Conditions: Advanced Melanoma Unresectable Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is Phase II trial of nivolumab plus axitinib for patients with unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant anti-CTLA4 therapy. Patients will receive treatment with nivolumab 480 mg intravenously every 4 weeks and axitinib 5 mg twice daily by mouth. Patients may continue both agents for up to two years if they do not experience disease progression or dose-limiting toxicities.

Detailed description:
This trial hypothesizes that decreasing hypoxia in the TME will re-sensitize melanoma tumors to anti-PD1 therapy. Axitinib has already been safely combined with anti-PD1 therapy and was overall well-tolerated. With nivolumab plus axitinib taken together, based on previously published work and data from our laboratories, it is hypothesized that axitinib can metabolically remodel the TME to render it more sensitive to ICB, specifically by reducing intra-tumoral hypoxia, increasing T cell infiltration, and increasing polyfunctional T cells. It will determined if treatment with nivolumab plus axitinib will prolong both progression-free and overall survival.

Arms:
arm 1: Nivolumab 480mg, IV, every 4 weeks, for up to two years.

Axitinib 5mg, PO, BID, for up to two years.

Interventions: intervention 1: Nivolumab intervention 2: Axitinib
Intervention descriptions: intervention 1: Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It is a type of Immunotherapy and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer. intervention 2: Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor.Its primary mechanism of action is thought to be vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours)

Protocol document:
Prot_SAP_000.pdf: 
 
Nivolumab and Axitinib Phase II Study  
  
 
 
1
  
 
TITLE: A Phase II Trial of Nivolumab plus Axitinib in Patients with Anti-PD1 Refractory 
Advanced Melanoma (HCC 20-101, CA209-7UE).  
Protocol Version 7.0, 01/03/2024  
IND NUMBER: 154662 
Principal Investigator: Yana Najjar, MD 
UPMC Hillman Cancer Center 
5115 Centre Ave 
Suite 1.32C 
Pittsburgh, PA 15232 
 
 
Statistician: Hong Wang, PhD  
 
 
 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
2
CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................5 
2.0 
TRIAL DESIGN ......................................................................................................5 
2.1 
Trial Design ..........................................................................................................5 
2.2 
Trial Diagram ......................................................................................................6 
OBJECTIVE(S) & HYPOTHESIS(ES) .............................................................................6 
2.3 
Primary Objective(s) & Hypothesis(es) ..............................................................6 
2.4 
Secondary Objective(s) & Hypothesis(es) ...........................................................6 
3.0 
BACKGROUND & RATIONALE..........................................................................7 
3.1 
Background ..........................................................................................................7 
3.1.1 Pharmaceutical and Therapeutic Background ................................................... 12 
3.1.2 Preclinical and Clinical Trial Data .................................................................... 13 
3.2 
Rationale ............................................................................................................ 13 
3.2.1 Rationale for the Trial and Selected Subject Population .................................... 13 
3.2.2 Rationale for Dose Selection/Regimen/Modification ........................................ 14 
3.2.3 Rationale for Endpoints .................................................................................... 15 
4.0 
METHODOLOGY ................................................................................................ 15 
4.1.1 Subject Inclusion Criteria ................................................................................. 15 
4.1.2 Subject Exclusion Criteria ................................................................................ 17 
4.2 
Trial Treatments ................................................................................................ 20 
4.2.2 Patient Compliance .......................................................................................... 21 
4.2.3 Duration of Therapy ......................................................................................... 21 
4.2.4 Starting Dose and Modifications ...................................................................... 21 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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4.2.5 Timing of Dose Administration ........................................................................ 23 
4.2.6 Trial Blinding/Masking .................................................................................... 24 
4.3 
Rescue Medications & Supportive Care ........................................................... 24 
4.3.1 Supportive Care Guidelines .............................................................................. 24 
4.4 
Diet/Activity/Other Considerations ................................................................... 28 
4.4.1 Diet .................................................................................................................. 28 
4.4.2 Contraception ................................................................................................... 28 
4.4.3 Use in Pregnancy ............................................................................................. 30 
4.4.4 Use in Nursing Women .................................................................................... 30 
4.5 
Subject Withdrawal/Discontinuation Criteria .................................................. 31 
4.5.1 Discontinuation of Study Therapy after CR ...................................................... 32 
4.6 
Clinical Criteria for Early Trial Termination .................................................. 32 
5.0 
TRIAL PROCEDURES......................................................................................... 33 
5.1 
Study Flow Chart ............................................................................................... 33 
5.1.1 Administrative Procedures ............................................................................... 35 
5.1.2 Clinical Procedures/Assessments ...................................................................... 36 
5.1.3 Laboratory Procedures/Assessments ................................................................. 38 
5.1.4 Other Procedures .............................................................................................. 39 
5.1.5 Visit Requirements ........................................................................................... 39 
5.2 
Assessing and Recording Adverse Events ......................................................... 40 
5.2.1 Reporting of Pregnancy and Lactation to the Sponsor ....................................... 40 
5.2.2 Immediate Reporting of Adverse Events to the Sponsor and to BMS and 
Pfizer ............................................................................................................... 41 
5.2.3 Evaluating Adverse Events ............................................................................... 45 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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5.2.4 Sponsor Responsibility for Reporting Adverse Events ...................................... 47 
6.0 
STATISTICAL Consideration .............................................................................. 47 
6.1 
Study Design....................................................................................................... 47 
6.2 
Safety monitoring ............................................................................................... 47 
6.3 
Sample Size and Accrual ................................................................................... 48 
6.4 
Statistical Analysis Plan ..................................................................................... 49 
6.4.1 Analysis Sets .................................................................................................... 49 
6.4.2 Analysis of ORR (Primary) .............................................................................. 49 
6.4.3 Safety Analysis (Secondary)............................................................................. 49 
6.4.4 Analysis of PFS and OS (Secondary) ............................................................... 50 
6.4.5 Correlative Translational Assays (Secondary) .................................................. 50 
7.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .............................................................................................................. 50 
7.1 
Investigational Product ...................................................................................... 50 
7.2 
Clinical Supplies Disclosure............................................................................... 51 
7.3 
Storage and Handling Requirements ................................................................ 51 
7.4 
Returns and Reconciliation ............................................................................... 51 
8.0 
ADMINISTRATIVE AND REGULATORY DETAILS   8.1 Data Safety and 
Monitoring Plan ..................................................................................................... 51 
9.0 
APPENDICES ........................................................................................................ 54 
9.1 
ECOG Performance Status ............................................................................... 54 
9.2 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ............... 54 
9.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 54 
 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Nivolumab Plus Axitinib in Anti-PD1 Refractory Advanced Melanoma  
Trial Phase 
Phase II 
Clinical Indication 
Unresectable Stage III or IV Melanoma 
Trial Type 
Interventional, Clinical Translational  
Type of control 
Single arm study with historical control  
Route of administration 
Nivolumab IV, Axitinib PO 
Trial Blinding 
No 
Treatment Groups  
1 Arm: Nivolumab plus Axitinib  
Number of trial subjects 
31 
Estimated enrollment period 
2.5 years 
Estimated duration of trial 
4.5 years (2.5 years accrual, up to 2 years on treatment).  
Duration of Participation 
Up to 2 years  
Estimated average length of 
treatment per patient 
Up to 2 years 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an investigator-initiated, phase II trial of nivolumab plus axitinib for patients with 
unresectable stage III or IV melanoma who have progressed on prior anti-PD1 therapy with or 
without concomitant anti-CTLA4 therapy. Patients will receive treatment with nivolumab 480 
mg IV every 4 weeks and axitinib PO 5 mg twice daily. Patients may continue both agents for 
up to two years if they do not experience progression or dose-limiting toxicity. Biopsies will 
be taken at baseline and at 12 weeks for an in-depth evaluation of the impact of the combination 
on the tumor and tumor microenvironment (TME), with an optional biopsy at the time of 
progression (Figure 1). We have shown that tumor oxidative metabolism and resultant hypoxia 
are associated with resistance to immunotherapy (IMT).1 We have shown that in mice, a low 
dose of axitinib decreases intra-tumoral hypoxia and synergizes with checkpoint inhibitors 
(ICB) to eradicate melanoma tumors. Thus, we hypothesize that decreasing hypoxia in the 
TME will re-sensitize melanoma tumors to anti-PD1 immunotherapy and overcome resistance. 
Blood for research studies will be drawn at baseline (up to 7 days prior to initiation of therapy), 
at week 12, and at the time of progression. Patients will receive an oral dose of pimonidazole 
(0.5 g/m2)2  before each biopsy to permit in vivo evaluation of intra-tumoral hypoxia. This 
drug is safe, well-tolerated, and has been previously used in cancer patients to evaluate hypoxia 
without reported toxicity.3-5 Pimonidazole hydrochloride (Natural Pharmacia International, 
Belmont, MA) has IND status for use for the clinical evaluation of hypoxia.3 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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2.2 
Trial Diagram 
 
