Phase I/II Study of Nivolumab and Axitinib in Patients With Advanced Renal Cell Carcinoma
Phase: PHASE1
Conditions: Renal Cell Carcinoma
Sponsor: Fox Chase Cancer Center

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IST-GU-102 Phase I/II study of nivolumab and axitinib in patients with advanced renal 
cell carcinoma 
 
 
Supported by (Bristol-Myers Squibb) 
 
 
Sponsor Investigator:   
 
 
 
 
 
 
 
Co-Investigators:  
 
 
 
 
 
 
 
Sub-Investigators:            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matthew Zibelman, MD 
Fox Chase Cancer Center  
333 Cottman Avenue 
Philadelphia PA 19111 
Phone: 215-728-3889 
Fax: 215-728-3639 
Email: Matthew.Zibelman@fccc.edu  
 
 
 
Elizabeth R. Plimack, MD, MS 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-3889 
Fax: 215-728-3639 
Email: Elizabeth.Plimack@fccc.edu 
Daniel M. Geynisman, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-3889 
Fax: 215-728-3639 
Email: Daniel.Geynisman@fccc.edu 
Pooja Ghatalia, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-3889 
Fax: 215-728-3639 
Email: Pooja.Ghatalia@tuhs.temple.edu 

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Statistician:  
 
 
 
 
 
 
 
 
 
 
 
 
Initial Version Date:   02/27/2017 
New Version Date: 11/09/2017 
Amendment 2: 12/04/2017 
Amendment 3: 03/21/2018 
Amendment 4: 01/08/2019 
Amendment 5: 06/14/2019 
 
Karthik Devarajan  
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-2794 
Fax: 215-728-2553 
Email: Karthik.Devarajan@fccc.edu 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population  
Phase I (3+3 design)- 6-12 patients exposed to at least 1 
prior TKI therapy 
Phase II- 2 parallel arms with 43 patients each.  
Arm 1: 43 treatment naïve patients  
Arm 2: 43 patients exposed to at least 1 prior TKI therapy 
Phase I DLT Assessment 
Cycle 1 and 2 
Phase II Disease Assessment 
Radiological tumor assessments conducted at baseline, after 8 
weeks of combination and every 3 cycles thereafter 
 
Continue treatment until: 
• Disease progression 
• Unacceptable toxicity 
• Patient withdraw of consent 
• Patient lost to follow up 
• Study is terminated by the Sponsor 
• Completion of therapy after 24 months 
Follow up 
• Every 3 months for the first 2 years, then every 6 months for 2 years, 
and then annually for survival.  
• Subjects who discontinue treatment for reasons other than disease 
progression should continue to have radiographic assessments of 
disease at least every 12 weeks until documented disease progression. 
Treatment (28 days per cycle): 
Phase I- Axitinib given initially at a dose of 3 mg PO BID for 1 
week starting on day -7 (+3 days) in the Lead-In phase, followed by 
Axitinib 3 mg PO BID + Nivolumab given as 30 min IV at 480 mg 
every 4 weeks for up to 2 years or until disease progression.  Dose 
escalation/de-escalation of Axitinib based on toxicity assessment by 
pre-specified DLT rules, which will determine Phase II dosing 
 

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Table of Contents 
Schema 
3 
1.0 
Introduction 
7 
1.1. 
Study Disease 
7 
1.2. 
Nivolumab 
7 
1.2.1. 
Mechanism of Action 
7 
1.2.2. 
Effects in Human 
8 
1.2.3. 
Rationale for using nivolumab flat dose of 480 mg in this study 
10 
1.3. 
Axitinib (Inlyta) 
10 
1.3.1. 
Mechanism of Action 
10 
1.3.2. 
Pharmacokinetics 
11 
1.3.3. 
Clinical Activity 
11 
1.4. 
Rationale for studying Axitinib and Nivolumab combination in RCC patients 
13 
1.5. 
Correlative Testing 
13 
2.0 
Objectives 
14 
2.1. 
Primary Objective 
14 
2.2. 
Secondary Objectives 
14 
3.0 
Study Plan 
14 
3.1. 
Description of Study Design, Population and Duration of Study Therapy 
14 
3.1.1. 
Phase I 
15 
3.1.2. 
Phase II 
18 
4.0 
Patient Selection Inclusion & Exclusion 
19 
4.1. 
Inclusion Criteria 
19 
4.2. 
Exclusion Criteria 
20 
4.3. 
Inclusion of Women and Minorities 
22 
4.4. 
Pregnancy 
22 
4.5. 
Patient Registration 
23 
5.0 
Treatment Plan 
23 
5.1. 
Treatment Regimen 
24 
5.2. 
Nivolumab Administration 
24 
5.2.1. 
Preparation and Administration 
25 
5.3. 
Axitinib Administration 
25 
5.4. 
Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions 
25 
5.4.1. 
Permitted Medications 
26 
5.4.2. 
Prohibited Medications 
26 
5.5. 
Duration of Therapy 
27 
5.6. 
Treatment beyond Progression 
28 

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5.7. 
Duration of Follow up 
29 
6.0 
Dose Modifications 
29 
6.1. 
Dose Level Adjustment Table(s) 
29 
6.2. 
Axitinib Dose Modifications 
29 
6.2.1. 
Axitinib Intra-Patient dose increase: 
29 
6.2.2. 
Axitinib dose modifications due to toxicity: 
29 
6.3. 
Nivolumab Dose Modifications 
32 
6.3.1. 
Dose Delay Criteria 
32 
6.3.2. 
Criteria to Resume Treatment 
33 
6.3.3. 
Criteria for Discontinuation 
33 
6.3.4. 
Recommended Dose Modification for Nivolumab 
35 
7.0 
Study Agent Information 
36 
7.1. 
Nivolumab 
36 
7.1.1. 
Product description 
36 
7.1.2. 
Availability 
37 
7.1.3. 
Recommended prepared drug storage and use condition 
37 
7.2. 
Axitinib 
37 
7.2.1. 
Product description 
37 
7.2.2. 
Availability 
38 
7.2.3. 
Storage requirements 
38 
7.3. 
Drug Ordering, Storage and Handling 
38 
7.4. 
Destruction of Drug 
38 
7.5. 
Records to be kept at Site; Dispensing and Accountability 
38 
8.0 
Correlative /Special Studies 
38 
8.1. 
Biopsy Specimen Analysis 
39 
8.1.1. 
Outcome measure 
39 
8.1.2. 
Assessment, method of assessment, timing of assessment 
39 
8.1.3. 
Site(s) performing correlative study 
39 
8.2. 
Biomarker Analysis 
39 
8.2.1. 
Outcome measure 
39 
8.2.2. 
Assessment, method of assessment, timing of assessment 
39 
8.2.3. 
Site(s) performing correlative study 
39 
9.0 
Study Calendar 
40 
10.0 
Adverse Events 
42 
10.1. 
Adverse Event Definition 
42 
10.2. 
Serious Adverse Event (SAE) 
42 
10.3. 
Severity Rating 
43 
10.4. 
Attribution/Relationship to study drug 
43 
10.5. 
Expectedness 
43 
10.6. 
Recording and Reporting Responsibilities 
44 
10.6.1. 
Investigative Site Recording Responsibilities: 
44 

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10.6.2. 
Investigative Site Reporting Responsibilities: 
44 
10.6.3. 
OCR Reporting Responsibilities: 
45 
10.7. 
OCR Reporting Responsibilities to BMS: 
46 
10.8. 
Pregnancy 
47 
11.0 
Measures of Effect 
47 
11.1. 
Response Evaluation Criteria in Solid Tumors (RECIST) 
47 
11.2. 
Definitions 
47 
11.3. 
Disease Parameters 
48 
11.4. 
Methods for Evaluation of Measurable Disease 
49 
11.5. 
Response Criteria 
50 
11.5.1. 
Evaluation of Target Lesions 
50 
11.5.2. 
Evaluation of Non-Target Lesions 
50 
11.6. 
Objective response rate (ORR) 
52 
11.7. 
Progression-Free Survival (PFS) 
52 
12.0 
Statistical Considerations 
52 
12.1. 
Analysis of Secondary Endpoints 
53 
12.2. 
Sample Size/Accrual Rate 
53 
12.3. 
Reporting and Exclusions 
53 
12.3.1. 
Evaluation of toxicity: 
53 
12.3.2. 
Evaluation of response: 
53 
13.0 
Data and Safety Monitoring Plan 
53 
13.1. 
Monitoring Plan 
53 
13.2. 
Data Safety Monitoring Committee 
54 
14.0 
Administrative 
54 
14.1. 
Data Reporting 
54 
14.2. 
Retention of Records 
54 
14.3. 
Study Agents 
55 
14.4. 
Informed Consent 
55 
15.0 References 
56 
15.0 
Appendix 
57 
15.1. 
Appendix I 
57 
15.2. 
Appendix II 
58 
15.3. 
Appendix III 
67 
 
 
 
 

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1.0 Introduction  
1.1. Study Disease 
Advanced renal cell carcinoma (RCC) is an incurable disease accounting for more 
than 10,000 new cases of metastatic disease diagnosed annually in the United States 
and nearly 14,000 deaths.[1]  Prior to 2005, treatment options for this disease were 
limited, but subsequently eight new drugs have received United States Food and Drug 
Administration approval for systemic treatment.  The mainstay of treatment has 
proven to be oral tyrosine kinase inhibitors targeting the vascular endothelial growth 
factor (VEGF) and capitalizing on the inherent biology and reliance on angiogenesis 
for tumor growth and proliferation.  Three oral TKIs targeting VEGF (sunitinib, 
pazopanib, and axitinib) have emerged as the primary options for most patients in the 
primary and second line of therapy.  These drugs are relatively well tolerated and lead 
to objective response rates ranging from 25-48% across trials, however most patients 
ultimately develop drug resistance within a year on treatment, and second line options 
are characterized by diminishing clinical returns.[2]  More durable disease control is 
desired. 
 
 
The programmed death 1 (PD-1) inhibitor nivolumab was approved for use by the 
USFDA in November 2015 for patients with TKI refractory metastatic RCC.  This 
drug is among the new class of immunotherapy drugs that block immune checkpoints 
to unleash an innate T-cell driven anti-tumor response.  Nivolumab improved overall 
survival compared to the mammalian target of rapamycin inhibitor everolimus for 
patients with advanced RCC who had progressed on a prior TKI.  Notably, though the 
overall response rate was 25% with nivolumab, nearly half of the patients who 
responded demonstrated prolonged or ongoing responses, which has been the 
hallmark of these agents.[3]  Additionally, toxicities related to nivolumab, though 
somewhat unique compared to other classes of agents, were generally manageable. 
 
1.2. Nivolumab  
 
1.2.1. Mechanism of Action 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody 
(HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its 
interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of 
T-cell activity that has been shown to be involved in the control of T-cell immune 
responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are 
expressed on antigen presenting cells and may be expressed by tumors or other 
cells in the tumor microenvironment, results in inhibition of T-cell proliferation 
and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-
tumor responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. 
In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumor 
growth. 
 

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1.2.2. Effects in Human 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been 
assessed in approximately 70 clinical studies sponsored by BMS, ONO, or other 
partners. Across those studies, approximately 12,300 subjects have received 
nivolumab monotherapy in single- or multiple-dose Phase 1/2/3 studies or studies 
with nivolumab in combination with other therapeutics (ipilimumab, cytotoxic 
chemotherapy, anti-angiogenics, and targeted therapies). 
 
Pharmacokinetics 
 
The PK of single-agent nivolumab was studied in patients over a dose range of 
0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
every 2 or 3 weeks. The geometric mean (% coefficient of variation [CV%]) 
clearance (CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at 
steady state (Vss) is 8.0 L (30.4%), and geometric mean elimination half-life 
(t1/2) is 26.7 days (101%). Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic 
accumulation was approximately 3-fold. The exposure to nivolumab increased 
dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 
weeks. 
 
Safety 
 
All available data suggest that nivolumab monotherapy has a consistent AE 
profile across tumor types. The safety profile is generally consistent across 
completed and ongoing clinical trials, with no maximum tolerated dose (MTD) 
reached at any monotherapy dose tested up to 10 mg/kg. There was no pattern in 
the incidence, severity, or causality of AEs to nivolumab dose level. Most AEs 
were low-grade (Grade 1-2) with relatively few drug-related high-grade (Grade 3-
4) AEs. The safety profile of nivolumab combination therapy varies with the 
agent combined with nivolumab, but is generally consistent with the safety 
profiles observed with either agent alone and, in some cases, both frequency and 
severity of AEs were greater than that observed with either agent alone. 
 
