
 
Infusion-related Reactions 
 
 
Criteria to Resume Nivolumab and Ipililumab 
Delayed doses of Nivolumab and Ipililumab should be administered as soon as the subject meets criteria 
to resume treatment. If a dose has been delayed, the subject should not wait until the next scheduled 
dosing date.  
Subjects may resume treatment with these study drugs when the drug-related AE(s) resolve to 
Grade  1 or baseline value, with the following exceptions: 
 
Subjects may resume treatment in the presence of Grade 2 fatigue.  
 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in the 
presence of Grade 2 skin toxicity.  
 
Systemic corticosteroids for control of infusion reactions or irAEs must have been tapered to a dose 
level ≤ 10 mg/day of prednisone equivalent before resuming treatment with Nivolumab and 
Ipililumab.  


 
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 
For subjects with AST, ALT, and/or total bilirubin abnormalities, dosing may resume when laboratory 
values return to baseline grade and corticosteroid therapy has been tapered to no higher than the 
equivalent of 10 mg of prednisone per day.   
 Note: Drug-related ALT or AST > 3x ULN in combination with total bilirubin > 2x ULN without 
reasonable other explanation, consistent with DILI mandates permanent discontinuation of all study 
drugs.  
Note: Nivolumab and Ipililumab, or Ipililumab alone, may be continued after a Grade 3 ALT or AST has 
been observed and managed appropriately after a positive benefit risk ratio has been determined and 
the Principal Investigator has been consulted (See Section 5.4.3) 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a steroid 
taper over at least 1 month may be eligible for retreatment if discussed with and approved by the 
Principal Investigator. 
 
Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement 
may resume treatment. 
 
If all study treatment is interrupted for > 12 weeks, the subject must be permanently discontinued 
from study treatment unless approved by the Principal Investigator.  
 
 
Criteria for Discontinuation of Nivolumab and Ipililumab 
Criteria for discontinuation of both Nivolumab and Ipililumab during the combination therapy period or 
the Nivolumab alone after no additional Ipililumab is to be given are specified in this section. If a subject 
meets criteria for discontinuation and the Investigator is unable to determine whether the event is 
related to both or one study drug, the subject should discontinue both Nivolumab and Ipililumab with 
the exception of certain cases of liver function test elevation (See Section 5.4.3). 
Nivolumab and Ipililumab should both permanently discontinued for any of the following reasons: 
 
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within the re-treatment period OR requires systemic 
treatment; 
 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, myocarditis, 
hypersensitivity reaction, or infusion reaction of any duration; 
 
Any Grade 3 adrenal insufficiency regardless of control with hormone replacement. 
 
Any Grade 3 drug-related non-skin AE lasting > 7 days or recurs; 
 
Grade 3 diarrhea or Grade 3 colitis  


 
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o Note: Nivolumab alone can be continued if grade 3 colitis or diarrhea lasts ≤ 7 days or if, 
upon permanent discontinuation of ipililumab, the Principal Investigator approves continued 
use due to a possible favorable benefit/risk ratio. 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding; 
 
Grade ≥ 3 drug-related AST**, ALT**, or total bilirubin; 
** In most cases of Grade 3 AST or ALT elevation, Nivolumab and Ipililumab will be 
permanently discontinued. Nivolimab alone or Nivolumab and Ipililumab may be continued 
with approval from the Principal Investigator if there is a possible favorable benefit/risk 
ratio. 
 
Drug-related ALT or AST > 3x ULN in combination with total bilirubin > 2x ULN without reasonable 
other explanation, indicative of potential DILI, mandates permanent discontinuation of all study 
drugs; 
 
Grade 4 drug-related AE or laboratory abnormality (including but not limited to creatinine, AST, ALT, 
or total bilirubin); 
 
Any grade meningoencephalitis, myasthenia gravis, or Guillain-Barré syndrome 
 
Any event that leads to delay in dosing lasting > 12 weeks from the previous dose. 
 
The following scenarios do not require discontinuation of the ipililumab and/or nivolumab: 
 
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic hormone 
replacement; 
 
Grade 4 neutropenia  7 days; 
 
Grade 4 lymphopenia or leukopenia; 
 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae 
and are corrected with supplementation/appropriate management within 72 hours of their onset; 
 
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Principal Investigator; 
 
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events are 
allowed. Drug-related adverse events are any toxicity temporally associated with administration of 
the investigational agent that may be at least possibly related to study treatment; 


 
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 
Dosing delays lasting > 12 weeks from the previous dose that occur for non-drug-related reasons 
may be allowed if approved by the Principal Investigator.  
 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 12 weeks, the Principal 
Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue as clinically 
indicated during such dosing delays. 
 
Management of Hepatocellular Toxicity Associated with Cabozantinib and Nivolumab and 
Ipililumab 
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during treatment with 
cabozantinib, anti-PD-(L)1 agents, and anti-CTLA-4 agents. 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 (e.g., cancer-related, infection) should 
be evaluated.   
The following condition requires discontinuation of all study drugs:  
 
Drug-related ALT or AST > 3x ULN in combination with total bilirubin > 2x ULN without reasonable 
other explanation, consistent with drug-induced liver injury (DILI).  
The table below provides suggested guidance on management of hepatotoxicity related to cabozantinib, 
Nivolumab and Ipililumab.  
In the event cabozantinib is interrupted and Nivolumab and Ipililumab delayed due to a Grade 2 
abnormality in a serum transaminase (ALT and/or AST) or serum bilirubin, Nivolumab and (if fewer than 
4 ipilulumab doses have been administered and no AE has occurred that led to discontinuation of the 
ipililumab alone) the ipililumab should be resumed upon return of liver function tests to baseline grade, 
at which time cabozantinib should be resumed with a dose reduction (from either 40 mg qd to 20 mg 
qd, or 20 mg qd to 20 mg qod as appropriate).  
If no additional ipililimab is to be administered, the dose of cabozantinib may be re escalated no sooner 
than 10 days after re-initiation of cabozantinib.  And then can be further escalated no sooner than 14 
days thereafter. 