Figure 1. Study Schema  
 
OBJECTIVE(S) & HYPOTHESIS(ES) 
2.3 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To assess the overall response rate (ORR) of nivolumab plus axitinib in 
patients with anti-PD1 refractory melanoma as measured by clinical tumor measurement 
and radiologic tumor measurement by CT scans at baseline and after 12 weeks of 
treatment. 
Hypothesis:  Patients treated with nivolumab and axitinib will have a response rate 
greater than the estimated response rate in anti-PD1 refractory patients, which is 
approximately 10%. We propose this improved response will be due to a reduction of 
intra-tumoral hypoxia and resultant T cell dysfunction. 
2.4 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective: To evaluate the safety of the combination of nivolumab and axitinib.  
 
Hypothesis: The combination of nivolumab and axitinib will be safe and well-tolerated.  
(2) Objective: To determine the progression-free survival (PFS) and overall survival (OS) for 
patients treated with nivolumab plus axitinib.  
Hypothesis: Treatment with nivolumab plus axitinib will prolong both PFS and OS.  


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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Exploratory Objectives: Correlative analyses will include and are not limited to 
evaluation of hypoxia in the TME, TIL function, immune phenotype and tumor cell 
metabolism.  
Hypothesis: Combination treatment will decrease intra-tumoral hypoxia, improve TIL 
function and yield a more favorable immune infiltrate.  
 
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
 
With the regulatory approval of multiple effective new agents, the treatment paradigm for 
metastatic melanoma has changed drastically over the past several years. IMT has emerged as 
a viable and effective treatment for melanoma. However, despite the fact that response rates 
have increased in patients with advanced disease, only 40% of patients receive benefit from 
anti-PD1 monotherapy.6 While response to the combination therapy (i.e., ipilimumab plus 
nivolumab) is closer to 60%, it is important to note that over half of these patients experience 
grade III/IV toxicities.7 Furthermore, many patients who initially respond to treatment, later 
acquire resistance and ultimately progress. The mechanism behind this heterogenous response 
to IMT remains unclear, and to date, no validated biomarkers can reliably predict response in 
patients with advanced melanoma. PD-L1 expression, tumor mutational burden, immune gene 
signatures, and various other predictive biomarkers are under active investigation.8,9 
Multiple mechanisms of resistance to IMT may be at play in melanoma. However, one key 
mechanism is the generation of an immunosuppressive and metabolically harsh TME.10-12 The 
TME is generally considered to be nutrient poor, with decreased essential nutrients for T cell 
function such as glucose and amino acids, along with concurrent buildup of toxic byproducts 
such as lactic acid.11 This altered metabolic landscape is induced by two main drivers: an 
altered angiogenic pattern as well as the intrinsic deregulated metabolism of the tumor itself. 
Unrestrained oxidative metabolism in the context of inadequate vasculature results in hypoxia, 
and increased glycolysis generates an acidic environment.13 T cell effector functions are bio-
energetically demanding and require fuel from the local environment.10 Thus, despite adequate 
recruitment, the immune response may be blunted due to T cell dysfunction in part due to a 
failure to generate the energy required to meet their metabolic needs.  
It is important to note that to date, there is no single standard of care to salvage patients who 
have progressed on IMT. Furthermore, metabolism represents a key, primordial mechanism by 
which T cells can be regulated, as we propose here.  


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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We have shown that TIL harvested from melanoma-bearing mice have low mitochondrial mass 
and depressed glucose uptake. Metabolic 
profiling of T cells from tumors using 
Seahorse 
cell 
analysis 
reveals 
dramatically 
repressed 
oxidative 
function.14 We have also shown that co-
inhibitory molecules (PD-1, TIM-3, LAG-
3) correlate with both T cell dysfunction 
and metabolic insufficiency. Thus, as T 
cells become increasingly ‘exhausted’, 
they also display increased metabolic 
insufficiency.  
We have utilized an immunometabolic 
profiling platform (Figure 2A) that allows 
for 
comprehensive 
analysis 
of 
the 
patients’ tumor metabolism, immune 
infiltrate and T cell function, and 
hypoxia.1 We have recently shown that 
tumor cells from a cohort of 30  melanoma 
patients obtained prior to treatment with 
IMT  exist across a wide metabolic 
spectrum 
(Figure 
2B), 
with 
high 
oxidative 
metabolism 
(OCR) 
and 
glycolytic 
metabolism 
(ECAR), 
hypermetabolic tumors that deregulate both pathways, or more indolent tumors with low 
metabolic activity.1 Further, we found that CD8+ TILs isolated from tumors with high OCR 
(irrespective of tumor cell glycolysis) have significantly decreased polyfunctionality [IFN-γ 
and TNF-α co-production (Figure 2C)], whereas glycolytic capacity of tumors as measured 
by ECAR did not significantly correlate with T cell functionality (Figure 2D).1  
Patient
tumor bx
Seahorse profiling 
of tumor cells
FACS analysis
of TIL function
0
1 0
2 0
3 0
4 0
5 0
0
2 5
5 0
7 5
1 0 0
1 2 5
1 5 0
n o rm a liz e d  E C A R  (m p H /m in )
n o rm a liz e d  b a s a l O C R
O C R  lo O C R  h i
0
2 0
4 0
6 0
8 0
% IF N 
+ T N F 
+  [in  C D 8
+ ]
*
E C A R  lo E C A R  h i
0
2 0
4 0
6 0
8 0
% IF N 
+ T N F 
+  [in  C D 8
+ ]
n s
A
B
C
D
Figure 2. Functionality of melanoma TILs is related 
to oxidative metabolism of tumor cells. A, Scheme 
for immunometabolic profiling. B, OCR and ECAR of 
tumor cells from individual melanoma patients before
immunotherapy. C,D, Polyfunctionality (IFN and 
TNF 
co-production) 
in 
PMA/ionomycin 
re-
stimulated TILs as a function of tumor cell (C) OCR 
or (D) ECAR. 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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To evaluate the impact that deregulated oxidative metabolism has on treatment response to 
anti-PD1, we characterized a cohort of 19 patients with metastatic melanoma just prior to anti-
PD1 treatment. Interestingly, patients who did not respond to anti–PD1 checkpoint blockade 
(n = 10) had tumor cells characterized by increased oxidative metabolism (Figure 3A) while 
glycolytic metabolism had no strong predictive value (Figure 3B). High oxidative tumor cell 
metabolism was associated with decreased PFS, DOR, and OS (Figure 3C) with anti–PD-1 
ICB. Of note, anti-PD1 non-responders had increased staining with CAIX, a marker of intra-
tumoral hypoxia. (Figure 3D).  
 