Across all studies conducted to date, drug-related AEs have included pulmonary 
toxicity, renal toxicity (including acute renal failure), endocrine abnormalities, GI 
toxicity, dermatologic toxicity (including rash), and hepatotoxicity. For 
nivolumab monotherapy and combination therapy, the majority of these AEs have 
been managed successfully with supportive care and, in more severe cases, a 
combination of dose delay, permanent discontinuation, and/or use of 
corticosteroids or hormone replacement therapy 
 
Clinical Activity 
 

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Nivolumab has demonstrated clinical activity in NSCLC, melanoma, RCC, and 
cHL (approved indications) and other tumor types as monotherapy or in 
combination with ipilimumab. The majority of responses were durable and 
exceeded 6 months. In randomized, controlled studies, nivolumab monotherapy 
demonstrated statistically significant improvement in OS over standard of care in 
subjects with advanced or metastatic melanoma, in subjects with advanced or 
metastatic NSCLC, and in subjects with advanced RCC[3-5] 
 
Efficacy in patients with Renal Cell carcinoma 
 
Nivolumab monotherapy has demonstrated clinical benefit in subjects with 
advanced RCC, and has been approved for use in this population in the US, EU, 
and other countries. 
 
Trial 6 was a randomized (1:1), open-label study in patients with advanced RCC 
who had experienced disease progression during or after one or two prior anti-
angiogenic therapy regimens. Patients had to have a Karnofsky Performance 
Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. 
Trial 6 excluded patients with any history of or concurrent brain metastases, prior 
treatment with an mTOR inhibitor, active autoimmune disease, or medical 
conditions requiring systemic immunosuppression. Patients were stratified by 
region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the 
number of prior anti-angiogenic therapies 
 
Patients were randomized to nivolumab (n=410) administered intravenously at 3 
mg/kg every 2 weeks or everolimus (n=411) administered orally 10 mg daily. The 
median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% 
≥75 years of age. The majority of patients were male (75%) and white (88%) and 
34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, 
respectively. The majority of patients (77%) were treated with one prior anti-
angiogenic therapy. Patient distribution by MSKCC risk groups was 34% 
favorable, 47% intermediate, and 19% poor. 
 
 
The major efficacy outcome measure was overall survival (OS). The trial 
demonstrated a statistically significant improvement in OS for patients 
randomized to nivolumab as compared with everolimus at the prespecified interim 
analysis when 398 events were observed (70% of the planned number of events 
for final analysis).OS benefit was observed regardless of PD-L1 expression level. 
Nivolumab treated patients achieved an objective response rate (ORR) of 21.5%, 
compared to only 3.9% with everolimus.  In patients who responded to 
nivolumab, the median duration of response was nearly 2 years (23 months), 
significantly longer than the 13.7 months from the everolimus group.   
 

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1.2.3. Rationale for using nivolumab flat dose of 480 mg in this study 
Nivolumab monotherapy has been extensively studied in a number of tumor types 
including NSCLC, melanoma, RCC, among others with body weight normalized 
dosing (mg/kg). Nivolumab PK and exposures of subjects have been 
characterized by population pharmacokinetic (PPK) analysis of data collected 
from these studies, together with PK data from several phase I, II, and III clinical 
studies of nivolumab monotherapy in solid tumors. PPK analyses have shown that 
the PK of nivolumab are linear, with dose proportional exposures over a dose 
range of 0.1 mg/kg to 10 mg/kg, and are similar across tumor types. Nivolumab 
clearance and volume of distribution were found to increase with increasing body 
weight, but the increase was less than proportional, indicating that mg/kg dose 
represents an over-adjustment for the effect of body weight on nivolumab PK. 
Given the relationship between nivolumab PK and body weight, a flat dose is 
expected to lead to lower exposures in heavier patients, relative to the exposures 
in lighter patients.  The initial approval of nivolumab was weight based at a dose 
of 3 mg/kg.  However, taken together, the PK, safety, and efficacy data indicated 
that 240 mg nivolumab would provide  similar outcomes to that of 3 mg/kg 
nivolumab and thus  a flat dose of 240 mg every 2 weeks was approved by the 
USFDA and initially recommended for investigation in this study 
 
Since study initiation, further data has provided updated dosing and schedule 
approval for nivolumab.  As presented at the 2017 AACR Annual Meeting, 
assessments of safety acrros trials of various tumor types, along with quantitative 
clinical pharmacology analyses, revealed that a regimen of 480 mg administered 
every 4 weeeks would  have a <1% difference in the predicted chance of 
response.[6]  This led to the approval of this dose and schedule across multiple 
tumor types, including RCC, and was approved by the USFDA on March 6, 2018. 
 
   
 
Please refer to Nivolumab Investigator’s Brochure for detailed information on 
Nivolumab 
 
1.3. Axitinib (Inlyta) 
1.3.1. Mechanism of Action 
Axitinib is an orally bioavailable, small molecule tyrosine kinase inhibitor (TKI) 
that is approved for the treatment of patients with advanced renal cell carcinoma 
after failure of at least one prior TKI.  It functions as a second generation TKI that 
impairs angiogenesis and subsequent tumor growth via inhibition of several 
vascular endothelial growth factor receptors (VEGFR) present on the endothelial 
cell, namely VEGFR 1, 2, and 3.  More specifically, axitinib binds to the non-
activated catalytic domain of the receptor and competitively inhibits adenosine 

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triphosphate.  Preclinical cell-based receptor-binding assays have confirmed that 
axitinib is a potent and selective inhibitor of all three mentioned VEGFRs. 
 
1.3.2. Pharmacokinetics 
The population pharmacokinetic analysis pooled data from 17 trials in healthy 
subjects and patients with cancer. A two-compartment disposition model with 
first-order absorption and lag-time adequately describes the axitinib 
concentration-time profile.  
 
Absorption and Distribution: Following single oral 5-mg dose administration, the 
median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady 
state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice 
daily resulted in approximately 1.4-fold accumulation compared to administration 
of a single dose. At steady state, axitinib exhibits approximately linear 
pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute 
bioavailability of axitinib after an oral 5 mg dose is 58%.  
 
Compared to overnight fasting, administration of axitinib with a moderate fat 
meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 
19% higher AUC. Axitinib can be administered with or without food. 
 
Axitinib is highly bound (>99%) to human plasma proteins with preferential 
binding to albumin and moderate binding to α1-acid glycoprotein. In patients with 
advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric 
mean (CV%) Cmax and AUC0-24 were 27.8 (79%) ng/mL and 265 (77%) 
ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent 
volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.  
 
Metabolism and Elimination: The plasma half-life of axitinib ranges from 2.5 to 
6.1 hours. Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a 
lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral 
administration of a 5-mg radioactive dose of axitinib, approximately 41% of the 
radioactivity was recovered in feces and approximately 23% was recovered in 
urine. Unchanged axitinib, accounting for 12% of the dose, was the major 
component identified in feces. Unchanged axitinib was not detected in urine; the 
carboxylic acid and sulfoxide metabolites accounted for the majority of 
radioactivity in urine. In plasma, the N-glucuronide metabolite represented the 
predominant radioactive component (50% of circulating radioactivity) and 
unchanged axitinib and the sulfoxide metabolite each accounted for 
approximately 20% of the circulating radioactivity. 
 
1.3.3. Clinical Activity 
Axitinib was assessed in a randomized, open-label, multi-center phase III trial of 
patients with advanced RCC (99% clear cell) whose disease had progressed on or 
after treatment with 1 prior systemic therapy.  Patients were randomized to 

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receive axitinib (N=361) or sorafenib (N=362).  Results revealed a statistically 
significant advantage for axitinib over sorafenib for the primary PFS endpoint, 6.7 
(95% CI: 6.3, 8.6) vs 4.7 (95% CI: 4.6, 5.6) months, respectively (p <0.0001).  
However, there was no statistically significant difference between the treatment 
arms in the secondary overall survival (OS) endpoint, 20.1 (95% CI: 16.7, 23.4) 
vs 19.2 (95% CI: 17.5, 22.3) for axitinib and sorafanib, respectively.  The ORR 
was reported as 19.4% (95% CI: 15.4, 23.9) for axitinib and 9.4% (95% CI: 6.6, 
12.9) for sorafenib. [4]  
   
In a separate phase III randomized trial, axitinib was also compared to sorafenib 
in the treatment naïve setting.  It has not been compared to sunitinib or pazopanib 
in this setting in a prospective, randomized trial.  In this study, patients were 
randomized (2:1) to receive axitinib (N=192) or sorafenib (N=96). In regards to 
the primary endpoint of median PFS, there was no significant difference between 
patients treated with axitinib or sorafenib (10.1 months vs 6.5 months, 
respectively), with stratified hazard ratio of 0.77, (95% CI 0.56, 1.05). [5]   
The safety of axitinib has been evaluated in 715 patients in monotherapy studies, 
which included 537 patients with advanced RCC. The data described below 
reflect exposure to axitinib in 359 patients with advanced RCC who participated 
in a randomized clinical study versus sorafenib.  
 
The most common (≥20%) adverse reactions observed following treatment with 
axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, 
dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight 
decreased, vomiting, asthenia, and constipation. 
 
Adverse Reactions Occurring in ≥10% of Patients who received axitinib were 
diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-
plantar erythrodysesthesia syndrome, weight decreased, vomiting, asthenia, 
constipation, hypothyroidism, cough, mucosal inflammation, arthralgia, 
stomatitis, dyspnea, abdominal pain, headache, pain in extremity, rash, 
proteinuria, dysgeusia, dry skin, dyspepsia.  
 
Selected adverse reactions (all grades) that were reported in <10% of patients 
treated with axitinib included dizziness (9%), upper abdominal pain (8%), 
myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), 
hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), 
rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-
vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack 
(1%), and RPLS (<1%) 
 
Please refer to Axitinib package insert for detailed information on Axitinib 
 

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1.4. Rationale for studying Axitinib and Nivolumab combination in RCC 
patients 
In order to improve response rates and prolong disease control for patients with 
advanced renal cell carcinoma, new agents or strategies or needed.  Checkpoint 
blockade remains promising, but the overall response rate must be improved to 
benefit a larger proportion of patients.  Combination strategies offer the potential to 
increase response rates while still maintaining the durability of response associated 
with checkpoint blockade.  Given the established efficacy and tolerability in RCC, 
pairing nivolumab with an oral VEGF TKI is a logical next step.  A prior phase I, 
multi-arm study combined nivolumab with sunitinib or pazopanib in patients with 
advanced disease.[7]  However, enhanced toxicity, namely elevations in liver 
transaminases, limited the clinical utility of these combinations.  Axitinib, a TKI 
targeting VEGF and known to cause less hepatotoxicity as a single agent, may be a 
better partner.  Reported results from the dose-finding portion of a phase Ib study 
combining axitinib with the PD-1 inhibitor pembrolizumab show the combination to 
be better tolerated, with only 2/11 patients experiencing grade 3 elevations in liver 
enzymes, neither of which needed to discontinue treatment for this reason.[8] 
Updated safety and efficacy results were published in 2018, revealing an ORR of 
73%, with no signal of increased toxicity than would be expected with either drug 
alone.[9] Combining axitinib with nivolumab thus warrants clinical evaluation.   
 
We propose a phase I/II trial of this combination first to test the safety of the 
combination, and then to explore efficacy in two RCC populations: patients who are 
treatment naïve (first line) and patients who have progressed after treatment with one 
or two prior treatments (second/third line).  The initial phase I portion would include 
a small cohort of patients who have progressed on prior therapy in order to establish 
safety and determine a recommended phase II dose (RP2D).  Once the RP2D is 
established, two parallel dose expansion arms including previously treated and 
treatment naïve patients, respectively, will be accrued simultaneously at the RP2D to 
get more robust safety data and secondarily explore efficacy in two homogenous 
populations. 
 
1.5. Correlative Testing 
1. Tumor biopsy assessment and translational studies:  Archival tissue from 
primary or metastatic lesions will be collected for retrospective assessment.  
Biomarker studies on tumor biospecimens including but not limited to tumor PD-
L1 expression and assessments of tumor infiltrating lymphocytes will be carried 
out to interrogate for potential biomarkers and assess for potential mechanisms of 
sensitivity and resistance. Such results may help in the future development of this 
combination and appropriate selection of patients.   
 