 
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Consult with the Principal Investigator to discuss further management should re-challenge be followed 
by any recurrence of a Grade 2 or higher liver function test. 
Dose delays should not alter the timing of other study assessments, including but not limited to tumor 
imaging.  
For additional information on dose modifications of Nivolumab and Ipililumab, refer to Section 5.4.2 or 
Appendix A. 


 
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Suggested Management of Hepatotoxicity Associated with Study Treatment 
Severity of LFTa 
Elevations 
Dose Modification Guidance 
Management/Follow-up Guidance 
AST or ALT  
> 1 – ≤ 3x ULN 
and/or  
total bili  
> 1 – ≤ 1.5x ULN 
 Cabozantinib: 
− Continue cabozantinib per 
protocol 
 Nivolimab/Ipilulimab: 
− Continue therapy per protocol 
 Monitor LFTs per protocol. 
 Discontinue concomitant hepatotoxic 
medications, if possible. 
AST or ALT  
> 3 – ≤ 5 x ULN  
or  
total bili  
> 1.5 – ≤ 3x ULN 
 Cabozantinib:  
− Interrupt cabozantinib dosing. 
− If LFTs return to baseline grade, 
resume cabozantinib at a 
reduced dose. After completion 
of ipililumab, re-escalate 
cabozantinib dose as per 
protocol. If no additional 
ipililumab  doses are to be 
administered, the dose of 
cabozantinib may be 
re-escalated no sooner than 
10 days after re-initiation of 
cabozantinib.   
− See above section for 
additional guidance. 
 Nivolimab/Ipilulimab: 
− Delay 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 judgmentb. 
− If LFTs return to baseline grade, resume 
with routine monitoring. 
 If LFT elevations persist > 3 days or worsen: 
− Administer 0.5-1 mg/kg/day 
methylprednisolone or oral equivalent. 
− When LFTs return to baseline grade or 
CTCAE Grade ≤1, taper steroids over at 
least 1 monthb. 
− Consider prophylactic antibiotics for 
opportunistic infections. 
AST or ALT  
> 5x ULN  
or  
total bili > 3x ULN or 
as otherwise 
specified 
 Cabozantinib:  
− Discontinue cabozantinib if  
ALT or AST > 8x ULN.  
− Otherwise interrupt 
cabozantinib dosing and 
resume at a reduced dose after 
LFTs return to baseline grade 
(Sponsor approval required) 
 Nivolimab/Ipilulimab: 
− Discontinue therapy for Grade 
3 ALT/AST, unless the 
Investigator in consultation 
with the Principal Investigator 
determines a favorable 
risk/benefit ratio that warrants 
continuation of both 
Nivolumab and Ipililumab or of 
Nivolumab alone 
 Monitor LFTs twice weekly or more 
frequently as deemed clinically necessary.  
 During steroid taper, monitor LFTs once 
weekly or more often per clinical 
judgmentb. 
 For Grade 3:  
− Administer 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV equivalent.  
 For Grade 4: 
− Administer 2.0 mg/kg/day 
methylprednisolone IV or IV equivalent.  
 Add prophylactic antibiotics for 
opportunistic infections. 
 Consult Gastroenterologist. 
 When LFTs return to baseline grade or 
Grade 2, taper steroids over at least 
1 monthb. 


 
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 If LFT elevations do not improve in > 3 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. 
ALT or AST > 3x ULN 
AND total bilirubin 
> 2x ULN AND no 
radiographic 
evidence of biliary 
obstruction 
 All study drugs must be 
discontinued. 
 Follow the above management/follow-up 
guidance by grade. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; bili, bilirubin; CTCAE, Common Terminology Criteria for 
Adverse Events; IV, intravenous; LFT, liver function tests; ULN, upper limit of normal 
a LFTs include AST, ALT and total bilirubin. 
b Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g., prednisone) at start of tapering 
or earlier, once sustained clinical improvement is observed. Lower bioavailability should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
 
CONCOMITANT MEDICATIONS AND THERAPIES 
 
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 (e.g., ASCO or ESMO guidelines).  
 
Bisphosphonates or RANK-L inhibitors 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 
5.4.1.2.9). 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. Withhold cabozantinib for at least 
3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold 
cabozantinib for development of ONJ until complete resolution 
 
Transfusions and hormone replacement should be utilized as indicated by standard clinical 
practice. 


 
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 
Inhaled, intranasal, intra-articular, and topical corticosteroids are allowed if minimal systemic 
absorption. Systemic corticosteroids are allowed for control of infusion reactions or irAEs and 
must be tapered to a dose level ≤ 10 mg/day of prednisone equivalent before next 
administration of the IO agent. Prophylactic steroid treatment for subjects with contrast 
allergies prior to tumor imaging is allowed.   
 