Preliminary studies: 
N R
R
0
2 0
4 0
6 0
8 0
1 0 0
n o rm a liz e d  O C R  (p m o l/m in )
*
N R
R
0
2 0
4 0
6 0
n o rm a liz e d  E C A R  (m p H /m in )
n s
0
1 0
2 0
3 0
4 0
0
5 0
1 0 0
m o n th s  p o s t tre a tm e n t
O v e ra ll s u rv iv a l
O C R  h ig h
O C R  lo w
* p  =  0 .0 4
0
1 0
2 0
0
5 0
1 0 0
d u ra tio n  o f re s p o n s e
P ro g re s s io n  fre e  re s p o n d e rs  (% )
O C R  h ig h
O C R  lo w
* p  =  0 .0 1 0
A
B
C
Figure 3. Tumor cells OXPHOS and
consequent hypoxia is correlated with 
resistance to PD1 blockade in melanoma.
A,B OCR (A) and ECAR (B) of tumor cells
from patients with progressive disease (NR) 
or stable disease (partial or complete
response, R). C, OR and PFS after anti-PD1
immunotherapy, as a function of tumor cell 
OCR. D, Carbonic anhydrase IX (CAIX;
upregulated by hypoxia) IHC staining in pre-
treatment biopsies from PD1 non-responders
or responders. 
e
CAIX
PD-1 non-responders
PD-1 responders
D


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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We have shown that patients whose tumors 
have high oxidative metabolism possess high 
intra-tumoral 
hypoxia, 
and 
that 
this 
phenotype is linked with T cell exhaustion 
and 
dysfunction.1 
Further, 
oxidative 
metabolism is associated with decreased 
PFS, DOR, and OS in patients with advanced 
melanoma. We have additionally found that 
tumor cells are more metabolically active 
after progression on IMT (Figure 4). Thus, 
strategies to remodel the TME’s metabolic 
landscape are especially important in patients 
progressing on IMT. 
 
However, as discussed above, 
patients progressing on anti-PD1 
therapy present a new problem—
their TME has changed to become 
more 
aggressive, 
more 
immunosuppressive, 
and 
even 
more metabolically deregulated, 
with altered angiogenic patterns to 
support this increased metabolic 
state. As previously described, 
tumors create a tortuous blood 
supply 
through 
increased 
expression of VEGF, which 
creates both zones of hypoxia 
and highly perfused areas. In 
a 
cohort 
of 
10 
paired 
melanoma patient samples (at 
baseline and at progression on 
anti-PD1), we found that 
VEGFR1 
is 
variably 
expressed, 
VEGFR2 
is 
consistently 
strongly 
expressed (consistent with 
previous 
studies), 
and 
VEGFR3 is upregulated in the 
TME at progression on anti-
PD1 (Figure 5). Here, we 
seek to target the VEGF 
pathway with axitinib to 
Figure 5: VEGFR expression in tumor biopsies from 
patients prior to anti-PD1 and at progression. Paired 
patient tissue prior to (pre) and at progression on (post) 
anti-PD1 based IMT was stained for VEGFR1, 
VEGFR2 and VEGFR3, all targets of axitinib. VEGFR1 
staining was low and variable, VEGFR2 staining was 
consistently strong, and VEGFR3 staining was 
upregulated at progression. *p=0.022 by paired t-test.  
Figure 6. Low-dose axitinib reduces intratumoral 
hypoxia. Hypoxia staining by anti-pimo antibodies of
B16 melanoma. Tumor-bearing mice received vehicle or
axitinib at high or low dose for 4 days. Mice were pulsed
with pimo before being euthanized. While high-dose
axitinib exacerbates hypoxia, low-dose axitinib lowers
intertumoral hypoxia. 
N R
R
p r o g
0
2 5
5 0
7 5
n o r m a liz e d  O C R  ( p m o l/ m in )
m e la n o m a  p t
t u m o r  c e lls
p r e - t r e a t m e n t
N R
R
p r o g
0
2 5
5 0
n o r m a liz e d  E C A R  ( m p H / m in )
m e la n o m a  p t
t u m o r  c e lls
p r e - t r e a t m e n t
Figure 
4. 
Tumor 
cells 
from 
melanoma patients who progress on
ICB are uniformly hypermetabolic. 
OCR and ECAR of patient tumor cells
pre-treatment (subdivided by response, 
as previously published) or obtained at


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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correct the vasculature and restore metabolic balance to promote a better immune response. 
Axitinib is a VEGF receptor small molecule tyrosine kinase inhibitor with demonstrated safety 
and tolerability when combined with anti-PD1.15,16 Further, axitinib has high inhibitory activity 
for VEGFR1, 2, and 3, which are each involved in altered angiogenesis. We hypothesize that 
by modulating/correcting angiogenesis, axitinib will decrease intra-tumoral hypoxia and 
thus reduce T cell dysfunction. We have shown that a low dose of axitinib is superior to a 
higher dose of axitinib in reducing intra-tumoral hypoxia in B16 melanoma (Figure 6). This 
finding is significant because we previously demonstrated that intra-tumoral hypoxia is 
associated with T cell exhaustion and decreased T cell effector function.1 We have also 
performed pre-clinical experiments with anti-PD1 plus axitinib in murine models. Here, 
axitinib was given concurrently in B16 melanoma (generally insensitive to ICB) or in MC38 
adenocarcinoma (partially sensitive to anti-PD1). The combination of low dose axitinib and 
ICB (CTLA4+PD1 in B16, PD1 monotherapy in MC38) provided an improved and durable 
response in both models (Figure 7). 
 
 
We hypothesize that decreasing hypoxia in the TME will re-sensitize melanoma tumors to anti-
PD1 therapy. We have chosen to use axitinib because it has already been safely combined with 
anti-PD1 therapy and was overall well-tolerated15,16. Importantly, the standard dose of axitinib 
(5 mg BID) corresponds to the low dose used in our murine models. The combination of 
pembrolizumab plus axitinib was superior to sunitinib in patients with advanced renal cell 
carcinoma, leading to FDA approval for combination treatment.15 In addition, while axitinib 
has been combined with anti-PD1 in mucosal melanoma patients with promising results, this 
study was done in the front-line setting and did not include the extensive correlative analyses 
we propose.16 Taken together, based on previously published work and data from our 
laboratories, we hypothesize that axitinib can metabolically remodel the TME to render it 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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more sensitive to ICB, specifically by reducing intra-tumoral hypoxia, increasing T cell 
infiltration, and increasing polyfunctional T cells.  
3.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  The PD-1 receptor-ligand interaction is a major 
pathway utilized by tumors to suppress the anti-tumor immune response. PD-1 is expressed on 
the cell surface of activated T-cells under healthy conditions, and it serves to down-modulate 
unwanted to excessive immune responses, such as autoimmune reactions. PD-1 (encoded by 
the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-
L1 and/or PD-L2). PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a 
cytoplasmic tail which is responsible for the binding of signaling molecules.  The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, yet distinct from 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-
cells, B-cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can 
be induced in a variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.  Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-
cell expansion in subjects with melanoma.  This suggests that the PD-1/PD-L1 pathway plays 
a critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  Nivolumab is approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma. It is 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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also indicated in the setting of disease progression following ipilimumab and/or a BRAF 
inhibitor (if BRAF V600E mutation positive).  
VEGF, produced by endothelial cells, is critical for the regulation of both physiologic and 
pathologic angiogenesis.17  This process plays a key role in tumor growth and metastasis. 
VEGF (also known as VEGF-A) is one of the members of the VEGF family also comprised of 
VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PLGF). Each member is uniquely 
expressed with varying receptor specificity and function.18  VEGF is encoded by a transcript 
composed of 8 exons and 7 introns. Through alternative splicing, several different isoforms 
are generated with each isoform having differing degrees of pro-angiogenic properties.19  
VEGF expression is further regulated by the tumor environment, predominantly by hypoxia, 
which induces the transcription factor HIF1a, leading to increased VEGF expression.20 The 
members of the VEGF family bind to varying combinations of VEGF receptors; VEGF binds 
only to VEGFR-1 and VEGFR-2, while VEGFR-3 binds VEGF-C and VEGF-D. VEGFR-1 
through 3 are tyrosine kinase receptors with similar structures consisting of an extracellular 
domain of 7 IgG folds, a single transmembrane domain, and split tyrosine kinase domain. 
Binding of the ligand to the receptor induces dimerization of the receptor which is necessary 
for downstream signaling. Of note, the VEGFR-2 has been identified as the major mediator of 
VEGF induced angiogenesis, VEGFR-3 is involved in angiolymphogenesis, and the exact role 
of VEGFR-1 is not fully understood. 
Axitinib is a second-generation tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, and 
VEGFR-3. Axitinib is approved by the FDA for the treatment of metastatic renal cell 
carcinoma alone and more recently in conjunction with either pembrolizumab or avelumab in 
the first line setting.21,22  
3.1.2 Preclinical and Clinical Trial Data 
Nivolumab: Refer to the Investigator’s Brochure for Preclinical and Clinical data of 
Nivolumab. 
Axitinib: Refer to the Investigator’s Brochure for Preclinical and Clinical data of Axitinib.   
 