2. Biomarkers analysis: Blood will be collected during screening, once on 
treatment, and at the conclusion of study for various exploratory biomarker 
assessments and blood levels of various markers and cytokines to assess effects of 
this combination and interrogate potential biomarkers of response.     

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2.0 Objectives 
 
2.1. Primary Objective 
 Phase I: To determine the safety and tolerability of the combination of 
axitinib and nivolumab in order to establish a recommended phase II dose 
(RP2D) 
 Phase II: Assess the overall response rate of the combination in two separate 
cohorts of patients with treatment naïve and previously treated advanced 
RCC 
 
2.2. Secondary Objectives  
1. To evaluate the overall safety profile of the combination of axitinib and 
nivolumab 
2. To assess the median progression free survival (PFS) and median overall 
survival (OS) of axitinib in combination with nivolumab in patients with 
advanced RCC 
3. To explore sensitivity and resistance mechanisms to axitinib in combination 
with nivolumab in tumor and blood specimens 
4. To explore the pharmacodynamic effect of axitinib in combination with 
nivolumab  
 
3.0 Study Plan  
3.1. Description of Study Design, Population and Duration of Study Therapy  
This is a Phase I/II, open-label, multi-center study of axitinib in combination with 
nivolumab in patients with previously treated and untreated advanced RCC. This 
clinical study will be composed of a dose finding phase (Phase I) and two parallel 
dose expansion phases (Phase II).  The dose finding phase will assess the safety of the 
combination and establish a recommended phase II dose (RP2D, the highest tested 
dose that is declared safe and tolerable by the Investigators and the Sponsor 
Investigator) in patients with advanced RCC who have received prior systemic 
therapy for metastatic disease.  Phase II will evaluate the efficacy of the combination 
at the RP2D in two parallel expansion cohorts in both previously treated and 
treatment naïve patients.  
 

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3.1.1. Phase I 
Phase I will be structured as a standard 3+3 phase I design, with increasing or 
decreasing doses of axitinib evaluated along with a standard, fixed dose of 
nivolumab based on DLTs.  Six to twelve patients will be assessed during phase I 
until a RP2D is established.   
 
Dose level for Phase I for Axitinib and Nivolumab 
 
Dose Level (DL) 
Axitinib 
Nivolumab 
+1  
5 mg 
480 mg 
0 (starting dose) 
3 mg 
480 mg 
-1 
2 mg 
480 mg 
 
 
Decision Rules for Dose Escalation and Cohort Expansion 
 
 See Appendix III for the dose escalation/de-escalation decision rules. 
 Dose escalation will occur in a 3+3 dose escalation/de-escalation design  
 Three patients will initially start at dose level 0 (DL0) 
o If 0 patients experience a DLT, the dose will be escalated one level and 
3 more patients will be accrued at DL+1  

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o If 1 patient of the first 3 experiences a DLT, 3 more patients will be 
accrued at the same dose level.  If no more DLTs, escalate to DL+1.  If 
a second DLT occurs, deescalate to  DL-1 
o If 2 or 3 patients experience a DLT, deescalate to DL-1 
 For patients escalated to dose level +1 (DL+1): 
o If 0-1 DLT is observed in the first 3 patients, 3 more patients will be 
accrued at this dose level.  If after 6 patients accrued no more than 0-1 
DLTs have been observed, DL+1 will be denoted the RP2D and the 
expansion cohorts may open at this dose level 
o If at any time 2 or more DLTs are observed at DL+1, deescalate back to 
DL0.  If 6 patients have already been treated at this dose with 0-1 
DLTs, declare this dose the RP2D.  Otherwise 3 more patients will be 
accrued at that level and RP2D declared as below.                                                                  
 Once 6 patients are accrued to dose level 0 (DL0): 
o If 0-1 DLT is observed, DL0 will be denoted the RP2D and the 
expansion cohorts may open at this dose level 
o If at any time 2 or more DLTs observed at this dose level, deescalate 
back to DL-1 and 3 more patients will be accrued at that level 
 For patients deescalated to DL-1: 
o If 0-1 DLT is observed in the first 3 patients, 3 more patients will be 
accrued at this dose level.  If after 6 patients accrued no more than 0-1 
DLTs have been observed, DL-1 will be denoted the RP2D and the 
expansion cohorts may open at this dose level 
o If at any time 2 or more DLTs are observed at this dose level, the study 
will be stopped for toxicity 
 
Determination of RP2D 
 
 The RP2D is the dose of axitinib and nivolumab in combination chosen for 
further clinical development.  In the context of this study, the final dose 
level during the dose escalation phase that yields ≤ 1 DLTs will define the 
RP2D selection for further study in the dose expansion cohorts 
 Further experience in the dose expansion cohorts may result in a 
modification of the RP2D to a dose lower than that chosen at the conclusion 
of the dose escalation.   
 For axitinib, intra-patient dose escalation to higher doses may be permitted 
as outlined in the dose modification section of this protocol.  However, the 
final RP2D will not be higher than axitinib 5 mg BID.  Nivolumab dosing 
remains unchanged. 
 If a patient does not receive at least 75% of the planned axitinib and two 
infusions of nivolumab within the DLT observation period for reasons other 
than study-drug related toxicity, another patient will be enrolled to replace 
that patient at the current dose level. 
 
DLT Definition 

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 The DLT assessment window will be 28 days, starting from the first day of 
combination therapy (denoted C1D1) after the axitinib run-in period and 
will conclude after 28 days (4 weeks).  One cycle is denoted as 28 days so 
the end of the DLT window may coincide with the conclusion of cycle #1. If 
the second dose of nivolumab on C#2 is delayed for any reason other than a 
DLT, the DLT window period would still conclude after 28 days 
 Toxicity will be evaluated according to the NCI CTCAE, version 4.03 
 A DLT will be defined as any of the following AEs that is “possibly” related 
to one or both drugs during the DLT assessment window period 
 
Hematologic 
 
Grade 4 neutropenia defined as < 500/mm3 lasting > 5 
days in duration 
Febrile neutropenia defined as ANC < 1000/mm3 with a 
single temperature of > 38.3°C (101°F) or a sustained 
temperature of ≥ 38°C (100.4°F) for more than one hour 
Grade ≥ 3 neutropenic infection 
Grade 4 thrombocytopenia (platelets <25,000 
cells/mm3) or Grade ≥ 3 thrombocytopenia with 
bleeding 
 
Non-Hematologic 
 
Grade ≥ 3 nausea, vomiting, or diarrhea that does not 
improve to grade < 2 within 72 hours despite maximal 
medical therapy 
Grade ≥ 3 rash that does not improve to grade < 2 within 
7 days despite maximal medical therapy, or at any time 
involves desquamation, mucosal involvement, or 
requires initiation of systemic steroids 
Grade ≥ 3 drug-related uveitis, iritis, episcleritis, eye 
pain, or blurred vision 
Grade ≥ 3 hypertension despite maximal medical 
therapy 
Any other grade ≥ 3 non-laboratory or symptom-based 
toxicity not improved to grade < 3 despite maximal 
medical or supportive therapy after 7 days 
Any grade encephalitis or Grade ≥ 2 pneumonitis that 
are at least possibly related to nivolumab 

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Laboratory 
Grade ≥ 2 AST and/or ALT (> 3x ULN) in combination 
with total bilirubin > 2x ULN 
Grade ≥ 3 non-hematologic laboratory value that does 
not return to grade 1 within 7 days despite maximal 
medical therapy OR that requires hospitalization 
Other 
 
Inability to complete at least 75% of axitinib dosing 
within the 4-week DLT observation period due to 
treatment-related toxicity 
> 2 dose reductions of axitinib during the DLT window 
 
 
 
 
3.1.2. Phase II 
Phase II will include 43 patients at the RP2D in each arm of treatment naïve or 
patients who have received prior TKIs. In all patients, treatment with study drugs 
will continue until confirmed disease progression, patient withdrawal of consent, 
patient lost to follow up, unacceptable toxicity, or if the study is terminated by the 
Sponsor.  Patients may remain on both axitinib and nivolumab if clinically 
benefitting for up to 12 months.  At that time patients may continue on one or 
both medications at the discretion of the treating clinician and with agreement by 
the patient.  The trial will end at the completion of 24 months of therapy, at which 
point patients can decide with their treating clinician how to proceed.  Patients 
who elect to stop one drug after one year and who develop progression of disease 
may elect to be retreated at that time as part of the trial.  Nivolumab, if stopped at 
one year, will be provided by the study in those instances, but up to a maximum 
total of 24 months of treatment. If either drug is stopped due to toxicity or 
investigator’s decision, the patient may continue to receive the other drug in the 
combination.   
 
Anti-tumor activity will be assessed by radiological tumor assessments conducted 
at baseline, then at 8 weeks after combination and every 3 cycles thereafter, using 
RECIST version 1.1.  In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (eg, symptomatic 
deterioration), and at the end of treatment/withdraw from study (if not done in the 
previous 6 weeks).  Patients may be treated beyond radiologic progression if the 
patient is deemed to be clinically benefitting by the study treatment, however two 
assessments documenting progression will necessitate the patient be removed 
from the study.  Primary assessments will be performed with computed 
tomography (CT) of the chest, abdomen and pelvis.  Bone scintigraphy will be 
performed at baseline, then with every subsequent restaging period ONLY if bone 
metastases are documented or suspected.  Brain CT or MRI scans are required at 

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baseline when there are known or suspected brain metastases. In case of no 
known or suspected brain metastases, brain imaging is not needed at any time. 
 
Overall survival will be assessed every 3 months for the first 2 years, then every 6 
months for 2 years, and then annually.   
 
4.0 Patient Selection Inclusion & Exclusion 
 
4.1. Inclusion Criteria   
4.1.1 Histologically or cytologically confirmed advanced RCC with any clear cell 
component. 100% sarcomatoid is permissible. 
4.1.2 Archival tumor biospecimen (when available) must be procured for correlative 
evaluation.  If tumor tissue is not available or accessible despite good faith 
efforts, patient may still be treated on study.  
 Formalin fixed, paraffin embedded [FFPE] tissue block(s) or at least 12 
unbaked, unstained slides are required. Tissue samples taken from a 
metastatic lesion prior to the start of screening are acceptable. 
4.1.3 At least one measureable lesion as defined by RECIST version 1.1. 
4.1.4 Age > 18 years. 
4.1.5 ECOG performance status 0 or 1 
4.1.6 Adequate bone marrow, kidney, and liver function as defined below: 
 
 WBC  
 
≥ 2000/μL 
 Neutrophils     ≥ 1500/μL 
 Platelets            ≥ 100 x103/μL 
 Hemoglobin   
> 9.0 g/dL 
 Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if 
using the Cockcroft-Gault formula below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                           72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
                            72 x serum creatinine in mg/dL 
 
 AST/ALT         ≤ 3 x ULN  
 Total Bilirubin  ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who 
can have total bilirubin < 3.0 mg/dL)  
 

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4.1.7 No evidence of pre-existing uncontrolled hypertension as documented by 2 
baseline blood pressure (BP) readings taken at least 1 hour apart. The baseline 
systolic BP readings must be ≤ 150 mm Hg, and the baseline diastolic BP 
readings must be ≤ 90 mm Hg 
4.1.8 Patients enrolled to the prior treatment arm of the expansion cohort must have 
been exposed to a TKI for metastatic disease.  Exposure to TKI as part of 
(neo)adjuvant treatment that completed within 1 year of study qualifies as prior 
exposure as well. 
 