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 At the time of first dose of study treatment: 
 
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 After first dose of study treatment: 
 
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 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 the potential adverse drug reactions, monitoring laboratory 
parameters, dose adjustments (e.g., 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 
 
Prohibited or Restricted Therapy 
The following therapies are prohibited until study treatment has been permanently discontinued: 
 
Any investigational agent or investigational medical device. 
 
Any non-protocol systemic anticancer treatment (e.g., chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer under 
investigation). 


 
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 
Immunosuppressive agents including immunosuppressive doses of systemic corticosteroids with 
exceptions as stated in Section 6.1. 
 
Live vaccines are prohibited while on study and until 5 months after last dose of IO agent (e.g., 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a 
typhoid vaccines). The use of inactivated (killed) vaccines for the prevention of infectious 
disease is permitted. 
 
Metamizole (dipyrone) because of its potential for causing agranulocytosis. 
 
Anticoagulants: Prohibits coumarin agents, direct thrombin inhibitors, direct factor Xa inhibitor 
betrixaban, platelet inhibitors, and aspirin above low-dose levels for cardio-protection until 4 
weeks after cabozantinib has been permanently discontinued 
 
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 RECIST 1.1 
has been established.  
 
Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin21. 
 
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 
(e.g., 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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 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., 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. 
 
Potential Drug Interactions with Cabozantinib and Effects of Food 
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 for lists of substrates, inducers, and inhibitors of selected 
CYP450 isozyme pathways: 
 


 
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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/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-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 
literature22. 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. 
 
Other Interactions: In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein 
(P-gp), but it does appear to have the potential to inhibit the P-gp transport activity. Therefore, 
cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of 
P-gp. 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. 
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. 
Concomitant 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 (i.e., PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects 
administered cabozantinib. 
 


 
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Food Effects: As food increases exposure levels of cabozantinib, subjects should fast (with the exception 
of water) for at least 2 h 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. 
 
Potential Drug Interactions  
No drug interactions between cabozantinib and ipilimumab and nivolumab have been observed in 
previously reported clinical trials. Cabozantinib does not affect metabolism or the serum half-life of 
ipilimumab or nivolumab. Cabozantinib has overlapping toxicity with ipilimumab/nivolumab including 
the potential to cause diarrhea, elevated liver enzymes, skin rash, and hypothyroidism. 
 
SAFETY 
 
Adverse Events and Laboratory Abnormalities 
 
Adverse Events (AEs) 
An AE is any untoward medical occurrence in a patient or clinical trial subject who has been enrolled in a 
clinical study and who may have been administered an investigational product, regardless of whether or 
not the event is assessed as related to the study treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of an investigational product, regardless of whether or not the 
event is assessed as related to the investigational product. This requirement includes specific events or 
symptoms associated with cancer progression or general clinical deterioration to ensure potential 
toxicities are not overlooked. Radiographic progression without associated clinical sequalae is not 
considered an AE: terms such as ‘disease progression’ should be avoided. An adverse event can arise 
from any use of the drug (eg 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. 
 


 
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All untoward events that occur after start of study therapy through 30 days (100 days for SAEs and 
certain other events [See AEs of Special Interest Table]) after the last study treatment are to be 
recorded by the investigational site.  
 
At each scheduled and unscheduled visit, AEs are to be identified and assessed based upon study 
procedures, routine and symptom-directed clinical investigations, and subject query/report. 
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). This study will use the NCI CTCAE v5.0. 
 
Assessment of the relationship of the AEs to individual study treatment by the Investigator is based on 
the following two definitions: 
 
Not Related: An event is assessed as not related to study drug if it is attributable to another 
cause and/or there is no evidence to support a causal relationship to the study treatment. 
 
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. 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final study 
reports as specified in the ISR agreement or, if a regulatory requirement [eg, IND US trial] as part of an 
annual reporting requirement.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate. 
 
Laboratory Abnormalities 
All laboratory data required by this protocol and any other clinical investigations should be reviewed by 
the Investigator. Any abnormal value that leads to a change in subject management (e.g., dose 
reduction, delay, discontinuation, 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 


 
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appropriate, unless this value is consistent with the subject’s present disease state or is consistent with 
values obtained prior to entry to the study. 
 
Serious Adverse Events (SAEs) 
 
Definitions 
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 immediately life-threatening (i.e., in the opinion of the Investigator, the AE places the subject 
at immediate 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 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 significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
 
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 medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of IMEs include 


 
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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. 
 
 Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE 
 
SAEs Reporting 
As soon as an Investigator becomes aware of an AE that meets the criteria for an SAE, the Investigator 
will document the SAE on an SAE Report Form in REDCap. SAEs must be recorded as Adverse Events 
using the electronic case report form in REDCap a clinical data management system (CTMS). 
 
In addition, SAEs regardless of causal relationship, must be reported to Exelixis and BMS within one (1) 
business day of the Investigator’s knowledge of the event by submitting a completed MedWatch report 
form. 
Exelixis Reporting: The reports must be emailed to drugsafety@exelixis.com or faxed to 650-837-7392 
with the below: 
 
Required Information: 
o Identity of Investigator 
o Site name 
o Subject identifiers 
o Drug name and dosage  
o Event description 
o Event terms (i.e., as recorded in the electronic database) 
o Investigator’s assessment of the relationship of the event to study treatment (Section 
7.1)  
o The reason why the event is considered to be serious (i.e., the seriousness criteria) 
(Section 7.2.1) 
 
 
Recommended Information:  
o Medications or therapeutic measures used to treat the event 
o Action taken with the study treatment because of the event 


 
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o Outcome/resolution of the event 
o Any additional SAE information 
 