3.2 
Rationale 
3.2.1 Rationale for the Trial and Selected Subject Population 
The critical role of angiogenesis in cancer biology has long been appreciated, and anti-
angiogenic therapies have been successfully utilized in several cancer types, including renal 
cell carcinoma and colorectal cancer. However, while the significance of anti-angiogenic 
therapy was first thought to be related to decreasing tumor blood supply, it is now appreciated 
that its effect on oxygen tension and immune infiltration are critical in maintaining antitumor 
activity, and that normalization of the blood supply may help the immune response. Melanoma 
is understood to be an angiogenic tumor, with new vessel formation implicated in the 


 
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14
progression from atypical melanocyte, to horizontal growth phase, and subsequently to the 
more aggressive vertical growth phase.23,24 Increased VEGF expression is associated with a 
greater depth of invasion. 25 Bevacizumab is an anti-VEGF monoclonal antibody that has been 
evaluated as monotherapy in the adjuvant setting, as well as in combination with chemotherapy 
or anti-CTLA4 in the advanced setting, with mostly disappointing results.26-30 Axitinib, on the 
other hand, is a small molecule inhibitor of the VEGF receptor and binds to VEGFR-1, 
VEGFR-2, and VEGFR-3. Axitinib monotherapy has been evaluated in patients with advanced 
melanoma, with an ORR of 18.8% in the first line setting.31 A phase II trial of axitinib with 
carboplatin and paclitaxel yielded an ORR of 22% and median PFS of 8.7 months.32 A more 
recent phase IB trial evaluated toripalimab (anti-PD1) and axitinib in 33 patients with treatment 
naive metastatic melanoma. No dose limiting toxicities were observed, and by the cut-off date, 
14/29 (48.3%) patients achieved an objective response, which is higher than would be expected 
with anti-PD1 monotherapy.16 However, it must be noted that 88% of these patients had 
mucosal melanoma. Our preclinical data suggests that although high dose axitinib exacerbates 
hypoxia, low dose axitinib improves hypoxia. We hypothesize this is through normalization of 
aberrant tumor vasculature, which allows for improved tumor perfusion and immune cell 
infiltration. We have previously shown that T cells in a hypoxic TME are exhausted and 
dysfunctional.10,33-35 Thus, combining axitinib with anti-PD1 may salvage a portion of patients 
with anti-PD1 refractory disease, which is supportive of other previously published findings 
utilizing immunotherapy with VEGF targeting.36-38 We therefore propose a phase II 
investigator-initiated study of nivolumab plus axitinib in patients with unresectable stage III or 
IV melanoma who have progressed on anti-PD1 therapy.   
3.2.2 Rationale for Dose Selection/Regimen/Modification  
The choice for 480 mg every 4 weeks of nivolumab was made based on standard clinical 
practice in patients with melanoma. Initial pharmacokinetics assessed using the population PK 
model of nivolumab found that nivolumab had a wide therapeutic index from 0.1 to 10 mg/kg 
every 2 weeks.8 The 3 mg/kg dose was found to be effective in phase III studies across tumor 
types and was approved by the FDA. Subsequently, a fixed dose of 240 mg every 2 weeks was 
approved based on comparable safety and efficacy data.39 A fixed dose simplifies the dosing 
regimen, which is both more convenient for physicians and reduces potential for dosing errors. 
More recently, the FDA has expanded the approval to include 480 mg every 4 weeks based on 
safety and efficacy data that suggested this dosing was comparable to 3 mg/kg every 2 weeks.40 
This dosing regimen provides additional convenience for patients, particularly those who will 
be treated over a long timeframe, such as our cohort.  
Regarding axitinib, 5 mg twice daily is the standard FDA approved dose. In a murine B16 
melanoma model, we administered vehicle, axitinib at a low dose (10 mg/kg), or axitinib at a 
high dose (50 mg/kg) for 4 days. We found that high dose axitinib exacerbates hypoxia, while 
low dose axitinib lowers intra-tumoral hypoxia (Figure 6). Importantly, the standard dose of 
axitinib (5 mg BID) corresponds to the low dose used in our murine models.    


 
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3.2.3 Rationale for Endpoints 
3.2.3.1 Efficacy Endpoints 
The primary endpoint is the overall response rate after treatment with nivolumab plus axitinib. 
We hypothesize that patients treated with nivolumab plus axitinib will have a greater response 
rate compared to historical responses in anti-PD1 refractory patients, which is estimated to be 
10%, based on responses to ipilimumab after anti-PD1 therapy.41 An ORR of 25% or higher 
would be of clinical interest. We hypothesize that the mechanism by which there will be an 
improved response rate is that the addition of low dose axitinib will renormalize tumoral 
vasculature, improve tumor perfusion, immune infiltration, and reduce hypoxia. Our 
preclinical model was notable for a reduction in hypoxia seen in the low-dose group. Secondary 
efficacy endpoints include safety, PFS, and OS. The combination of pembrolizumab plus 
axitinib has been approved by the FDA for advanced renal cell carcinoma, and its toxicity 
profile is well-established. Here, we will use nivolumab in place of pembrolizumab.  
Nivolumab and pembrolizumab are virtually identical in terms of cellular target and known 
toxicity, thus we expect toxicity rate of the current combination therapy and dose to be 
acceptable. We hypothesize that treatment with nivolumab plus axitinib will prolong both PFS 
and OS.  
3.2.3.2 Biomarker Research 
The secondary endpoints of this study seek to identify the functional consequences of axitinib-
induced remodeling of the tumor microenvironment with concomitant anti-PD1 blockade. We 
will analyze biopsy samples prior to treatment with axitinib plus nivolumab as well as 12 weeks 
after treatment. First, we will immunophenotype the TIL from patient tumor samples using 
antibodies to T cell markers (CD4, CD8, PD1, TIM-3, CD45RO, CD45RA, FOXP3, among 
others) via 14-color flow cytometry. Second, we will profile intra-tumoral hypoxia and 
immune architecture of patient samples, assessed via staining for CAIX, HIF1a, and VEGF 
utilizing highly multiplexed immunofluorescent imaging (CODEX) and pimonidazole CITE-
seq to evaluate transcriptional changes. Third, we will assess proliferation and functional 
analysis with Ki-67 and cytokine production of TIL. Lastly, we will also metabolically profile 
the biopsies utilizing Seahorse. 
4.0 METHODOLOGY 
4.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial.  
2. Be  18 years of age on day of signing informed consent. 