4.2. Exclusion Criteria   
4.2.1 Prior therapy with axitinib 
4.2.2 Prior systemic therapy directed at advanced RCC is not allowed for patients 
enrolled to the expansion cohort, treatment naïve arm.  If prior (neo)adjuvant 
treatment given as part of a clinical trial, this would be allowed as long as last 
dose was > 1 year prior to start of treatment 
4.2.3 Patients enrolled to the prior treatment arm of the dose escalation cohort must 
not have received anti-cancer therapy less than 14 days prior to the first dose of 
study drug or palliative, focal radiation therapy less than 14 days prior to the 
first dose of study drug.  
4.2.4 Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways).  Prior high dose interleukin-2 is allowed 
and patients who received this as their only prior line of treatment for 
metastatic disease may be included in the treatment naïve group.  
4.2.5 Patients are excluded if they have active, symptomatic brain metastases or 
leptomeningeal metastases. Subjects with known brain metastases are eligible 
if metastases have been treated and there is no magnetic resonance imaging 
(MRI) evidence of progression for four weeks (after treatment is complete and 
within 28 days prior to study drug administration. 
4.2.6 Second malignancy requiring active systemic treatment 
4.2.7 Diagnosis of immunodeficiency  
4.2.8 Active, known or suspected autoimmune disease. Subjects are permitted to 
enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, psoriasis 
not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger 
4.2.9 Patients have a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration. 
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune 
disease. 

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4.2.10 Major surgery <4 weeks or radiation therapy <2 weeks of study entry. Prior 
palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at 
least one measurable lesion that has not been irradiated. 
4.2.11 Gastrointestinal abnormalities including: 
 Inability to take oral medication; 
 Requirement for intravenous alimentation; 
 Prior surgical procedures affecting absorption including total gastric 
resection; 
 Treatment for active peptic ulcer disease in the past 6 months; 
 Active gastrointestinal bleeding as evidenced by hematemesis, 
hematochezia or melena in the past 3 months without evidence of resolution 
documented by endoscopy or colonoscopy; 
 Malabsorption syndromes. 
4.2.12 Evidence of inadequate wound healing. 
4.2.13 Active bleeding disorder or other history of significant bleeding episodes 
within 30 days before study entry. 
4.2.14 Known prior or suspected hypersensitivity to study drugs or any component in 
their formulations. 
4.2.15 Current use or anticipated need for treatment with drugs or foods that are 
known strong CYP3A4/5 inhibitors including but not limited to atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and 
grapefruit or grapefruit juice. The topical use of these medications (if 
applicable), such as 2% ketoconazole cream, is allowed. 
4.2.16 Current use or anticipated need for treatment with drugs that are known strong 
CYP3A4/5 inducers, including but not limited to carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort. 
4.2.17 As there is potential for hepatic toxicity with nivolumab, drugs with a 
predisposition to hepatotoxicity should be used with caution in patients treated 
with nivolumab-containing regimen. 
4.2.18 Known hepatitis B virus (HBV) or hepatitis C virus (HBV) infection. 
4.2.19 Known history of human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS) 
4.2.20 History of any of the following cardiovascular conditions within 12 months of 
screening: 
 Myocardial infarction 
 Unstable angina pectoris 
 Cardiac angioplasty or stenting 
 Coronary/peripheral artery bypass graft 
 Class III or IV congestive heart failure per New York Heart Association 
 Cerebrovascular accident or transient ischemic attack 

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4.2.21 
History of deep vein thrombosis or pulmonary embolism within 6 months 
of screening. Patients who are currently taking anticoagulation therapy for a prior 
history (> 6 months from screening) of thrombosis may still be eligible. 
4.2.22 Pregnant or breast feeding. Refer to section 4.4 for further detail. 
 
4.3. Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for 
this study.   
 
4.4. Pregnancy 
 Women of childbearing potential (WOCBP) must use appropriate method(s) of 
contraception. WOCBP should use an adequate method to avoid pregnancy for 
23 weeks after the last dose of investigational drug.  
 Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours of beginning study treatment. 
 Men who are sexually active with WOCBP must use any contraceptive method 
with a failure rate of less than 1% per year and will be instructed to adhere to 
contraception for a period of 31 weeks after the last dose of investigational 
product.  
 Women who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile) as well as azospermic men do not require contraception 
 
WOCBP is defined as follows: Any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or a bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea > 12 consecutive months, or women on hormone replacement therapy 
(HRT) with documented plasma follicle-stimulating hormone (FSH) level > 35 
mIU/ml).  Even women who are using oral, implanted, or injectable contraceptive 
hormones or mechanical products (diaphragm, condoms, spermicides) to prevent 
pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should 
be considered to be WOCBP. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  In addition, men enrolled on this study should understand the risks to any 
sexual partner of childbearing potential. 
 
Should a woman or female partner of a male study participant become pregnant or 
suspect she is pregnant while participating in this study, she must inform her treating 
physician immediately. 
 

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4.5. Patient Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the study monitor at: FCCC.MONITOR@fccc.edu. Eligible participants 
will be entered on study centrally once the following items have been received by 
email: 
 
 Completed registration form  
 Consent and HIPAA signature pages  
 Eligibility checklist 
 
Following registration, participants must begin protocol treatment within 14 calendar 
days of registration.  Issues that would cause treatment delays must be discussed with 
the Sponsor- Investigator.  If a registered participant does not receive protocol 
therapy following registration, the participant will be recorded as withdrawn from 
study.  The Study Monitor must be notified as soon as possible if a participant does 
not begin protocol treatment as scheduled. For additional registration questions, 
please email FCCC.MONITOR@fccc.edu or call (215) 728-5544. 
 
The study monitor or their designee will notify the site by email once registration is 
confirmed and the sequence number has been assigned.  Participants must be 
registered and have received a sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
 
5.0 Treatment Plan 
Phase I 
During the phase I portion, patients will be treated with 3 mg of axitinib orally (PO) 
twice daily (BID) , with or without food, for a seven day lead-in period prior to 
combination therapy (1st day of dosing axitinib during lead-in will be denoted day -7 and 
proceed to day -1 as last day of axitinib alone).  Dose for lead-in period will be same as 
assigned dose level.  Patients will then start treatment with nivolumab in addition to 
continuing daily axitinib dosing (1st day of combination treatment denoted cycle 1, day 1 
[C1D1]).  Nivolumab will be administered as a 30-minute intravenous (IV) infusion at 
480 mg every 4 weeks.  Patients will be accrued in a standard 3+3 design.  If that is 
deemed safe, dose escalation of axitinib to a standard dosing of 5 mg PO BID (DL+1 as 
outlined in section 3.1.1 above) will be evaluated.  Nivolumab dosing will remain 
unchanged at 480 mg.  The combination of axitinib with nivolumab that meets the pre-
specified definition of safety outlined in the protocol will be denoted the RP2D and will 
move forward for further study. A patient who is unable to start at the assigned Cycle 1 
Day 1 dose level after the lead-in period will not be evaluable for DLTs but may remain 
in the study and will be evaluated for safety and efficacy, though they will be replaced for 
the primary endpoint. 
 
 

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Phase II 
During the phase II portion, patients will be treated at the RP2D determined in the Phase 
I portion of the study. There will be two parallel dose expansion phase cohorts: one for 
patients with prior TKI exposure and a second for treatment naïve patients. In all patients, 
treatment with study drugs will continue until confirmed disease progression, patient 
withdrawal of consent, patient lost to follow up, unacceptable toxicity, or if the study is 
terminated by the Sponsor.  Patients may remain on both axitinib and nivolumab if 
clinically benefitting for up to 12 months.  At that time patients may continue on one or 
both medications at the discretion of the treating clinician and with agreement by the 
patient. See section 3.1.2 above for discussion of options at one year and total length of 
treatment allowed. 
 
5.1. Treatment Regimen 
 
Regimen description 
Agent 
Premedications, 
precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
No 
premedication 
480 mg 
IV over 
30 min (-
5/+ 30 
min) 
Day 1of 
each cycle 
 
4 weeks 
(28 days) 
Axitinib 
Swallow whole 
with a glass of 
water 
2 mg or 3 mg 
or 5 mg (see 
dose level 
chart) 
PO  
BID, 
continuous 
dosing 
 
 
5.2. Nivolumab Administration 
Subjects may be dosed no less than 26 days or more than 30 days from the previous 
dose of drug. Subjects should be carefully monitored for infusion reactions during 
nivolumab administration. If an acute infusion reaction is noted, subjects should be 
managed according to infusion reaction guidelines described in Appendix I. 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 
1.2-micron pore size, low-protein binding polyethersulfone membrane in-line filter at 
the protocol-specified doses. It is not to be administered as an IV push or bolus 
injection. Nivolumab injection must be diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to protein concentration as low as 0.35 mg/mL. 
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any antimicrobial preservative or bacteriostatic agent.  
 

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5.2.1. Preparation and Administration 
1. Visually inspect the drug product solution for particulate matter and 
discoloration prior to administration.  Discard if solution is cloudy, if there is 
pronounced discoloration (solution may have a pale-yellow color), or if there 
is foreign particulate matter other than a few translucent-to-white, amorphous 
particles. 
Note: Mix by gently inverting several times.  Do not shake. 
 
2. Aseptically withdraw the required volume of nivolumab solution into a 
syringe, and dispense into an IV bag.  If multiple vials are needed for a 
subject, it is important to use a separate sterile syringe and needle for each vial 
to prevent problems such as dulling of needle tip, stopper coring, repeated 
friction of plunger against syringe barrel wall. 
   
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 
5% Dextrose Injection solution. It is acceptable to add nivolumab solution 
from the vials into an appropriate pre-filled bag of diluent. 
 
Note: Nivolumab infusion concentration must be approximately 0.35 
mg/mL. 
 
Note: It is not recommended that so-called “channel” or tube systems are 
used to transport prepared infusions of nivolumab. 
 
4. Attach the IV bag containing the nivolumab solution to the infusion set and 
filter. 
 
5.  Nivolumab should be infused over 30 minutes, -5/+ 30 minutes. For patients 
who require rate reduction to accommodate infusion reactions, longer infusion 
time would be permitted and advised. 
 
6. At the end of the infusion period, flush the line with a sufficient quantity of 
approved diluents. 
 
5.3. Axitinib Administration 
Administer axitinib doses approximately 12 hours apart with or without food. 
Axitinib should be swallowed whole with a glass of water. If the patient vomits or 
misses a dose, an additional dose should not be taken. The next prescribed dose 
should be taken at the usual time. 
 
5.4. Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions 
 

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5.4.1. Permitted Medications  
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Physiologic 
replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day 
prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by contact allergen) is permitted. 
 
5.4.2. Prohibited Medications 
Medications specifically prohibited in the exclusion criteria are not allowed 
during the study. If there is a clinical indication for medications specifically 
prohibited during the trial, discontinuation from the study may be required. 
 
As there is potential for hepatic toxicity with nivolumab, drugs with a 
predisposition to hepatotoxicity should be used with caution during the study. 
 
In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a 
lesser extent, CYP1A2, CYP2C19, and uridine diphosphate- 
glucuronosyltransferase (UGT) 1A1. Therefore concomitant use of strong 
CYP3A4/5 inhibitors and strong CYP3A4/5 inducers should be avoided. 
 
Strong CYP3A4/5 Inhibitors:  
The concomitant use of strong CYP3A4/5 inhibitors should be avoided.  When 
such a medicine is needed, selection of an alternative with no or minimal 
CYP3A4/5 inhibition potential is desired where possible.  Please see a partial but 
not necessarily complete list of drugs to avoid below: 
 
 Ketoconazole 
 Itraconazole 
 Clarithromycin 
 Atazanavir, 
 Indinavir 
 Nefazodone 
 Nelfinavir 
 Ritonavir 
 Saquinavir 
 Telithromycin 
 Voriconazole 
 
Although axitinib dose adjustment has not been studied in patients receiving 
strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-
administered, axitinib dosing should be decreased approximately by half, as this 
dose reduction is predicted to adjust the axitinib area under the plasma 
concentration vs time curve (AUC) to the range observed without inhibitors.  

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Subsequent doses can be modified as needed by the treating clinician based on 
individual safety and tolerability. If and when the strong inhibitor is discontinued, 
the axitinib dose should be returned (after 3 – 5 half-lives of the inhibitor) to the 
dose used prior to initiation of the strong CYP3A4/5 inhibitor. 
 