Note – Medical records should not be sent to Exelixis unless requested. 
BMS Reporting: All SAEs that occur from first study treatment through 100 days of discontinuation of 
dosing must be reported to BMS Worldwide Safety, whether  related or not related to study drug, 
including those thought to be associated with protocol-specified procedures (eg, a follow-up skin biopsy) 
within 24 hours \ 1 business day to comply with regulatory requirements. MedWatch 3500 form should 
be completed and submitted to BMS to report the SAEs. 
Note:  Please include the BMS Protocol number on the SAE form or on the cover sheet with the SAE form 
transmission. Medical Records should not be sent to BMS unless requested. 
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
All SAEs must be reported by confirmed facsimile (fax) transmission or reported via electronic mail to the 
below email address and the BMS Protocol number must be included on the SAE form or on the cover 
sheet with the SAE form transmission 
SAE Email Address: Worldwide.Safety@BMS.com  
SAE Facsimile Number:  +1-609-818-3804  
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the same 
procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
The causal relationship to study drug is determined by a physician and should be used to assess all adverse 
events (AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  


 
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Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding 
the specific occurrence of one or more AEs.) 
The Sponsor-Investigator will reconcile the clinical database AE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com).  
- 
The Investigator will request from BMS GPV&E, aepbusinessprocess@bms.com the SAE 
reconciliation report and include the BMS protocol number every 3 months and prior to data base 
lock or final data summary 
- 
GPV&E will send the investigator the report to verify and confirm all AE and SAEs have been 
transmitted to BMS GPV&E. 
- 
The data elements listed on the GPV&E reconciliation report will be used for case identification 
purposes. If the Investigator determines a case was not transmitted to BMS GPV&E, the case should 
be sent immediately to BMS (Worldwide.Safety@bms.com). 
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, suspected serious 
adverse reactions (whether expected or unexpected) shall be reported by BMS to the relevant competent 
health authorities in all concerned countries according to local regulations (either as expedited and/or in 
aggregate reports). 
In accordance with local regulations, BMS will notify sponsor investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously described in the IB). 
An event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Sponsor investigator notification of these events will be in the form of either a SUSAR Report or a Semi-
Annual SUSAR Report.  
 
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered associated 
with study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, 
animal) study, important safety recommendations from a study data monitoring committee, or 
sponsor or BMS decision to end or temporarily halt a clinical study for safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. 
Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor 
will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the 
informed consent requires revision. The investigator should also comply with the IRB/IEC 
procedures for reporting any other safety information. 
Although pregnancy and potential drug-induced liver injury (DILI), are not always serious by regulatory 
definition, however, these events must be reported within the SAEs timeline. 
Any component of a study endpoint that is considered related to study therapy should be reported as an 
SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported). 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and should be 
included in the protocol. 


 
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The following hospitalizations are not considered SAEs in BMS clinical studies:  
 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
 
elective surgery, planned prior to signing consent 
 
admissions as per protocol for a planned medical/surgical procedure 
 
routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
 
Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. Appropriate documentation is required in these cases. 
 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
 
Admission for administration of anticancer therapy in the absence of any other SAEs (applies to 
oncology protocols) 
 
The Investigator will perform adequate due diligence with regard to obtaining follow-up information on 
incomplete reports. All follow-up information must be sent to Exelixis and BMS within one (1) business 
day of the Investigator’s receipt of the new information. 
 
SAEs that must be recorded on an SAE Reporting form include the following: 
 
SAEs that occur after initiation of study therapy and through 100 days after the date of the 
decision to permanently discontinue study treatment 
 
SAEs assessed as related to study treatment or study procedures, even if the SAE occurs more 
than 100 days after the date of the decision to permanently discontinue study treatment. 


 
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In all cases, the Investigator should continue to monitor the clinical situation and report all material facts 
relating to the progression or outcome of the SAE. Furthermore, the Investigator may be required to 
provide supplementary information as requested by Exelixis and/or BMS. 
 
When reporting SAEs, the following additional points will be noted: 
 
When the diagnosis of an SAE is known or suspected, the Investigator will report the diagnosis 
or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and symptoms 
may then be described in the event description. 
 
Death will not be reported as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. Terms of “Unexplained Death” or “Death from unknown 
origin” may be used when the cause is unknown. In these circumstances the cause of death 
must be investigated, and the diagnosis amended when the etiology has been identified. If an 
autopsy was performed, the autopsy report should be provided. 
 
Regulatory Reporting 
The Investigator will assess the expectedness of each related SAE to the study treatment. 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. 
 
The Investigator is responsible for reporting relevant SAEs to the relevant regulatory authorities, and 
participating investigators, in accordance with FDA regulations (21 Code of Federal Regulations [CFR] 
312.32), ICH guidelines, European Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory 
requirements.  
 
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form)  
 
Exelixis Drug Safety group (or designee) will process and evaluate all SAEs as the reports are 
received. For each SAE received, Exelixis will make a determination as to whether the criteria for 
expedited reporting to relevant regulatory authorities have been met. Exelixis reserves the right 
to upgrade the Investigator assessment of an SAE based on Exelixis assessment. 


 
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 
Institutions and Investigators shall promptly provide all information requested by Exelixis 
regarding all adverse events occurring during the conduct of the study.  
 
The Investigator is responsible for complying with all regulatory authority reporting 
requirements for the study that are applicable to the Principal Investigator of a clinical trial.  
 