 
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3. Have unresectable (stage III) or advanced (stage IV) cutaneous or mucosal melanoma.  
Patients with uveal melanoma are not eligible.  
4. Progressed on prior anti-PD1 therapy with or without anti-CTLA4 therapy. Patients 
may have progressed in the adjuvant setting if treated within the last 6 months. Prior 
treatment with BRAF/MEK inhibitors permitted, however, not required. Progression 
must be radiographic, and progression of disease will be confirmed by a radiologist. 
Patients must have progressed during anti-PD-1 therapy, defined as unequivocal 
progression on or within 3 months of the last dose of anti-PD-1 therapy if treated in the 
metastatic setting, or within 6 months if treated in the adjuvant setting. 
5. Have measurable disease based on RECIST 1.1. 
6. Patients do not have to have biopsiable disease to be eligible. However, patients with 
biopsiable disease must undergo biopsy at study entry and at week 12.  
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1. All screening labs should 
be performed within 14 days of treatment initiation.   
Table 1:  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥50,000 / mcL 
Hemoglobin 
≥7 g/dL without transfusion or EPO dependency (within 7 days 
of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculated creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl*) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
 *Creatinine clearance should be calculated per institutional standard. 
 


 
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9. Patients with brain metastases are permitted if they are asymptomatic or previously 
treated with CNS directed therapy with stable CNS disease for at least 2 weeks. 
Stable is defined as asymptomatic or not progressing on imaging.  
 
10. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 7 days from the time of registration. Also, within 24 hours prior 
to receiving the first dose of study medication then every 4 weeks while on treatment.  
 
11. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile or abstain from heterosexual activity for the course of 
the study and for 5 months after the last dose of study medication. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year.  
 
12. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 7 months after the last dose of study therapy. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
4.1.2 Subject Exclusion Criteria 
The subject will be excluded from the trial if the subject: 
1. Prior history of Grade 3 or 4 immune-related adverse events or immune-related 
adverse events requiring discontinuation of prior therapies. 
 
2. History of hypertensive crisis or hypertensive encephalopathy 
 
3. Significant thrombotic (e.g, deep vein thrombosis or pulmonary embolism) or 
hemorrhagic event within 6 months prior to enrollment). 
 
4. Has a history of prior immune-related adverse event due to an anti-PD1 or anti-CTLA4 
that has not resolved to grade 1 on a steroid dose of prednisone 10 mg or less at the 
time of study entry (excluding vitiligo and endocrine toxicity). 
- 
Patients with prior myocarditis or other immune-mediated cardiac adverse 
events are excluded regardless of grade. 
- 
Patients with prior Guillain-Barre syndrome, encephalitis, meningitis, or 
transverse myelitis are excluded regardless of grade. 


 
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- 
Patients with prior Stevens-Johnson syndrome or toxic epidermal necrolysis are 
excluded regardless of grade. 
5. Has poorly controlled hypertension defined as systolic blood pressure (SBP) > 160 
and/or diastolic blood pressure (DBP) > 100 despite antihypertensives. If subject is 
above this goal, treatment with anti-hypertensives to achieve better blood pressure 
control is permitted. Ambulatory blood pressure assessment is permitted if there is 
concern for discrepant blood pressure readings while patients are in clinic.  Note: 
measurement of screening blood pressure (BP) reading is based on an average of 3 
readings at least 2 minutes apart if the subject has an initial BP ≥150/90. Subjects with 
initial screening BP ≥150/90 mmHg can be treated with anti-hypertensive medication 
to achieve a well-controlled status and are eligible with reassessed SBP/DBP of < 
160/100 mm Hg. 
6. Has Class III or IV heart failure based on the New York Heart Association  
7. Has had major surgery within 4 weeks of randomization. This does not include 
outpatient surgeries that do not require post-operative admission.  
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (greater 
than the equivalent of prednisone 10 mg daily, unless for prior endocrine toxicity) or 
any other form of immunosuppressive therapy within 7 days prior to the first dose of 
trial treatment. Premedication with steroids for contrast imaging studies is permitted.  
9. Has a known history of active TB (Bacillus Tuberculosis). 
 
10. Hypersensitivity to nivolumab or axitinib, or any of their excipients. 
 
11. Has had prior chemotherapy or targeted small molecule therapy within 1 week prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
12. Has had radiation within 2 weeks of randomization 
13. Has current use or anticipated need for treatment with drugs or foods that are known 
strong cytochrome P450 (CYP34A4/5) inhibitors including but not limited to 
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
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nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and 
grapefruit or grapefruit juice. NOTE: The topical use of these medications, such as 2% 
ketoconazole cream is allowed. 
14. Has current use or anticipated need for treatment with drugs known to be strong 
CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s wort. 
15. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy, in situ cervical cancer, in situ 
colon cancer, or nonmetastatic prostate cancer not on systemic therapy. 
16. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 2 weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
17. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
18. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
19. Has an active infection requiring systemic IV antibiotic therapy. 
20. Has had any of the following within the past 6 months 
- 
Myocardial infarction or unstable angina  
- 
Ventricular arrythmia  
- 
Acute decompensated heart failure  
- 
Cerebrovascular accident  
- 
Hypertensive emergency requiring ICU admission  


 
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21. Presence of a disorder that may impact absorption of axitinib, such as inability to take 
oral medication, requirement for IV alimentation, prior gastric resection, treatment for 
active peptic ulcer confirmed by endoscopy within the past 3 months, active GI bleed, 
malabsorption syndrome.  
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
24. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through  
5 months after the last dose of trial treatment for females and 7 months after the last 
dose of trial treatment for males. 
25. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
if the CD4 count is less than 350 mm3 or serum HIV viral load is < 25,000 IU/mL.  
26. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen 
[HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is 
detected).  Note: Without known history, testing only needs to be performed if there is 
clinical suspicion for Hepatitis B or C. 
27. Is currently incarcerated or otherwise detained. 
28. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal iNinfluenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
4.2 
Trial Treatments 
The treatment plan is outlined in Table 2 
Table 2: Treatment Schedule. Treatment with nivolumab and axitinib begins on C1D1. 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Nivolumab 
480 mg 
Q4W 
IV infusion 
Day 1 of each 4-week 
cycle 


 
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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Axitinib 
5 mg  
Twice 
daily 
Oral  
Daily   
 
4.2.2 Patient Compliance  
Patients will be required to return all bottles of axitinib at the beginning of each 4-week period. 
The number of tablets remaining will be documented and recorded.  
4.2.3 Duration of Therapy 
Treatment will continue for up to 2 years or until progression of disease or unacceptable 
toxicities.  
 