CYP3A4/5 Inducers:  
The concomitant use of strong CYP3A4/5 inducers should be avoided.  When 
such a medicine is needed, selection of an alternative with no or minimal 
CYP3A4/5 induction potential is desired where possible.  Please see a partial but 
not necessarily complete list of drugs to avoid below: 
 
 Rifampin 
 Dexamethasone 
 Phenytoin 
 Carbamazepine 
 Rifabutin 
 Rifapentin 
 Phenobarbital 
 St. John’s Wort 
 
Moderate CYP3A4/5 inducers:  
Moderate CYP3A4/5 inducers may also reduce the plasma exposure of axitinib 
and should be avoided when possible.  Examples are listed below and should not 
be considered complete: 
 Bosentan 
 Efavirenz 
 Etravirine 
 Modafinil 
 Nafcillin 
 
5.5. Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment will continue until 
one of the following criteria applies: 
 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse events 
 If nivolumab held > 8 weeks with exceptions described in section 6.3.3 
 Patient required > 2 dose reductions of axitinib 
 Patient becomes pregnant 
 Patient lost to follow up 
 Patient decides to withdraw from the study or 
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 

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 Study is terminated by the Sponsor 
 Patient completes therapy as specified in section 3.1.2 
 Non-compliance 
 
5.6. Treatment beyond Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy 
may derive clinical benefit despite initial evidence of PD. Subjects will be permitted 
to continue treatment beyond initial RECIST 1.1 defined PD as long as they meet the 
following criteria determined by the investigator: 
 
• 
Investigator-assessed clinical benefit 
• 
Tolerance of study drug 
• 
Stable performance status 
 
The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued 
treatment.  
 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (eg, CNS metastases).  
 
A radiographic assessment/ scan should be performed ≥ 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in 
the tumor size or continued PD. The assessment of clinical benefit should be balanced 
by clinical judgment as to whether the subject is clinically deteriorating and unlikely 
to receive any benefit from continued treatment with nivolumab. 
 
For the subjects who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden from time of 
initial PD. This includes an increase in the sum of diameters of all target lesions and/ 
or the diameters of new measurable lesions compared to the time of initial PD. 
Nivolumab treatment should be discontinued permanently upon documentation of 
further progression. 
 
New lesions are considered measureable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes which must 
have a short axis of at least15 mm). Any new lesion considered non-measureable at 
the time of initial progression may become measureable and therefore included in the 
tumor burden if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions that become measurable, these new lesions must demonstrate 
an absolute increase of at least 5 mm. 
 

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5.7. Duration of Follow up 
Patients will be followed every 3 months for the first 2 years, then every 6 months for 
2 years, and then annually for survival. Subjects who discontinue treatment for 
reasons other than disease progression should continue to have radiographic 
assessments of disease at least every 12 weeks until documented disease progression. 
Patients removed from study for unacceptable adverse events that are related to the 
study treatment will be followed until resolution or stabilization of the adverse event. 
 
6.0 Dose Modifications 
6.1. Dose Level Adjustment Table(s) 
Dose level 
Axitinib Dose 
Nivolumab Dose 
+1  
5mg BID 
480 mg 
0 
3mg BID 
480 mg 
-1 
2mg BID 
480 mg 
-2 
1 mg BID 
480 mg 
 
 
6.2. Axitinib Dose Modifications 
6.2.1. Axitinib Intra-Patient dose increase: 
For the phase II portion of the study, or in phase I once patients complete the DLT 
assessment phase, those patients who tolerate axitinib exceptionally well may 
undergo further dose escalations of axitinib if deemed indicated by the treating 
clinician and meeting the following criteria:   
 At least two consecutive weeks with no adverse reactions > Grade 2 
(according to the Common Toxicity Criteria for Adverse Events 
[CTCAE]) 
 Blood pressure ≤ 150/90 and receiving ≤ 2 anti-hypertensive medications 
 
In these instances, patients may have their dose increased.  When the initial dose 
is 3 mg BID, they may increase to 5 mg BID.  When they start at, or escalate to, 5 
mg BID, the dose may be increased to 7 mg BID, and further to 10 mg BID using 
the same criteria. 
 
6.2.2. Axitinib dose modifications due to toxicity: 
Axitinib dose modifications or reductions due to toxicity may occur at any time 
on study if deemed necessary.  Dose interruptions with or without dose reductions 
may occur as indicated.  Patients may undergo two dose reductions of axitinib 
from the dose level at which they initiated treatment.  If further dose reduction 
recommended after this, patients should discontinue axitinib.  If they are 
otherwise clinically benefitting and dose discontinuation achieves the desired 
recovery of toxicity, patients may remain on treatment with nivolumab.  However, 
if this occurs in the DLT window, this would be considered a DLT. 

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Toxicity Class 
NCI CTCAE Severity 
Grade 
Axitinib 
Hypertension 
BP ≥ 140 systolic or ≥ 90 
diastolic but < 160 systolic or 
< 100 diastolic on at least 2 
BP readings > 1 hour apart 
Start new, increase, or add 
additional anti-hypertensive 
medication and continue at 
same dose level. 
 
If on maximal anti-
hypertensive medical 
therapy, reduce dose by 1 
level 
Recurrent grade 2 (140-160 
systolic and 90-100 diastolic) 
after previous dose reduction 
and on maximal anti-
hypertensive therapy 
Dose reduce axitinib a 
second dose level 
 
Systolic BP reading ≥ 160 
mmHg OR diastolic BP ≥ 
100 mmHg of at least 2 BP 
readings > 1 hour apart 
Withhold dose of axitinib 
until BP ≤ 140/90 and adjust 
anti-hypertensive 
medications as appropriate. 
 
Reduce axitinib dose by 1 
dose level and resume. 
Hematologic 
Abnormalities 
Grade 1-3 
Continue at the same dose 
level 
Grade 4 (except for 
lymphopenia not associated 
with infection) 
Withhold until recovery to ≤ 
grade 2 then reduce dose by 
1 dose level and resume. 
Liver Function test 
Abnormalities (AST, 
ALT, Bilirubin) 
Grade 1 
Continue at the same dose 
level 
Grade 2 
Withhold until grade < 2 or 
baseline and restart at the 
same dose level. 

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Recurrent Grade 2 or Grade 
3-4 
Withhold until grade < 2 or 
baseline and reduce by one 
dose level. 
Non-Hematologic 
Laboratory 
abnormalities 
Grade 1-2 
No Change 
Grade 3 - Asymptomatic 
May continue at same dose 
level or reduce 1 dose level 
as deemed appropriate by 
treating clinician. 
Grade 3 - Symptomatic 
Treat as appropriate with 
supportive measures and 
reduce dose by 1 dose level. 
Grade 4 
Hold treatment until 
recovery to ≥ grade 2, then 
reduce by 1 dose level and 
resume treatment. 
Diarrhea 
Grade 1-2 
Continue at the same dose 
level.  Add supportive 
medicines as needed. 
Grade 3 
Hold until grade ≤ grade 2 
and reduce by 1 dose level 
Grade 4 
Discontinue medication 
Pneumonitis 
Grade 1-2 
No change 
Grade 3-4 
Discontinuation 
Hypo/Hyperthyroidism 
Grade 1-2 
No change 
Grade 3 
Continue at the same dose 
level.  Add supportive 
medicines as needed. May 
decrease one dose level if 
deemed appropriate by 
treating clinician. 
Grade 4 
Hold drug until recovery to 
< grade 2, treat as 
appropriate, and resume at 
dose reduced one level. 
 

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6.3. Nivolumab Dose Modifications 
Dose reductions or dose escalations are not permitted. Missed doses are not to be 
made up. If treatment is delayed or interrupted for > 8 weeks, the subject must be 
permanently discontinued from study therapy unless discussed with medical monitor 
and study team for exception due to extenuating circumstances.  
 
6.3.1. Dose Delay Criteria 
Dose delay criteria apply for all drug-related adverse events (regardless of 
whether or not the event is attributed to nivolumab). However, if in opinion of 
treating clinician, drug-related AE is most likely a result of one drug, that drug 
may be held and the other drug may continue as planned. If held drug is axitinib, 
it can be restarted as per improvement in AE per below guidelines at any point in 
treatment cycle.  If the held drug is nivolumab, it should be skipped and not made 
up and if AE resolves per criteria should be restarted at start of next cycle 
 
Nivolumab administration should be delayed for the following: 
 
 Any Grade ≥ 2 non-skin, drug-related immune related AE, with the following 
exceptions: 
 
o Grade 2 drug-related fatigue does not require a treatment delay 
o Grade 2-4 endocrine abnormalities such as hypothyroidism, 
hyperthyroidism, or hyperglycemia that may be treated with appropriate 
supportive therapy or hormonal replacement do not require a treatment 
hold or delay 
 
 Any Grade 3 skin, drug-related AE 
 
 Any Grade 3 drug-related laboratory abnormality, with the following 
exceptions for lymphopenia, leukopenia, AST, ALT, total bilirubin, or 
asymptomatic amylase or lipase: 
 
o Grade 3 lymphopenia or leukopenia does not require dose delay. 
o If a subject has a baseline AST, ALT, or total bilirubin that is within 
normal limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity. 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis does 
not require dose delay. The Investigator should be consulted for such Grade 
≥ 3 amylase or lipase abnormalities. 
o Any grade endocrine abnormalities attributed to nivolumab but that can be 
managed solely with hormone replacement therapy (physiologic steroids, 

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levothyroxine, insulin, etc) do not require dose delay, but decision to 
continue or resume treatment if held may be left to the treating investigator 
in discussion with the patient 
 
 Any AE, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment 
criteria are met. 
 
6.3.2. Criteria to Resume Treatment 
Subjects may resume treatment with study Nivolumab 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  
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin 
may resume treatment in the presence of Grade 2 AST/ALT OR total 
bilirubin 
 Subjects with combined Grade 2 AST/ALT AND total bilirubin values 
meeting discontinuation parameters should have treatment permanently 
discontinued 
 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 within 6 weeks may be 
eligible for retreatment if treating clinician allows 
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment if investigator allows 
 
If the criteria to resume treatment are met, the subject should restart treatment at 
the next scheduled time point per protocol.  In regards to axitinib, that would 
mean the next day regardless of point in cycle.  For nivolumab that would mean 
day one of next cycle. 
 
6.3.3. Criteria for Discontinuation 
Nivolumab should be permanently discontinued for the following: 
 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within 
the re-treatment period OR requires systemic treatment  

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 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, and infusion 
reactions, and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with 
only physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require 
treatment discontinuation except those noted below 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 Any drug-related liver function test (LFT) abnormality that meets 
the following criteria require discontinuation:  
• AST or ALT ≥ Grade 3 
 
• Total bilirubin ≥ Grade 3 
• Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x 
ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except 
for the following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not 
associated with symptoms or clinical manifestations of pancreatitis 
and decrease to < Grade 4 within 1 week of onset.  
o 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 
o Grade 4 lymphopenia or leukopenia 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, 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 
Investigator  
 Any dosing interruption lasting > 8 weeks with the following exceptions:  
o Dosing delays or interruptions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 8 weeks, the 
Sponsor-Investigator must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted or delayed 
o Dosing interruptions or delays lasting > 8 weeks that occur for non-
drug-related reasons may be allowed if approved by the Sponsor-
Investigator. Prior to re-initiating treatment in a subject with a dosing 

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interruption lasting > 8 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is 
interrupted 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in 
the judgment of the site Investigator or Sponsor-Investigator, presents a 
substantial clinical risk to the subject with continued nivolumab dosing 
 
6.3.4. Recommended Dose Modification for Nivolumab  
Toxicity 
Severity Grade 
Nivolumab 
Colitis or 
Diarrhea 
Grade 2 
Withhold dosea 
Grade 3 
Withhold dosea 
Grade 4 
Permanently discontinue 
Pneumonitis 
Grade 2 
Withhold dosea 
Grade 3 or 4 
Permanently discontinue 
Hepatitis 
Grade 2 AST or ALT or total 
bilirubin 
 
Withhold dosea 
Grade 3 or 4 AST/ALT/ total 
bilirubin 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dosea 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 
Withhold dose, but may 
consider restarting if 
stable with appropriate 
replacement  
Grade 3 or 4 
Withold dose, but may 
consider restarting if 
stable with appropriate 
replacement  
Type 1 
Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Withhold dose, may 
consider restarting if 
adequate glucose control 
instituted. Patients who 
have known type 2 
diabetes at study onset do 

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not need to be held for 
grade 3 hyperglycemia 
Grade 4 hyperglycemia 
Withhold dose, may 
consider restarting if 
adequate glucose control 
instituted 
Nephritis and 
Renal 
Dysfunction 
Grade 2 or 3 serum creatinine 
Withhold dosea 
Grade 4 serum creatinine 
Permanently discontinue 
Rash 
Grade 3 
Withhold dosea 
Grade 4 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe 
neurologic signs or symptoms 
Withhold dosea 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
- 
First occurrence 
- 
Recurrence of same Grade 3 
adverse reactions 
 
Withhold dosea 
Permanently discontinue 
Life-threatening or Grade 4 adverse 
reaction 
Permanently discontinue 
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse 
reactions lasting 12 weeks or longer 
Permanently discontinue 
a Resume treatment when adverse reaction returns to Grade 0 or 1. 
 