The Investigator 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 Principal Investigator to disseminate these 
updates to participating Investigators. 
 
Reporting of SAEs by the Investigator to his or her Institutional Review Board (IRB)/Ethics 
Committees (ECs) will be done in accordance with the standard operating procedures and 
policies of the IRB/EC. Adequate documentation must be maintained showing that the IRB/EC 
was properly notified. 
 
In the case of blinded studies, the treatment blind will be broken by the Principal Investigator 
and/or other necessary personnel prior to reporting an SAE that meets the criteria for 
expediting reporting to the Regulatory Authorities and to some central ECs. All personnel that 
are not involved in the unblinding and submission processes will remain blinded to the 
treatment assignment.  
 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) consist of immune-mediated AEs associated with ICIs, cases of 
potential DILI, and suspected transmission of an infectious agent by the study treatment. AECIs must be 
recorded as Adverse Events using the Events of Clinical Interest electronic case report form in REDCap’s 
clinical data management system (CTMS). 
 
AESIs will be reported to the Principal Investigator or designee using the SAE reporting form irrespective 
of whether the event is serious or nonserious; all AESIs must be reported within one (1) business day 
using the SAE process as described in Section 7.2.2.  
 
Guidance for management of immune-mediated AEs is provided in the protocol (Section 5.4.2 – 5.4.3) 
and can also be found in the local prescribing information for each IO agent. 


 
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Adverse Events of Special Interest  
Event 
Cases of potential DILI that include an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined by Hy's Law and based on the following observations: 
 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term applies only when a contamination of study treatment is 
suspected. 
Pneumonitis 
Colitis 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and hypophysitis 
Hepatitis, including AST or ALT > 10x ULN 
Systemic lupus erythematosus 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, and 
meningoencephalitis 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, influenza-like 
illness, systemic inflammatory response syndrome, and systemic immune activation 
Nephritis 
Ocular toxicities (e.g., uveitis, retinitis) 
Myositis 
Myopathies, including rhabdomyolysis 
≥ Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
Vasculitis 
 
General Information on Immune-Related Adverse Events 
The immune-modulating properties of IO agents are able to undermine immunologic tolerance and 
generate a subset of AEs (called irAEs) with an autoimmmune inflammatory pathomechanism. Immune-
related AEs may involve any organ or tissue23. Most irAEs occur within the first 12 weeks of exposure to 
IOs but some may appear with a delayed onset. Diagnosis of irAEs should be based on exposure to an IO 
and a reasonable immune-based mechanism of the observed AE. Whenever possible, histologic 
examination or other immune-based diagnostic evaluations should be used to support the diagnosis. 
Other etiologic causes including AEs from tumor progression should be ruled out.  
 


 
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The spectrum of irAEs is wide and can be general or organ-specific. Examples of general irAEs in subjects 
treated with IOs are fatigue, fever, and chills. Organ-specific irAEs consist of dermatitis (rash, pruritus, 
vitiligo, oral mucositis, and gingivitis), enterocolitis (diarrhea with abdominal pain and clinical or 
radiological evidence of colonic inflammation), and endocrinopathies (pituitary, thyroid, adrenal, testes). 
Diagnosis of endocrine dysfunction is challenging with relatively unspecific symptoms. The following 
additional laboratory testing of the endocrine axes may be helpful: prolactin (pituitary-hypothalamic 
function), FT4 and TSH (pituitary-thyroid function), luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH; pituitary-gonadal function), adrenocorticotropic hormone (ACTH) and cortisol (pituitary-
adrenal function). 
 
Additional organ-specific irAEs include hepatitis (AST/ALT increases, hepatomegaly, periportal edema, 
periportal lymphadenopathy, lymphocyte infiltration of periportal tissue and surrounding primary biliary 
ducts) and pneumonitis (acute interstitial pneumonia). Less frequent irAEs include neurologic 
syndromes (myasthenia gravis, Guillian-Barré syndrome, meningoencephalitis), ocular AEs (uveitis), 
renal AEs (interstitial nephritis), cardiac AEs (myocarditis), and pancreatic AEs (lipase increase).  
 
Follow-up of Adverse Events 
Nonserious AEs will be followed until 30 days after the date of the decision to discontinue study 
treatment. All SAEs and AESIs (regardless of seriousness) will be followed until 100 days after the date of 
decision to discontinue study treatment.  
 
All AESIs (regardless of seriousness) and all related SAEs that are ongoing 100 days after the date of the 
decision to discontinue study, and AEs assessed as related that led to study treatment discontinuation 
that are ongoing 100 days after the date of the decision to discontinue study treatment, are to be 
followed until either: 
 
The AE has resolved. 
 
The AE has improved to Grade 2 or lower. 
 
The investigator determines that the event has become stable or irreversible. 


 
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Other Safety Considerations 
 
Pregnancy/Lactation Exposure 
Use of highly effective methods of contraception is very important during the study and must continue 
for 4 months after the last dose of cabozantinib and 3 months after the last dose of ipilimumab and 5 
months after the last dose of nivolumab. 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 and the infant should 
have follow up for at least 6 months after birth. If a female partner of a male subject becomes pregnant 
during the study, the Investigator will ask the pregnant female to consent to be followed through the 
end of her pregnancy and for the infant to be followed for at least 6 months after birth. Furthermore, 
male subjects must refrain from donating sperm in order to avoid transmission of study treatment in 
semen for the duration of study treatment and through 5 months after their last dose of study 
treatment. Both male and female subjects should seek advice and consider fertility preservation before 
receiving study treatment. 
 