4.2.4 Starting Dose and Modifications 
4.2.4.1 Nivolumab 
The Nivolumab dose if 480 mg IV every 4 weeks.  
Adverse events (both non-serious and serious) associated with nivolumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Nivolumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per table 3 below. See Section 4.3.1 for 
supportive care guidelines, including use of corticosteroids. 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply 
study drug to subjects/investigators unless the Sponsor-Investigator chooses to extend the 
study. The treating physician is responsible to ensure that the subject receives appropriate 
standard of care or other appropriate treatment. 
No modifications in the dose of nivolumab are permitted. Dose delays are permitted, as 
outlined below.   
Table 3: Nivolumab Dose Delay and Discontinuation Guidelines for Drug-Related Adverse 
Events 
Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 


 
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Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes mellitus 
(if new onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold for new onset Type 1 diabetes 
mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell 
failure 
Resume when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with can be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with can be continued while 
thyroid replacement therapy is instituted 
Therapy with can be continued while thyroid 
replacement therapy is instituted 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; Refer to 
Table 5– Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug 
for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
 
4.2.4.2 Axitinib  
Axitinib will be administered at the standard dosing of 5mg po twice daily. 


 
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Table 4. Axitinib Dose Modification Guidelines for Drug-Related Adverse Events  
Toxicity 
Action 
Grade 4 non-hematologic toxicity considered 
related to axitinib per investigator judgment 
(including persistent nausea, vomiting, diarrhea, 
hypertension despite optimal medical therapy), 
excluding clinically manageable laboratory 
abnormalities (e.g. electrolytes).  
Discontinue axitinib. 
Grade 3 non-hematologic toxicity considered 
related to axitinib per investigator judgment 
(including persistent nausea, vomiting, diarrhea, 
hypertension, proteinuria despite optimal medical 
therapy), excluding clinically manageable 
laboratory abnormalities (e.g. electrolytes).  
 
Hold axitinib until recovery to Grade 0-1 or baseline and resume at the same 
dose level.  
 
If grade 3 toxicity reoccurs despite reduction, patient may be dose reduced by 1 
dose level upon recovery to Grade 0-1 or baseline.  
 
Prompt palliative and supportive measures mandated per local standard of care 
(eg, antiemetic).  
Grade 3 Thrombocytopenia, ie, PLTS <50,000 
mm3 (50.0 x 109/L) with bleeding.  
Discontinue Axitinib 
Grade 3 hematologic toxicity considered related to 
axitinib per investigator judgment  
-Hold axitinib until recovery to Grade ≤ 2 or baseline and resume axitinib at the 
same dose level.  
 
-If grade 3 toxicity reoccurs, patient may either be held until recovery and 
continued at same dose, or undergo dose reduction by 1 dose level.  
Grade 4 toxicity considered related to axitinib per 
investigator judgment  
Discontinue Axitinib 
No recovery of toxicities within 6 weeks to grade 0 
or grade 1 
Discontinue Axitinib  
 
Table 5. Axitinib Dose Levels 
Dose Level 
Dose 
Level 0 (starting 
dose) 
5 mg po bid 
Level -1 
3 mg po bid 
Level -2 
2 mg po bid 
 
4.2.5 Timing of Dose Administration 
Nivolumab: Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0).  
Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 


 
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Nivolumab 480 mg will be administered as a 30 minute IV infusion every 4 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Nivolumab will be prepared and infused per institutional standards 
Axitinib: Axitinib 5 mg PO twice daily, 12 hours apart, will be taken for the entire duration of 
treatment. Patients will be given specific instructions on how to take axitinib. If a dose is 
missed, it may be taken up to 8 hours later that same day. 
Dosing interruptions of nivolumab and axitinib are permitted in the case of medical / surgical 
events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects should be placed back on study 
therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the patient's study record.  
Should the combination of nivolumab and axitinib be further investigated for the treatment of 
anti-PD1 refractory melanoma, given the  potential for late onset immune-related toxicities 
for nivolumab, any such late toxicity will be considered in the determination of the final dose 
and dose schedule. The number of required dose reductions of axitinib will also be taken into 
full consideration.  
 
4.2.6 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
4.3 
Rescue Medications & Supportive Care 
4.3.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to study drug(s). 


 
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Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 4.2.4 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
For toxicities where the attribution is Nivolumab (immune mediated toxicity) 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  


 
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▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
27
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of nivolumab. 
Table 6: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
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 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
No subsequent dosing 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
28
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
For toxicities where the attribution is Axitinib (non-immune mediated toxicity) 
Dose modifications as in Section 4.2.4.2. Management of hypertension and febrile neutropenia 
per investigator. 
 
 
4.4 
Diet/Activity/Other Considerations 
4.4.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. Diet should exclude grapefruit and grapefruit juice.  
4.4.2 Contraception 
Nivolumab and axitinib may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if these agents have transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  


 
Nivolumab and Axitinib Phase II Study  
  
 
 
29
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for  5 months after the 
last dose of study drug for females and 7 months for males by complying with one of the 
following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  


 
Nivolumab and Axitinib Phase II Study  
  
 
 
30
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
4.4.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study treatment, or may have been 
pregnant, including at least 5 half-lives after product administration, the subject will 
immediately be removed from the study and the investigational product will be permanently 
discontinued in an appropriate manner.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to BMS and Pfizer without delay 
and within 24 hours to the Sponsor and within 2 working days to BMS and Pfizer if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). The investigator must 
immediately notify worldwide.safety@bms.com of this event and complete the appropriate 
form in accordance with SAE reporting procedures within 24 hours of awareness of the event. 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the participant. Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome, and where applicable, offspring information must be reported 
to BMS as well. Please note: if needed, a BMS pregnancy surveillance form can be provided.  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor and to BMS and Pfizer. Information on this 
pregnancy will be collected on the Pregnancy Surveillance Form. In order for Sponsor or 
designee to collect any pregnancy surveillance information from the female partner, the female 
partner must sign an informed consent form for disclosure of this information.  
4.4.4 Use in Nursing Women 
It is unknown whether the study drugs are excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 


 
Nivolumab and Axitinib Phase II Study  
  
 
 
31
4.5 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with nivolumab or 24 administrations 
of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose.  
• After trial discontinuation (whether due to subject withdrawal, progression, or dose 
limiting toxicity), patients will be seen at week 4 for follow up, and then followed 
once 100 days after the last day of treatment even if they start a new anticancer 
therapy. Patients will be contacted by phone for survival follow up for up to 5 years.  


 
Nivolumab and Axitinib Phase II Study  
  
 
 
32
4.5.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with nivolumab and axitinib and had at least 
two treatments with axitinib beyond the date when the initial CR was declared.   
4.6 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of BMS or Pfizer deciding to no longer supply study drug(s), ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 
 


Nivolumab and Axitinib Phase II Study   
33 
  
 
 
 
 
 
 
5.0 TRIAL PROCEDURES 
5.1 
Study Flow Chart 
 
Baseline* 
C1 
+/-3 
days 
C2 
+/-3 
day 
C3 
+/-3 
day 
C4 
+/-3 
day 
C5 
+/-3 
day 
C6 
+/-3 
day 
C7 
+/-3 
day 
C8 
+/-3 
day 
C9 
+/-3 
day 
C10 
+/-3 
day 
C11 
+/-3 
day 
C12
+ 
+/-3 
day 
EOT 
Follow up# 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
X 
X 
Physical exam  
X 
X---------------------------------------------------------------------------------------------X 
X 
X 
Vital signs 
X 
X---------------------------------------------------------------------------------------------X 
X 
X 
Performance status (ECOG) 
X 
X---------------------------------------------------------------------------------------------X 
X 
X 
CBC w/diff, plts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine dipstick 
X 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
X 
Radiologic evaluation 
& 
Tumor measurements  
X 
Tumor measurements will be evaluated with the first scans at week 12 (+/- 1 
week). Subsequent scans will be repeated every 12 weeks (+/- 1 week).  
Patients with complete or partial response will have confirmation scans at least 
4 and up to 12 weeks later. Documentation (radiologic) must be provided for 
patients removed from study for progressive disease.  
Brain MRI will be obtained at baseline, and will be repeated at 12 weeks if 
patients have known brain mets, or develop neurological symptoms** . CT 
scans of the brain can be utilized if MRI cannot be obtained in a timely manner 
per the treating physician.  
 