 
7.0 Study Agent Information 
 
 
7.1. Nivolumab  
7.1.1. Product description 
 

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*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab include laboratory coats and 
gloves. 
7.1.2. Availability  
 Nivolumab used in this study will be supplied by Bristol Myers Squibb. 
 
7.1.3. Recommended prepared drug storage and use condition 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a 
maximum of 4 hours of the total 24 hours can be at room temperature (20° to 
25°C, 68° to 77°F) and room light. The maximum 4-hour period under room 
temperature and room light conditions includes the product administration period. 
 
 
7.2. Axitinib 
 
7.2.1. Product description  
1 mg tablets are red film-coated, oval tablets debossed with “Pfizer” on one side 
and “1 XNB” on the other; available in bottles of 180.  
 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1) 
Product Description 
and Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) 
/Label Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab (BMS-
936558-01)* Injection 
drug product is a sterile, 
non-pyrogenic, single-
use, isotonic aqueous 
solution formulated at 10 
mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
 
40 
mg/vial 
(10 
mg/mL) 
10-cc Type 
1 flint glass 
vials 
stoppered 
with butyl 
stoppers 
and sealed 
with 
aluminum 
seals/open 
label 
Carton of 5 or 
10 vials (100 
mg vials) or 
Carton 
containing 2 
x 100 mg 
vials and 1 x 
40 mg 
vial/open 
label 
 
Clear to 
opalescent, 
colorless to 
pale yellow 
liquid.  May 
contain 
particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing  

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5 mg tablets are red film-coated, triangular tablets debossed with “Pfizer” on one 
side and “5 XNB” on the other; available in bottles of 60 
 
7.2.2. Availability   
Axitinib will be ordered through usual mechanisms as standard of care as an 
FDA-approved drug for this indication (TKI-refractory).  For patients treated in 
the treatment-naïve cohort, the NCCN guidelines list axitinib as an acceptable 
alternative for 1st line therapy for selected patients.  
 
7.2.3. Storage requirements 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F) 
 
7.3. Drug Ordering, Storage and Handling 
Following submission and approval of the required regulatory documents, 
participation in the study initiation meeting and receipt of the site activation letter 
from the IST Regulatory Specialist, the initial order may be placed.  Drug order forms 
and ordering procedure will be presented at the site initiation meeting. 
 
7.4. Destruction of Drug   
At the time of study closure, the unused, used and expired study drug will be 
destroyed at the site per Institutional SOPs unless otherwise specified by sponsor. 
 
7.5. Records to be kept at Site; Dispensing and Accountability 
It is the responsibility of the Sponsor-Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed.  Records or logs must comply 
with applicable regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area.  
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product 
inventory entry/movement. 
 Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 
8.0 Correlative /Special Studies 
We will collect archival tumor tissue (when available) for all patients for biomarker 
exploration as well as serum and plasma samples at three time points on study.   
 

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8.1. Biopsy Specimen Analysis 
8.1.1. Outcome measure 
Tissue will be collected at baseline from archival specimens or fresh biopsy 
samples, when available, to assess for markers that may predict for response that 
may include but are not limited to: PD-L1 expression, tumor infiltrating 
lymphocytes, markers of interferon signaling 
 
8.1.2. Assessment, method of assessment, timing of assessment 
This may include but is not limited to immunohistochemistry, NanoString, and 
next generation sequencing 
 
 
8.1.3. Site(s) performing correlative study 
Fox Chase Cancer Center will perform the analysis.All sites will collect and ship 
the samples to Fox Chase Cancer Center. 
 
8.2. Biomarker Analysis 
8.2.1. Outcome measure  
Blood will be collected to analyze for levels of various cytokines, chemokines and 
other biomarkers that may predict for response or resistance.   
 
8.2.2. Assessment, method of assessment, timing of assessment 
This may include but is not limited to- specific antibody assays, cell free DNA 
 
Timing of assessment- blood will be collected at three time points: 
1. Lead-in day -7 
2. Prior to Cycle 2 Day 1 
3. End of treatment 
 
8.2.3. Site(s) performing correlative study  
Fox Chase Cancer Center will perform the analysis.All sites will collect and ship 
the samples to Fox Chase Cancer Center.

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9.0 Study Calendar 
 
Study Phase 
Pre-Studyb 
Lead-In 
Phase 
Treatment (1 cycle is 28 days) 
End of 
Treatment 
Follow-Up 
 
 
 
Cycle 1 
Cycle 2 and 
beyond 
 
Safety 
Follow-up 
Follow-up  
Treatment Days 
 
Day -7 to 0 
(+3 days) 
Day 1 
Day 
15 
Day 1 (+/-2) 
At time of 
Discon 
100 days 
post 
Discon 
 
Informed consent & HIPAA 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examᴺ 
X 
X 
X 
X 
X 
 
 
 
Weight 
X 
 
 
X 
 
 
 
 
Vital signs (T, P, R, BP)a 
X 
X 
X 
X 
X 
 
 
 
Performance status 
X 
X 
X 
X 
X 
X 
 
 
CBC w/diff, plts 
X 
X 
Xe 
X 
Xe 
X 
 
 
Serum chemistryᵉ 
X 
X 
Xe 
X 
Xe 
X 
 
 
Thyroid (TFTs) 
X 
 
Xf  
 
 
 
 
 
β-HCGd 
X 
 
Xf 
 
 
 
 
 
Urinalysis 
X 
 
Xf 
 
 
 
 
 
Pulse Oximetryg 
X 
 
X 
 
X 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------Xo 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------Xp 
 
Disease Assessmenth 
X 
After 8 weeks of the combination (+/- 7 days) 
and then every 3 cycles (+/- 7 days)   
Xj 
 
Xk 
Bone Scan (if indicated)i 
X (if 
indicated) 
After 8 weeks of the combination (+/- 7 days) 
and then every 3 cycles (+/- 7 days) 
Xj 
 
Xk 
Survivall 
 
 
 
 
 
 
 
X 
Blood collection for 
correlative studiesm 
 
X 
 
 
C2D1 only 
X 
 
 
 Archival Tumor Tissue 
X 
 
 
 
 
 
 
 
Axitinib 
 
X 
 
 
 
Nivolumab 
 
 
X 
 
X ͨ 
 
 
 
a: 2 baseline blood pressure (BP) readings will be taken at least 1 hour apart. The baseline systolic BP readings must be ≤ 150 mm 
Hg, and the baseline diastolic BP readings must be ≤ 90 mm Hg 
 
b:  Pre-study H&P and all labs must be < 28 days prior to registration.  Tumor measurements and radiologic evaluations must be < 28 
days prior to registration.  Pre-study assessments may be used for lead-in day -7 if completed < 28 days from day one of 
treatment. 

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c:   Nivolumab is given on day 1 of every cycle. 
 
d:  Serum pregnancy test (women of childbearing potential) must be completed < 72 hours before beginning treatment. 
 
 
 
 e:  Following Laboratory test must be done prior to each dose of Nivolumab: CBC w/ differential, LFTs (ALT, AST, total bilirubin, alkaline 
phosphatase), BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, Glucose  
 f:   TSH should be done every 2 cycles starting cycle 1, with free T4 and free T3 done only if TSH is abnormal. Β-HCG, if applicable, 
and urinalysis are also to be conducted every 2 cycles starting with cycle 1, ie, C1, C3, C5…etc (odd numbered cycles). 
g:   Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen if applicable) should be assessed at pre-
study visit and prior to dosing with Nivolumab on day 1 of each cycle. 
 
h:  Imaging modality in order of preference is as follows: 1. CT Chest, Abdomen, and Pelvis with contrast  2. Non-contrast CT of the 
chest, and MRI of the abdomen/pelvis  3. CT Chest, Abdomen, and Pelvis without contrast. The same imaging modality should be 
used at baseline and follow-up. 
 
i:    Bone scintigraphy will be performed at baseline then with every subsequent restaging period only if bone metastases are 
documented or suspected. Bone scans are not needed at any time if no known or suspected bone metastases. 
 
j:   Tumor measurements including CT/bone scan/MRI will be done at the end of treatment visit only  if not done in the previous 6 
weeks 
 
k:   Subjects who discontinue treatment for reasons other than disease progression should continue to have radiographic 
assessments of disease at least every 12 weeks until documented disease progression. 
 
l:    Follow-up every 3 months for the first 2 years, then every 6 months for 2 years, then annually for study survival. 
 
m:  Blood samples will be collected at lead-in phase (time 1), prior to C2D1 (time 2) and at end of treatment (time 3). Sera, plasma 
and whole blood will be collected. Sera- 1(10mL) red top tube clotted sample.  Plasma and whole blood control- 1(10mL) EDTA 
tube. 
n.   Physical exam must be done day 1 of each cycle..  
 
o:   During safety follow-up period, any new cancer treatment and concomitant medicines used to treat irAEs will be reported 
 
p:   During safety follow-up period, any new or ongoing protocol treatment-related AEs will be reported  
 
 

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10.0 
Adverse Events 
10.1. Adverse Event Definition 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of investigational product, whether or 
not considered related to the investigational product.  
 
10.2. Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing 
hospitalization  
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [eg, medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above.) Examples of such events 
include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.)  
 Potential drug induced liver injury (DILI) is also considered an important 
medical event.  
 Suspected transmission of an infectious agent (eg, pathogenic or 
nonpathogenic) via the study drug is an SAE.  
 Although pregnancy, overdose, and a new cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
 
Potential drug induced liver injury (DILI) is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 

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2) Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other drug(s) 
known to be hepatotoxic. 
Definition of Overdose: 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important.  
 
10.3. Severity Rating  
The site Investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity 
tables provided in the protocol define severity.  If not included in CTCAE v.4.0, 
severity is expressed in numerical grade using the following definitions: 
1. Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2. Grade 2: Moderate-minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL. 
3. Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. Grade 5: Death related to AE 
 
10.4. Attribution/Relationship to study drug  
1. Definite – clearly related 
2. Probable – likely related 
3. Possible – may be related 
4. Unlikely – doubtfully related 
5. Unrelated – clearly not related 
 
10.5. Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with 
the current information available from the resources. 
 
An Unexpected Adverse Event is one where the nature, severity, or frequency of the 
event is related to participation in the research is not consistent with either: 
 

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1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the protocol-
related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts: or 
 
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the subjects(s) 
predisposing risk factor profile for the adverse event. 
 
10.6. Recording and Reporting Responsibilities 
10.6.1. Investigative Site Recording Responsibilities: 
1. Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event.  Each category listed 
above must be recorded for each event. 
 
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) 
and in progress reports with details about the grade and attribution of 
each episode, action taken with respect to the study drug, and the 
patient’s outcome will be recorded in the CRF.  All events will be 
recorded on case report forms during the treatment period.  All new, or 
on-going protocol treatment-related AEs will be followed for a 
minimum of 100 days following the last dose of study treatment. All 
treatment-related AEs should be followed to resolution or stabilization.  
 
3. All reportable SAEs will be recorded on the FDA MedWatch form 
3500a.  After submitting the initial report it may be necessary to submit 
follow up reports to the OCR should the event require further 
investigation. 
 
10.6.2. Investigative Site Reporting Responsibilities: 
1.  The site Investigator/ site is responsible to report all SAEs that occur 
on or after the first day of study treatment to the IST Regulatory 
Specialist within 24 hours of becoming aware of the event.  All 
subsequent SAEs must be reported for up to 100 days after the last 
treatment. 
 
 
Each site Investigator is responsible to report all AEs/SAEs to their 
local IRB following guidelines set by that IRB.  The FCCC OCR 
reserves the right to request an event be reported to the IRB at their 
discretion.  Copies of events reviewed by the IRB must be sent email 
to the IST Regulatory Specialist at SAE.FCCC@fccc.edu.  
 

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2. If the site Investigator or site IRB feels the event warrants a revision 
to the informed consent that was not already initiated by the OCR, 
draft revisions will be made in track changes and submitted to the 
OCR for consideration.  Any consent revisions must receive OCR 
approval prior to submission to the IRB. 
 