The Investigator must inform Exelixis/BMS of the pregnancy. 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/BMS. 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. 
 
Females should not breastfeed while receiving study treatment and for up to 4 months from the last 
dose of cabozantinib and up to 5 months from the last dose of ipilimumab or nivolumab.  
 
Medication Errors/Overdose 
Medication error is defined as the administration of each study drug medication outside or above the 
established dosing regimens per the specific protocol.  Any study medication overdose, misuse, abuse, 
or medication error (excluding missed doses) that results in an AE, even if it does not meet the definition 
of serious, requires reporting within one (1) business day to Exelixis and BMS. 
 
In case of overdose, the Principal Investigator should be contacted promptly to discuss how to proceed. 
Any AEs that occur as a result of an overdose have to be treated according to clinical standard practice. 


 
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Please refer to the cabozantinib Investigator Brochure for additional management recommendations 
regarding overdoses of cabozantinib. 
 
STATISTICAL CONSIDERATIONS 
Data and Statistical plan: 
Recent clinical trials have demonstrated median PFS as high as 5 months with the combination of low 
dose ipilimumab (1 mg/kg IV every 3 weeks) with anti-PD-1 therapies in patients with anti-PD1 
refractory cutaneous melanoma. In this clinical trial, we will use the 5 month mPFS as our benchmark. In 
order to show a 4 month improvement in mPFS over the 5 month historical data benchmark (with a 
power of 0.8 and a one-sided test given a type I error rate of 0.05), a total of 41 subjects would need to 
be enrolled.  
This signal seeking pilot study will enroll 25 subjects at our site (single institution) in less than 2 years. If 
we find that this treatment combination results in a mPFS of at least 8 months or an ORR of 45% or 
higher, we will review these results with BMS and Exelixis and propose protocol and budget 
amendments to add 1-2 additional sites to expedite to a total of at least 41 subjects to be enrolled in a 
rapid timeframe. 
Descriptive Statistics: 
Descriptive statistics will be provided for all baseline, efficacy, and safety variables, as appropriate. 
Frequency counts and percentages will be provided for categorical data. Mean (standard deviation), 
median (interquartile range) will be calculated for continuous variables.  
Statistical Analyses for Primary and Secondary Endpoints:  
Primary endpoint: The progression-free survival (PFS) analyses will be performed considering the risk of 
dying from any cause before experiencing progression related events using the competing risk 
regression method24 . Cumulative incidence functions will be displayed and summarized for the median 
time to progression as well as percentage of patients without disease progression at 12, 18, and 24 
months. 
 Secondary endpoints: ORR will be determined as the rate of the confirmed best overall response of 
either PR or CR per iRECIST. Using the efficacy evaluable analysis set, the Kaplan-Meier method will be 
used to estimate PFS, OS and DOR, and the summary statistics (e.g., 12-month survival and median 


 
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survival with 95% confidence intervals). DOR will be estimated only among responders (i.e. participants 
achieving at least once CR or PR). Data visualization tools such as waterfall plots (% change in tumor size) 
or swimmer plot (DOR) will be used to display the data.  
 
Using the safety evaluable analysis set, the incidence of having Grade ≥ 3 AEs will be determined for 
study participants that received at least one dose of their assigned treatment. The point estimate and 
95% confidence interval will be reported. 
For correlative molecular profiling endpoint, paired t-test or Wilcoxon signed-rank test will be 
performed to evaluate tumor infiltrating immune cell profiling and gene expression changes between 
pre- and post-treatment. 
 
 DATA QUALITY ASSURANCE 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case Report 
Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data analysis.  All 
study data will be entered into REDCap clinical data management system (CTMS) via eCRFs.  The Clinical 
Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study 
visit. 
 
The information collected on CRFs shall be identical to that appearing in original source documents.  
Source documents will be found in the patient’s electronic medical records.  All printed source 
documentation should be kept in separate research folders for each patient. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto CRFs.  The PI will approve all completed CRFs to attest 
that the information contained on the CRFs is true and accurate. 
 
All source documentation and CTMS data will be available for review/monitoring by the Regional 
Research Quality Assurance Department and regulatory agencies.  
 


 
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The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At study 
completion, when the CRFs have been declared to be complete and accurate, the database will be 
locked.   
 
ETHICAL ASPECTS 
 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” (GCP) ICH 
E6 Tripartite Guideline (January 1997) and remain consistent with the most recent version of the 
Declaration of Helsinki. 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.” 
 
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 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. 
 
The investigator or the study designated staff will ensure all participants are provided a consent form 
describing the study with sufficient information for each participant to make an informed decision 
regarding their participation.  Participants must sign the IRB-approved informed consent form prior to 
participation in any study specific procedures.  The participant must be offered/provided a copy of the 


 
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signed and dated consent document.  The original signed copy of the consent document must be 
retained in the research file. Please see 21CFR, Part 50 for additional guidance.   
 
 
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 and BMS(or designee) before subject enrollment and whenever subsequent 
modifications to the protocol are made. 
 
The protocol, the proposed informed consent form, and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed by the Providence Health & 
Services IRB.  The initial protocol and all protocol amendments must be approved by the IRB prior to 
implementation. 
 
 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications (including protocol amendments) may be made and will be prepared, reviewed, 
and approved by representatives of the Principal Investigator. Protocol modifications or amendments 
must be reviewed and approved by Exelixis and BMS 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 (e.g., change in monitor 
or change of telephone number). 
 