 
X 
B-HCG b 
X 
X--------------------------------------------------------------------------------------------- X 
 
 
TSH, free T4c  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 


Nivolumab and Axitinib Phase II Study   
34 
  
 
 
 
 
 
 
Tumor bxd 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Research Blood draws e 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Axitinib administration f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Nivolumab administration  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Microbiome sampling g 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
*: Baseline is within 30 days of start of treatment, except for labs (14 days).  
#: After trial discontinuation (whether due to subject withdrawal, progression, or dose limiting toxicity), patients will be seen at week 4 for follow up. 
Survival follow-up will be obtained at day 100 days after the last day of treatment (this can be done by phone), even if they start a new anticancer therapy. 
Patients will be contacted by phone for survival follow up for up to 5 years.  
**: If known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI evaluation within 
2 weeks from SRS or WBRT treatment. CT scans of the brain can be utilized if MRI cannot be obtained in a timely manner per the treating physician 
at baseline and also at 2 week follow up, if asymptomatic.  
a. albumin, alkaline phosphatase, total bilirubin, direct bilirubin (if total bilirubin is > ULN), bicarbonate, BUN, calcium, chloride, CPK, creatinine, fasting 
glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: Urine or serum pregnancy test (women of childbearing potential) (+/- 3 days). To be done at screening, within 24 hours prior to receiving the first dose of 
study medication and then every 4 weeks while on treatment.  
c:  TSH and free T4 to be done at screening, cycle 2 and then q 8 weeks (even cycles) while on treatment (+/- 3 days).      
d: Baseline biopsy will be obtained up to 30 days prior to initiation of treatment and at C4 week 12, (+/-7 days). Patients will be treated with pimonidazole 
0.5g/m2 po 16-24h before each biopsy. Biopsy at progression of disease is optional. Patients must have eligibility completed and be registered on study 
prior to the baseline biopsy. 
e: Research Blood draws are to be done at baseline (up to 30 days prior to initiation of therapy), cycle 4 week 12 and at progression (+/- 7 days). This includes 
10 green top tubes, 2 red top tubes and an ACD yellow top tube (yellow top at baseline only).  
f: Axitinib pill counts will be reviewed and axitinib dispensed at each study visit (every 4 weeks). Patients will in addition be provided an axitinib drug diary, 
which should be returned at each visit.  
g. Microbiome sampling will be obtained at baseline (up to 30 days prior to initiation of therapy), cycle 4 week 12 and at progression (+/- 7 days). Samples 
may be brought into clinic.   


Nivolumab and Axitinib Phase II Study   
35 
  
 
 
 
 
 
 
The Trial Flow Chart – Section 5 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
5.1.1 Administrative Procedures 
5.1.1.1 Informed Consent 
The Investigator will make certain that an appropriate informed consent process is in place to 
ensure that potential research subjects, or their authorized representatives, are fully informed 
about the nature and objectives of the clinical study, the potential risks and benefits of study 
participation, and their rights as research subjects. The Investigator, or a sub-investigator(s) 
designated by the Investigator, will obtain the written, signed informed consent of each subject, 
prior to performing any study-specific procedures on the subject. The date and time that the 
subject, or the subject’s authorized representative, signs the informed consent form and a 
narrative of the issues discussed during the informed consent process will be documented in 
the subject’s case history. The Investigator will retain the original copy of the signed informed 
consent form, and a copy will be provided to the subject, or to the subject’s authorized 
representative. 
The Investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or 
the risk-to-benefit ratio of study participation, the Investigator will obtain the informed consent 
of enrolled subjects for continued participation in the clinical study. 
5.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
5.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.   
5.1.1.4 Concomitant Medications Review 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
Concomitant medications will stop being collected at the time of starting a new anti-cancer 
therapy. 


Nivolumab and Axitinib Phase II Study   
36 
  
 
 
 
 
 
 
5.1.1.5 Disease Details and Treatments 
5.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
5.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
5.1.1.6 Assignment of Screening Number 
Screening numbers will be assigned by sequential numbering.  
5.1.1.7 Assignment of Treatment Number 
Treatment numbers will be assigned by sequential numbering.  
5.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Axitinib pills will be counted at each monthly visit.   
5.1.2 Clinical Procedures/Assessments 
Patients will undergo study treatments and evaluation at the UPMC-Hillman Cancer Center.  Patients 
will continue to be evaluated every 12 weeks (+/- 1 week) with scans, labs and MD visit.  
5.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 5.0 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
5.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  


Nivolumab and Axitinib Phase II Study   
37 
  
 
 
 
 
 
 
5.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 5.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
5.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
5.1.2.5 Tumor Imaging and Assessment of Disease 
PET/CT and CT 
-At baseline and week 12, extra-cranial tumor assessment will be conducted with contrast-
enhanced PET/CT or CT and applied using RECIST 1.1 criteria. 
-A screening scan will be performed prior to enrollment unless a recent (within 28 days of 
enrollment) scan is available. Target and non-target lesions must be identified at time of 
screening scan and the same lesions must be re-assessed at each restaging scan.  
-Repeat PET/CT or CT imaging will be obtained at week 12, and then CT will be obtained at 
12 week intervals. 
-Complete response/partial response confirmation assessments must take place at least 4 and 
up to 12 weeks after the documentation of initial response. If the last radiographic assessment 
for extra-cranial disease was more than 8 weeks prior to discontinuation from study and 
progressive disease has not been documented, disease assessment should be obtained at the 
time of study discontinuation. 
-If patients have PD by RECIST 1.1 criteria, the Immune Related Response Criteria (irRC) 
will be used for assessment of tumor response for the purposes of managing patients on 
protocol treatment and decision making for discontinuation of study therapy due to disease 
progression. These disease assessments will be performed by the investigator with site 
radiology reading.  
- For the purposes of the secondary efficacy endpoint of the study, response assessment 
based on RECIST 1.1 will be applied as the primary measure and irRC by investigators will 
be evaluated as a secondary assessment only if patient have PD by RECIST 1.1. If patients 
have PD by RECIST 1.1 but have SD or PR by irRC, they will be permitted to continue 
treatment. In order for a patient to continue to receive study treatment beyond progression by 
RECIST 1.1, in addition to having SD or PR by irRC, patients must not have symptoms or 
signs of disease progression, including significantly worse laboratory values or a decline in 
ECOG performance status.  
- At the time of radiographic progression of disease, if treatment is to continue beyond PD, 
patients will be re-consented and adequately informed of all FDA-approved therapy, and 
potential clinical benefit, that the patient may be foregoing in order to continue receiving the 
investigational product. 


Nivolumab and Axitinib Phase II Study   
38 
  
 
 
 
 
 
 
MRI 
Intra-cranial tumor assessments will be conducted with contrast-enhanced MRI.  
A screening scan will be performed prior to enrollment unless a recent (within 4 weeks of 
enrollment) scan is available. If brain metastases are known or identified at screening, brain 
imaging should be repeated at 12 weeks or as it is standard, unless acute neurological 
symptoms develop. If no brain metastases are known or identified at pre-study imaging, no 
brain imaging need be performed following pre-study assessment unless acute neurological 
symptoms develop. CT scans of the brain can be utilized if MRI cannot be obtained in a 
timely manner per the treating physician. 
 