3. Any investigator who is in doubt of whether a particular AE needs to 
be reported is directed to call the Study Monitor for confirmation with 
the Sponsor Investigator 
 
4. If the results of an investigator or OCR investigation show an adverse 
event not initially determined to be reportable is so reportable, the 
investigator will report the event following the above guidelines 
based on the date the determination is made. 
 
5. Copies of all related correspondence and reporting documents must 
be submitted to the IST Regulatory Specialist and will be maintained 
in the trial master file.  
 
Participating sites should report events to: 
 
IST Regulatory Specialist 
Fox Chase Cancer Center 
Office of Clinical Research 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone 215-214-1439 
SAE.FCCC@fccc.edu 
 
10.6.3. OCR Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported 
to all participating institutions for IRB submission within 2 weeks of 
notification of the event.   
a. Unexpected (in terms of nature, severity, or frequency) given  
i. (a) the research procedures that are described in the 
protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and  
ii. (b) the characteristics of the subject population being 
studied; 
b. Possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
c. Serious (refer to above definition) or otherwise one that suggests 
that the research places subjects or others at a greater risk of 

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physical or psychological harm than was previously known or 
recognized. 
2. If the adverse event requires modification of the study protocol and 
informed consent, these changes will be provided to all participating 
institutions in the form of an amendment from the OCR for each site’s 
IRB of record along with the report of the adverse event.   
3. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at OCR. 
4. SAEs that are related, unexpected, fatal, or life-threatening are 
reportable through the Food and Drug Administration (FDA) MedWatch 
program by telephone or fax no later than 7 calendar days after initial 
receipt of the information.  Further information on the timing of 
submissions is as directed by FDA guidelines 
(http://www.fda.gov/medwatch/index.html).  Serious, unexpected events 
that suggest significant clinical risk will be submitted to within 15 
calendar days after initial receipt of this information.   
 
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-332-FDA-0178 
http://www.fda.gov/medwatch/report.htm 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
10.7. OCR Reporting Responsibilities to BMS: 
 Serious Adverse Events (SAEs) 
All Serious Adverse Events (SAEs) that occur on or after the first day of study 
treatment to 100 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety. 
 
SAEs, whether related or not related to study drug, must be reported to BMS within 24 
hours of becoming aware of the event.  SAEs must be recorded on FDA MedWatch 
form 3500a. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  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.)  

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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 
of becoming aware of the changes to the BMS (or designee) using the same procedure 
used for transmitting the initial SAE report.  
 Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that 
a study subject is pregnant or may have been pregnant at the time of investigational 
product exposure, including 23 weeks after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (eg, dose tapering 
if necessary for subject safety).  
The sponsor must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
10.8. Pregnancy  
All WOCBP should be instructed to contact their site Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the site 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor 
who will notify Dr. Matthew Zibelman.  
 
11.0 
Measures of Effect 
Provide response criteria.  If RECIST criteria below are not applicable delete the 
following text and provide disease appropriate criteria with references. 
 
11.1. Response Evaluation Criteria in Solid Tumors (RECIST)  
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used 
for objective tumor response assessment.  Assessments will be performed after every 
two cycles of treatments. Once protocol treatment has been completed subjects will 
be assessed every three months or sooner as indicated and judged by treating 
physicians. 
 
11.2. Definitions 
Please use or modify the following text as appropriate. 

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Evaluable for adverse events.  All patients will be evaluable for adverse events from 
the time of their first treatment with Axitinib and Nivolumab. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.3. Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
 

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Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on 
the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected.  A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up.  
 
11.4. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
 
CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 

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MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, 
lesion conspicuity, and measurement.  Furthermore, the availability of MRI is 
variable globally.  As with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation of the type and 
site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
11.5. Response Criteria 
11.5.1. Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study 
 
11.5.2. Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 

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Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Sponsor-Investigator). 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
 
For patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 

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11.6.   Objective response rate (ORR) 
Objective response rate (ORR) is defined as the proportion of subjects with metastatic 
RCC who achieve a best response of complete response (CR) or partial response (PR) 
using the RECIST 1.1 criteria. It will be determined by the investigator for each 
subject as either CR or PR and will be calculated as percentage CR + PR.  
 
11.7. Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
12.0 
Statistical Considerations 
The phase I portion of the study is based on a standard 3+3 dose escalation design 
enrolling 6-12 patients and will be used to determine DLTs and RP2D. The phase II 
portion of the study will enroll 43 patients each in two separate cohorts of patients – 
previously treated and treatment naïve – with advanced RCC with the primary goal of 
assessing the overall response rate in each cohort.  
 
Power and sample size:  
 
Arm 1 (treatment naïve, first line): With 43 patients in this arm, we would be able to 
detect a 20% improvement in treatment response and achieve 82% power at the 5% 
significance level (one-sided). This calculation is based on a baseline response rate of 
30% obtained from historical data. [5] 
 
Arm 2 (prior TKI, no immunotherapy): With 43 patients in this arm, we would be able to 
detect a 19% improvement in treatment response and achieve 81% power at the 5% 
significance level (one-sided). This calculation is based on a baseline response rate of 
19% obtained from historical data. [4] 
 
 
Early stopping rule for toxicity:  
 
Evaluation of adverse events will be done separately in each cohort. We will stop the 
study early if 4 or more of the first 15 patients enrolled into each cohort experience a 
treatment related death or develop a grade 3 or grade 4 treatment related AEs that does 
not resolve or diminish in grade after 12 weeks of intervention.  Intervention can include 
but is not limited to treatment discontinuation, administration of steroids, administration 
of immune modulatory agents, or other supportive measures. The table below lists the 
probability of early stopping due to adverse events based on pre-specified true 
probabilities of such events in these individuals. 
 
 
Probability of stopping the study early due to adverse events in each cohort based 
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Probability of adverse 
event in an individual 
10% 
20% 
 
30% 
 
 
40% 
Probability of stopping 
early due to adverse 
events 
5.6% 
35.2% 
70.3% 
90.9% 
 
12.1. Analysis of Secondary Endpoints 
Adverse events and laboratory abnormalities will be summarized by type, frequency 
and severity; and serum biomarkers will be summarized using descriptive statistics. 
Time-to-event endpoints such as duration of response, overall survival and 
progression-free survival will be analyzed and summarized using Kaplan-Meier 
methods.   
 
12.2. Sample Size/Accrual Rate 
We anticipate accrual of 92-98 total patients over 18 months. 
 
12.3. Reporting and Exclusions 
12.3.1. Evaluation of toxicity:  
All patients will be evaluable for toxicity from the time of their first treatment 
with axitinib and nivolumab. 
 
12.3.2. Evaluation of response: 
Only those patients who have measurable disease present at baseline, have 
received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. Each patient will be assigned one of the 
following categories:  1) complete response, 2) partial response, 3) stable disease, 
4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates 
the “unknown” status of any type of data in a clinical database.] 
 
Patients in response categories 4-9 should be considered to have a treatment 
failure (disease progression).  An incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.   
 
13.0 
Data and Safety Monitoring Plan 
13.1. Monitoring Plan  
FCCC OCR will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the OCR will collect and report data 

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to the study Sponsor Investigator who will review these data on a regular basis at a 
rate dependent on subject accrual.  All serious adverse events (SAEs) will be 
reviewed on a real time basis first by the study site PI and subsequently by the OCR 
and Sponsor Investigator as applicable. 
 
13.2. Data Safety Monitoring Committee   
Interim analysis of toxicity, outcome and ongoing scientific investigations may be 
performed at least every 3 months by the Fox Chase Cancer Center Data Safety 
Monitoring Board (FCCC DSMB).  In this capacity the FCCC DSMB will serve as an 
advisory committee to the Study Sponsor-Investigator, the Associate Director of 
Clinical Research, and the Protocol Management Executive Committee.  The FCCC 
DSMB will review those aspects of this trial that are outlined in the responsibilities 
section of the Data and Safety Monitoring Plan (DSMP).  If the committee decides 
that changes should be made to this trial, it will make recommendations in writing to 
the Study Sponsor-Investigator, the Associate Director of Clinical Research, and the 
Protocol Management Executive Committee, which, in turn, have the authority to 
approve or disapprove these recommendations.  These changes will be discussed with 
the Study Sponsor-Investigator before they are implemented.  These changes may 
include early termination of accrual.  Other changes might include altering the accrual 
goals or changing the eligibility criteria for the trial. 
 
14.0 
Administrative   
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
14.1. Data Reporting 
The FCCC Clinical Research Monitor will request case report forms to be completed 
within 2 weeks of the protocol visit.  Participating sites are responsible to respond to 
queries prior to the next scheduled monitoring visit 
The OCR staff is responsible for compiling and submitting data to the Sponsor 
Investigator and statistician on an ongoing basis for monitoring as described in the 
data safety monitoring plan and reporting to the Data and Safety Monitoring 
Committee. 
 
All patient information will be stored in an EDC system accessible only to the study 
team members for the purpose of entering, reviewing and analyzing data.  Any paper 
records, such as case report files, produced will be stored in a secure location.  
 
The IST Regulatory Specialist is responsible for distributing and tracking review of 
all IND Action Letters, Safety Reports, and study specific Serious Adverse Events. 
 
14.2. Retention of Records   
Time points for the retention of records are described in detail in the contract between 
the grantor and the OCR and passed on to the participating site.  Please refer to the 

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study specific terms for specific time points.  In all cases the FCCC Clinical Research 
Monitor must be notified of any plans to move records to an offsite location prior to 
doing so. 
 
14.3. Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol.  The 
agent may not be transferred to any party not participating in the clinical trial. 
 
14.4. Informed Consent 
The IRB approved informed consent documents must be signed by the patient before 
his or her participation in the study.  The case history for each patient shall document 
that informed consent was obtained prior to participation in the study.  A copy of the 
informed consent documents must be provided to the patient.  If applicable, they will 
be provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical 
record with a copy in the study file. 
 
 
 

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15.0 References 
1. 
Institute, N.C., SEER Stat Facts Sheet: Kidney and Renal Pelvis Cancer, in Surveillance, 
Epidemiology, and End Results (SEER) Program. 2016. 
2. 
Thomas, J.S. and F. Kabbinavar, Metastatic clear cell renal cell carcinoma: A review of 
current therapies and novel immunotherapies. Critical reviews in oncology/hematology, 
2015. 96(3): p. 527-533. 
3. 
Motzer, R.J., et al., Nivolumab versus everolimus in advanced renal-cell carcinoma. New 
England Journal of Medicine, 2015. 
4. 
Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-
Cell Lung Cancer. N Engl J Med, 2015. 
5. 
Wolchok, J.D., et al., Nivolumab plus Ipilimumab in Advanced Melanoma. New England 
Journal of Medicine, 2013. 369(2): p. 122-133. 
6. 
Zhao, X., et al. A model-based exposure–response (ER) assessment of a nivolumab (NIVO) 
4-weekly (Q4W) dosing schedule across multiple tumor types. in Proceedings of the 
AACR Annual Meeting. 2017. 
7. 
Hammers, H.J., et al. Expanded cohort results from CheckMate 016: A phase I study of 
nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). in 
ASCO Annual Meeting Proceedings. 2015. 
8. 
Choueiri, T., et al. Phase Ib Dose-Finding Study of Axitinib Plus Pembrolizumab in 
Treatment-Naive Patients With Advanced Renal Cell Carcinoma. in Kidney Cancer 
Symposium. 2015. Miami, FL. 
9. 
Atkins, M.B., et al., Axitinib in combination with pembrolizumab in patients with 
advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-
expansion phase 1b trial. The Lancet Oncology, 2018. 
 
 
 
 

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15.0 
Appendix  
15.1. Appendix I 
Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other 
symptoms of allergic-like reactions.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE guidelines. 
Treatment recommendations are provided below:  
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; 
intervention not indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen), famotidine 
20 mg PO or IV (or alternative H2 antagonist), and could consider addition of 
paracetamol at least 30 minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; 
prophylactic medications indicated for 24 hours). 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent), famotidine 20 mg IV or equivalent 
and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor 
subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If patient continues to react, rate can be decreased sequentially 
by 50% as low as 1/8 rate and then increased as tolerated in cycle or with subsequent 
cycles. If patient is unable to tolerate at 1/8 rate or unable to be escalated, alternative 
options may need to be arranged with study team and medical monitor. If symptoms 
recur then no further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent), famotidine 
20 mg IV or equivalent and/or paracetamol 325 to 1000 mg (acetaminophen) should be 
administered at least 30 minutes before additional nivolumab administrations. If 

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necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated).  
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 
to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 
mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Subject should 
be monitored until the investigator is comfortable that the symptoms will not recur. 
Nivolumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (eg. appearance of a localized 
or generalized pruritis within 1 week after treatment), symptomatic treatment may be 
given (eg. oral antihistamine, or corticosteroids). 
 