CONDITIONS FOR TERMINATING THE STUDY 
At any time, the study may be terminated by the Principal Investigator, the Principal Investigator’s 
institution, or by Exelixis or BMS. Should this be necessary, Exelixis, BMS  and the Principal Investigator 


 
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will arrange the procedures on an individual study basis after review and consultation. In terminating 
the study, Exelixis, BMS and the Principal Investigator will ensure that adequate consideration is given to 
the protection of the subjects’ interests. Upon study termination, the Principal Investigator and all 
Investigator(s) shall cease enrolling subjects into the study and shall discontinue conduct of the study as 
soon as is medically practicable. 
 
STUDY DOCUMENTATION AND RECORD-KEEPING 
 
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. 
 
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 and 
BMS. If the Investigator wants to assign the study records to another party or move them to another 
location, Exelixis and BMS must be notified in advance. 


 
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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. 
 
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), 
BMS or to health authority inspectors. The verification of the CRF data must be by direct inspection of 
source documents. 
 
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.  
 
Clinical data will be recorded on the study-specific electronic case report form (eCRF) in the REDCap 
clinical data management system (CTMS). For each subject enrolled, the CRF (paper or electronic) must 
be completed and signed by the PI or authorized delegate from the study staff. This also applies to 
records for those subjects who fail to complete the study. If a subject stops dosing or terminates from 
the study, the dates and reasons must be noted. 
 
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.  
 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data in the 
CRFs and in all required reports. 


 
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MONITORING THE STUDY 
Oversight and Monitoring Plan 
Oversight of patient safety will include review of adverse events as well as study progress and 
outcomes.  Patient updates, outcomes, and recruitment and retention of patients will be reviewed on a 
regular basis by the PI, research nurse, and data coordinator.  Deviations will be reviewed during 
oversight meetings and/or through internal reporting procedures.  Aggregate protocol deviations are 
monitored for trends to be reviewed by the Providence Cancer Institute Clinic and Research Quality 
Committee. In addition, a “first patient review” is conducted and documented for all clinical trials.  This 
review includes treatment administration, deviations, and SAEs to ensure any compliance and/or safety 
issues are addressed prior to the enrollment of additional patients. 
Study monitoring activities (Quality Control Reviews) are performed by clinical research staff members 
who have completed specialized training in study monitoring procedures and human subjects’ 
protections.  Individuals who perform study monitoring activities do not report to Principal Investigators 
or research scientists and may not monitor studies for which they have direct responsibility.  Results of 
study monitoring activities will be reported to applicable study personnel, Clinical Trials Management 
and Quality Assurance.  Study monitoring activities are conducted regularly and include (but are not 
limited to) review and verification of the following:  
 
 
Eligibility 
 
Informed Consent process 
 
Adherence to protocol treatment plan 
 
Case Report Forms (CRFs) 
 
Source Documentation 
 
Adverse Events 
 
Regulatory  
Quality Assurance  
Quality Assurance (QA) personnel will perform monitoring activities on a routine basis following the 
monitoring plan. If necessary, QA will determine follow-up actions to resolve significant findings. QA has 
the authority to request immediate corrective action if significant patient safety issues are identified.  QA 
will track and trend results from routine monitoring activities as well as associated corrective and 
preventive actions. If necessary, a QA summary report will be provided to the IRB at the time of 
continuing review. QA personnel do not have a direct reporting relationship to the principal investigator 
and are not responsible for enrollment or coordination of care for study participants. 
 
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 


 
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showing codes, names, and addresses. The Investigator should maintain documents (e.g., subjects’ 
written consent forms) in strict confidence. 
 
 
PUBLICATIONS OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator holds the primary responsibility for publication of the study results; provided 
that the Principal Investigator will provide Exelixis and BMS 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 
Principal Investigator’s institution (e.g., institution name.) and Exelixis and BMS, Inc. in the Clinical Trial 
Agreement related to this study.  


 
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REFERENCES 
1. 
Zhang, Z., et al. T Cell Dysfunction and Exhaustion in Cancer. Front Cell Dev Biol 8, 17 (2020). 
2. 
Larkin, J., et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced 
Melanoma. N Engl J Med 381, 1535-1546 (2019). 
3. 
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Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin 
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APPENDICES 
Appendix A 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Principal Investigator. The guidance applies to all immuno-oncology agents and 
regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to standard 
medical practice. Non-inflammatory etiologies should be considered and appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
For recommendations on dose modifications of BOTH cabozantinib and IO treatment due to 
hepatocellular toxicity, see Section 5.4.3. 


 
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Infusion-related Reactions 
 
Infusion-related reactions (IRRs) are known to occur with the administration of monoclonal antibodies 
and have been reported with IO therapies. These reactions, which are thought to be due to release of 
cytokines and/or other chemical mediators, occur within 24 h of administration and are generally mild 
to moderate in severity. 
 
Infusion reactions may manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, back pain, or other allergic-like reactions. Regardless of 
whether the event is attributed to these study drugs, all Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the Principal Investigator and reported as an SAE if it meets the criteria.  
 
Subjects who experience an IRR with IO therapy may receive premedication with antihistamines, 
antipyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
 
High-level treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
Management of Infusion Reactions 
Event 
Management 
Grade 1 
 
Consider reducing the infusion rate. 
 
Monitor vital signs as clinically indicated. 
 
Consider premedication prior to the next infusion. 
Grade 2 
 
Interrupt infusion. 
 
Provide supportive therapy. 
 