 
15.2. Appendix II 
Management for immune related Adverse Events 
 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. 
 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab. The 
frequency of pulmonary AEs may be greater with nivolumab combination therapies 
than with nivolumab monotherapy. The majority of cases reported were Grade 1 or 2, 
and subjects presented with either asymptomatic radiographic changes (eg. focal 
ground glass opacities and patchy infiltrates) or with symptoms of dyspnea, cough, or 
fever. Subjects with reported Grade 3 or 4 pulmonary AEs were noted to have more 
severe symptoms, more extensive radiographic findings, and hypoxia. 
 
Pulmonary Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Evaluate with imaging and pulmonary consultation. 

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Grade of 
Pneumonitis 
Management 
Follow-up 
Grade 1 
Radiographic changes 
only 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and 
Infectious Disease (ID) consults 
• Re-image at least every 3 
weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Mild to moderate new 
symptoms 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, 
consider hospitalization 
• 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Consider bronchoscopy , lung 
biopsy 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to 
near baseline, taper steroids 
over at least 1 month and then 
resume I-O therapy per 
protocol and consider 
prophylactic antibiotics 
If not improving after 2 weeks 
or worsening: 
• Treat as Grade 3-4 
Grade 3-4 
Severe new 
symptoms; 
New/worsening 
hypoxia; Life-
threatening 
• Discontinue I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
sy 
If improves to baseline: 
• Taper steroids over at least 6 
weeks 
If not improving after 48 hours 
or worsening: 
• Add additional 
immunosuppression (e.g. 
infliximab, cyclophosphamide, 
intravenous immunoglobulin 
(IVIG), or mycophenolate 
mofetil) 
 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 

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Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. 
Most cases of diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently 
than diarrhea. High-grade cases of diarrhea and colitis were managed with 
corticosteroids and, in all cases, the events resolved. 
 
GI Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue I-O therapy. Opiates/narcotics may mask symptoms of 
perforation. Infliximab should not be used in cases of perforation or sepsis. 
 
Grade of Diarrhea/ 
Colitis 
Management 
Follow-up 
Grade 1 
Diarrhea:< 4 stools/day over 
baseline;  
Colitis: asymptomatic 
• Continue I-O therapy 
per protocol 
• Symptomatic 
treatment 
• Close monitoring for worsening 
symptoms. 
• Educate patient to report 
worsening immediately 
If worsens: 
• Treat as Grade (G) 2 or 3/4 
Grade 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated <24 hours (hrs); not 
interfering with ADL 
Colitis: abdominal pain; blood 
in stool 
• Delay I-O therapy per 
protocol 
• Symptomatic 
treatment 
If improves to grade 1: 
• Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
• 0.5-1.0 mg/kg/day 
methylprednisolone or oral 
equivalent 
• When symptoms improve to grade 
1, taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O therapy 
per protocol. 
If worsens or persists > 3-5 days 
with oral steroids: 
• Treat as grade 3/4 
Grade 3-4 
• Discontinue I-O 
therapy per protocol 
If improves: 

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Diarrhea (G3): ≥7 stools per 
day over baseline; incontinence; 
IV fluids ≥24 hrs; interfering 
with activities of daily living 
(ADL) 
Colitis (G3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs 
G4: life-threatening, perforation 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consider lower 
endoscopy 
• Continue steroids until grade 1, 
then taper over at least 1 month 
If persists > 3-5 days, or recurs after 
improvement: 
• Add infliximab 5 mg/kg (if no 
contraindication). 
Note: Infliximab should not be used 
in cases of perforation or sepsis 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, DILI, 
have been observed following treatment with nivolumab and nivolumab in 
combination with ipilimumab. Most cases were of low or moderate grade. Higher-
grade hepatic AEs, including DILI, were managed with corticosteroids (with or 
without mycophenolate mofetil) and, in almost all cases, the events resolved. 
 
Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider imaging for obstruction. 
 
Grade of Liver 
Test Elevation 
Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 
3.0 x ULN and/or Total 
bilirubin (T. bili) > ULN 
- 1.5 x ULN 
• Continue I-O therapy per 
protocol 
 
• Continue liver function tests 
(LFT) monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 3.0 to ≤ 5 
x ULN and/or T. bili > 
1.5 to ≤ 3 x ULN 
• Delay I-O therapy per 
protocol 
• Increase frequency of 
monitoring to every 3 days 
If returns to baseline: 
• Resume routine monitoring, 
resume I-O therapy per protocol 
If elevations persist > 5-7 days or 
worsen : 

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• 0.5-1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT returns to 
grade 1 or baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
I-O therapy per protocol 
Grade 3-4 
AST or ALT > 5 x ULN 
and /or T.bili >3 x ULN 
• Discontinue I-O therapy* 
• Increase frequency of 
monitoring to every 1-2 days 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics 
for opportunistic infections 
• Consult gastroenterologist 
If returns to grade 2: 
• Taper steroids over at least 1 
month  
If does not improve in >3-5 days, 
worsens or rebounds: 
• Add mycophenolate mofetil 1 
gram (g) twice daily (BID) 
• If no response within an additional 
3-5 days, consider other 
immunosuppressants per local 
guidelines 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN and 
T.bili ≤ 5 x ULN. 
 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day 
methylprednisolone IV. 
 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment 
with nivolumab. The rash was typically focal with a maculopapular appearance 
occurring on the trunk, back, or extremities. Most cases have been of low or moderate 
grade. In some cases, rash and pruritus resolved without intervention. Topical 
corticosteroids have been used for some cases of rash. Anti-histamines have been 
used for some cases of pruritus. More severe cases responded to systemic 
corticosteroids. 
 
Skin Adverse Event Management Algorithm 

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Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Grade of Rash 
Management 
Follow-up 
Grade 1-2 
 
Covering ≤ 30% 
body surface area 
(BSA) 
• Symptomatic therapy (e.g. 
antihistamines, topical 
steroids) 
 
• Continue I-O therapy per 
protocol 
 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral equivalent. 
Once improving, taper steroids over at least 
1 month, consider prophylactic antibiotics 
for 
opportunistic infections, and resume I-O 
therapy per protocol 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
 
Covering >30% 
BSA; 
Life threatening 
consequences 
• Delay or discontinue I-O 
therapy per protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV 
methylprednisolone 
IV or IV equivalent 
If improves to Grade 1: 
• Taper steroids over at least 1 month and 
add 
prophylactic antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic 
nephritis have been infrequently observed following treatment with nivolumab. The 
frequency of renal AEs may be greater with nivolumab combination therapies than 
with nivolumab monotherapy. Most cases were Grade 2 or 3 and based on creatinine 
elevation. Subjects with a history of RCC or prior nephrectomy did not appear to be 
at higher risk. Events were managed with corticosteroids and, in all cases, renal 
function partially or fully improved. 
 
Renal Adverse Event Management Algorithm 

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Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy 
Grade of Creatinine 
Elevation 
Management 
Follow-up 
Grade 1 
Creatinine > upper limit 
of normal (ULN) and > 
than baseline but ≤ 1.5x 
baseline 
• Continue I-O therapy per 
protocol 
• Monitor creatinine weekly 
 
If returns to baseline: 
•Resume routine creatinine 
monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine > 1.5x 
baseline to ≤ 6x ULN 
• Delay I-O therapy per 
protocol 
• Monitor creatinine every 2-
3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• Consider renal biopsy 
If returns to Grade 1: 
•Taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O therapy 
and routine creatinine monitoring 
per protocol 
If elevations persist > 7 days or 
worsen: 
•Treat as Grade 4 
Grade 4 
Creatinine > 6x ULN 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
If returns to Grade 1 : 
 Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 
 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Neurologic Adverse Events 

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Neurologic AEs have been uncommonly observed following treatment with 
nivolumab. Neurologic AEs can manifest as central abnormalities (eg, aseptic 
meningitis, encephalopathy, or encephalitis) or peripheral sensory/motor neuropathies 
(eg, Guillain-Barre Syndrome, myasthenia gravis complicated with sepsis and 
fatality). 
 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Grade of Neurological 
Toxicity 
Management 
Follow-up 
Grade 1 
Asymptomatic or mild 
symptoms; Intervention 
not indicated 
• Continue I-O therapy per 
protocol 
 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local 
guidelines 
• Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
•Resume I-O therapy per protocol 
when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
Severe symptoms; 
Limiting self-care ADL; 
Life-threatening 
• Discontinue I-O therapy per 
protocol 
• Obtain neurology consult 
• Treat symptoms per local 
guidelines 
• 1.0-2.0 mg/kg/day IV 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade 2: 
• Taper steroids over at least 1 
month 
If worsens or atypical 
presentation: 
• Consider IVIG or other 
immunosuppressive therapies per 
local guidelines 
 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Endocrinopathies 

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Endocrinopathies have been observed following treatment with nivolumab. Most 
cases were of low or moderate grade. The events have typically been identified 
through either routine periodic monitoring of specific laboratories (eg, TSH) or as 
part of a work-up for associated symptoms (eg, fatigue). Events may occur within 
weeks of beginning treatment, but also have been noted to occur after many months 
(while still on treatment). More than 1 endocrine organ may be involved (eg, 
hypophysitis [pituitary inflammation] may need to be evaluated at the time adrenal 
insufficiency or thyroid disorder is suspected). Moderate- to high-grade cases were 
managed with hormone replacement therapy and, in some cases, with the addition of 
corticosteroids. In some cases, nivolumab treatment was held until adequate hormone 
replacement was provided. 
 
Endocrinopathy Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider visual field testing, endocrinology consultation, and 
imaging. 
 
Asymptomatic thyroid 
stimulating hormone (TSH) 
elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x lower limit of normal (LLN), or TSH > 2 x 
ULN, or consistently out of range in 2 subsequent 
measurements: include free thyroxine (fT4) at subsequent 
cycles as clinically indicated; consider endocrinology 
consult 
Symptomatic 
endocrinopathy 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal 
lab/pituitary scan: 
• Delay I-O therapy per 
protocol 
• 1-2 mg/kg/day 
methylprednisolone IV or by 
mouth (PO) equivalent 
• Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary MRI 
scan but symptoms persist: 
If improves (with or 
without hormone 
replacement): 
• Taper steroids over at 
least 1 month and 
consider prophylactic 
antibiotics for 
opportunistic infections 
• Resume I-O therapy per 
protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid 
component 

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• Repeat labs in 1-3 weeks 
/MRI in 1 month 
Suspicion of adrenal crisis 
(e.g. severe dehydration, 
hypotension, shock out of 
proportion to current illness 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as above for 
symptomatic endocrinopathy 
 
Patients 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 of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
15.3. Appendix III 
Dose escalation/de-escalation decision rules 
 
First 3 patients on Dose Level 0 (DL0) 
0 out of 3 DLT 
Escalate to DL+1 and accrue 3 patients. 
1 out of 3 DLT 
Keep at DL0 and accrue 3 more patients. 
≥ 2 DLT 
De-escalate to DL -1. 
For patients escalated to Dose Level +1 (DL+1) 
0-1 out of 3 DLT 
Keep at Dose Level +1 and accrue 3 more patients. If 0-1 DLT 
out of 6 patients at DL+1, this is RP2D. 
≥ 2 DLT 
De-escalate back to DL0 and accrue 3 patients. If 6 patients have 
already been treated at DL0 with 0-1 DLT, declare DL0 as RP2D. 
Once 6 patients accrue to DL0 
0-1 DLT 
DL0 is RP2D. 
≥ 2 DLT 
De-escalate to DL-1 and accrue 3 patients. 
For patients de-escalated to DL-1 
0-1 out of first 3 
patients 
Keep at DL-1 and accrue 3 patients. If no more than 0-1 DLT out 
of 6 patients at DL-1, declare this as RP2D. 
≥ 2 DLT 
Stop study for toxicity.