Monitor vital signs as clinically indicated. 
 
Restart infusion at a lower rate if symptoms resolve. 
 
Premedicate prior to the next infusion. 
Grade 3- 4 
 
Interrupt infusion and permanently discontinue IO therapy. 
 
Provide supportive therapy. 
 
Monitor vital signs as clinically indicated. 
 
Hospitalize as indicated for clinical sequelae. 
 
 
 
Cytokine Release Syndrome (CRS) 


 
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Cytokine-release syndrome (CRS) is defined as a supraphysiologic response following administration of 
any immune therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the onset, and may 
include hypotension, capillary leak (hypoxia), and end-organ dysfunction25. CRS has been well 
documented with chimeric antigen receptor T cell therapies and bispecific T-cell engager antibody 
therapies but has also been reported with immunotherapies that target PD-1 or PD-L126,27. 
 
Subjects who experience a CRS with IO therapy may receive premedication with antihistamines, 
antipyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  


 
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Event 
Management 
Grade 1a 
Feverb with or without 
constitutional symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate may 
be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatmentc, including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS (> 2 days) or in subjects with significant 
symptoms and/or comorbidities, consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral premedication with 
antihistamines, antipyretics, and/or analgesics, and monitor closely for IRRs and/or 
CRS. 
Grade 2a 
Feverb with hypotension not 
requiring vasopressors 
and/or 
Hypoxia requiring low-flow 
oxygend by nasal cannula or 
blow-by 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms 
of HLH or MAS. 
 Consider IV corticosteroids (suggest: methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Consider hospitalization until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 3, i.e., hospitalize subject (monitoring in the 
ICU is recommended), permanently discontinue IO agent, and contact the Principal 
Investigator. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of 
IO agent may be administered. For subsequent infusions, consider administration 
of oral premedication with antihistamines, antipyretics, and/or analgesics and 
monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact the 
Principal Investigator. 


 
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Grade 3a 
Feverb with hypotension 
requiring a vasopressor (with 
or without vasopressin) 
and/or 
Hypoxia requiring high-flow 
oxygend by nasal cannula, 
face mask, non-rebreather 
mask, or venturi mask 
 Permanently discontinue IO agent and contact the Principal Investigator. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus and vasopressor as needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring in the ICU 
is recommended. Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms 
of HLH or MAS. 
 Administer IV corticosteroids (suggest: methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Hospitalize subject until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 4, i.e., admit subject to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for subjects who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator 
and in consultation with the Principal Investigator. 
Grade 4a 
Feverb with hypotension 
requiring multiple 
vasopressors (excluding 
vasopressin) and/or 
Hypoxia requiring oxygen by 
positive pressure (e.g., CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
 Permanently discontinue IO agent and contact the Principal Investigator. 
 Administer symptomatic treatment.c 
 Admit subject to ICU and initiate hemodynamic monitoring, mechanical ventilation, 
and/or IV fluids and vasopressors as needed. Monitor other organ function closely. 
Manage constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms 
of HLH or MAS. 
 Administer IV corticosteroids (suggest: methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapye. For subjects who are refractory to anticytokine 
therapy, experimental treatmentsf may be considered at the discretion of the 
investigator and in consultation with the Principal Investigator. 
 Hospitalize subject until complete resolution of symptoms. 
ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bi-level positive airway pressure; CAR, chimeric antigen 
receptor; CPAP, continuous positive airway pressure; CRS, cytokine-release syndrome; CTCAE, Common Terminology Criteria for 
Adverse Events; eCRF, electronic Case Report Form; HLH, hemophagocytic lymphohistiocytosis; ICU, intensive care unit; IRR, infusion-
related reaction; MAS , macrophage activation syndrome; NCCN, National Cancer Comprehensive Network; NCI, National Cancer 
Institute. 
Note: The management guidelines have been adapted from NCCN guidelines for management of CAR T-cell-related toxicities 
(Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI CTCAE (version as specified in the 
protocol) should be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. 
Organ toxicities associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature > 38°C not attributable to any other cause. In subjects who develop CRS and then receive 
antipyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when subsequently determining event severity 
(grade). In this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretics, analgesics, bronchodilators, and/or oxygen. For 
bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional practice. 


 
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d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at > 6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune checkpoint inhibitors26,27 
but data are limited, and the role of such treatment in the setting of antibody-associated CRS has not been established. 
f Refer to Riegler et al (2019) for information on experimental treatments for CRS28. 
 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).  
Subjects with suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2014). A subject should be classified as having HLH if five of the following eight criteria are 
met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
o Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
o Platelet count  100  109/L (100,000/L) 
o ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L (150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 
Subjects with suspected MAS should be diagnosed according to published criteria for systemic juvenile 
idiopathic arthritis by Ravelli et al (2016). A febrile patient should be classified as having MAS if the 
following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
o Platelet count  181  109/L (181,000/L) 
o AST  48 U/L 
o Triglycerides  1.761 mmol/L (156 mg/dL) 


 
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o Fibrinogen  3.6 g/L (360 mg/dL) 
Patients with suspected HLH or MAS should be treated according to the guidelines the table below. 
Management Guidelines for Suspected HLH or MAS 
Event 
Management 
Suspected HLH or 
MAS 
 
Permanently discontinue IO therapy and contact Principal Investigator. 
 
Consider patient referral to hematologist. 
 
Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
 
Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B 


 
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FACT-M Non-Surgery (Version 4) Quality of Life Questionnaire 
 
 
 
 


 
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