5.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Patients will have blood drawn for correlative studies at baseline (up to 30 days prior to 
treatment initiation), at week 12 (+/- 3 days) study flow chart says +/- 7 days, which is correct?, 
and at progression. This includes 10 green top tubes, 2 red top tubes and an ACD yellow top 
tube (yellow top at baseline only). Refer to lab manual for full details.  
Patients will undergo biopsy for tumor tissue collection at baseline (up to 30 days prior to 
treatment initiation) and at week 12 (+/- 7 days). A biopsy at time of progression is optional. 
Refer to lab manual for full details.  
5.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis): Laboratory tests for 
hematology, chemistry, urinalysis, and others are specified in Table 7.   
 


Nivolumab and Axitinib Phase II Study   
39 
  
 
 
 
 
 
 
Table 7:  Laboratory Tests 
Hematology 
Chemistry 
Other 
Hematocrit 
Albumin 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
 (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Free thyroxine (T4) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
Lactate dehydrogenase (LDH) 
 
 
Calcium 
 
 
Chloride 
Blood for correlative studies 
 
Glucose 
  
 
Potassium   
  
 
Sodium 
  
 
Phosphorous  
 
 
Total Bilirubin 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
Total protein 
 
 
Blood Urea Nitrogen 
 
 
CPK 
 
† Perform on women of 
childbearing potential only. If 
urine pregnancy results cannot be 
confirmed as negative, a serum 
pregnancy test will be required.   
 
 
 
5.1.4 Other Procedures 
5.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
nivolumab may discontinue treatment.   
5.1.5 Visit Requirements 
Visit requirements are outlined in Section 5.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 6.0 - Trial Procedures. 
 


Nivolumab and Axitinib Phase II Study   
40 
  
 
 
 
 
 
 
5.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the treatments agents, is also an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 100 days following cessation of 
treatment, or until the participant initiates new anticancer therapy, whichever is earlier, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe for 
adverse events meeting any serious criteria is described in section 7.2.3.1. The investigator will 
make every attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
5.2.1 Reporting of Pregnancy and Lactation to the Sponsor  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 100 days following cessation 
of treatment if the subject initiates new anticancer therapy, including during at least 5 half-
lives after product administration, whichever is earlier, must be reported by the investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 


Nivolumab and Axitinib Phase II Study   
41 
  
 
 
 
 
 
 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 24 hours (1 business 
day) to BMS and Pfizer Global Safety.  
5.2.2 Immediate Reporting of Adverse Events to the Sponsor and to BMS and Pfizer 
If any SAE meets FDA/IRB reporting guidelines, we would transfer the information onto a 
Medwatch form for submission to BMS and/or Pfizer.  
5.2.2.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
nivolumab and/or axitinib that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via 
the study drug; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
THE FOLLOWING HOSPILIZATIONS ARE NOT CONSIDERED SAEs:  
− a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
− Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 


Nivolumab and Axitinib Phase II Study   
42 
  
 
 
 
 
 
 
− Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
− Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to 
BMS Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation 
should be every 3 months and prior to the database lock or final data summary. BMS GPV&E 
will email, upon request from the Investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the Investigator 
determines a case was not transmitted to BMS GPV&E, the case should be sent immediately 
to BMS. 
Refer to Table 3 in Section 4.2.4 for additional details regarding each of the above criteria. 
For the time period following the subject’s written consent to participate in the study through 
100 days of discontinuation of dosing, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details) that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 24 hours or 1 business day to BMS and 
Pfizer Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 100 days 
following cessation of treatment with nivolumab, or until the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), whether or not related to study 
treatment, must be reported within 24 hours to the Sponsor and within 24 hours or 1 business 
day to BMS and Pfizer Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to treatment that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in 
the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to BMS and Pfizer Global 
Safety. 
REPORTING OF SERIOUS ADVERSE EVENTS  
 
All events meeting the definition of a serious adverse event should be reported according to 
the departmental SAE checklist and SAE form. The initial SAE form should be sent to the 
following within 24 hours / 1 business day of the Principal Investigator becoming aware: 


Nivolumab and Axitinib Phase II Study   
43 
  
 
 
 
 
 
 
1. Yana Najjar, Principal Investigator (and Sponsor) 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
4. BMS Global Safety by email at Worldwide.Safety@BMS.com or by facsimile at +1 
609-818-3804 
5. Pfizer: 
USA.AEReporting@pfizer.com 
(CEPs, Non Clinical Trial reports) 
  
Fax: 
Toll-Free (local): 1 866 997-8322 
(Clinical Trial, Compassionate Use , IIR reports) 
  
Technical Support: 
Tel.: 800 752-9737 (toll-free) 
ONLY  for  technical support if fax number is not working 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include as applicable the following information that is available 
at the time of report within the Sections B and C of the departmental SAE form: 
• CTCAE term(s) and grade(s)  
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
 
Follow-up reports:   
Additional information may be added to a previously submitted report by adding to the 
original departmental SAE form and submitting it as follow-up or creating supplemental 
summary information and submitting it as follow-up with the original departmental SAE 
form. 
 
All subjects with serious adverse events must be followed up for outcome. 
5.2.2.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to BMS 
Global Safety.  
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 


Nivolumab and Axitinib Phase II Study   
44 
  
 
 
 
 
 
 
reported within 24 hours to the Sponsor and within 24 hours/1 business day to BMS and Pfizer 
Global Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 100 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to treatment, must be reported within 24 hours to the Sponsor and within 24 
hours to BMS and Pfizer Global Safety. 
Events of clinical interest for this trial include: 
1.  An overdose of nivolumab or axitinib, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
5.2.2.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to BMS and Pfizer as 
described in Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to 
BMS and Pfizer, unless there is evidence suggesting a causal relationship between the drug 
and the event. Any such event will be submitted to the Sponsor within 24 hours and to BMS 
and Pfizer Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to BMS and Pfizer Global Safety as a 
SAE within 2 working days of determination that the event is not progression of the cancer 
under study. 
Hospitalization related to convenience (e.g., transportation issues etc.) will not be considered 
a SAE. 
 


Nivolumab and Axitinib Phase II Study   
45 
  
 
 
 
 
 
 
5.2.3 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


Nivolumab and Axitinib Phase II Study  
46 
  
 
 
  
 
 
 
Table 8:  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during the course of study treatment 
that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior 
to the use of study treatment and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable); 
or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event for collection purposes. An overdose that is not associated with an adverse 
event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor 
and to BMS and Pfizer within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time 
and units 
 
 


Nivolumab and Axitinib Phase II Study  
47 
  
 
 
  
 
 
 
5.2.4 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
6.0 STATISTICAL CONSIDERATION 
6.1 
Study Design  
This is a single arm phase II clinical trial to test the efficacy of nivolumab plus axitinib in 
patients with advanced melanoma who have progressed on anti-PD1 (+/- anti-CTLA4). The 
primary endpoint of this study is the object response rate (ORR). We use Simon’s minimax 
two-stage design as detailed in Section 6.3. 
6.2 
Safety monitoring  
The combination of pembrolizumab plus axitinib has been approved by FDA for advanced 
renal cell carcinoma, and its toxicity profile has been well established. In this study, we will 
use nivolumab in place of pembrolizumab, and we expect these two drugs are very similar, 
thus we expect the toxicity rate of the current combination therapy and dose is acceptable, so 
we don’t think it necessary to conduct a phase I dose-finding study. However, to be cautious, 
we will 1) use a Bayesian monitoring scheme and 2) incorporate a trial stopping rule into the 
protocol. The Bayesian monitoring scheme will continuously monitor the rate of severe 
adverse events (SAE). The SAE is defined as grade 3 and higher toxicity that are attributable 
to the combination therapy.  A non-informative prior of Beta(1, 1) for the SAE rate will be 
used. We will hold the recruit if the posterior probability Pr(SAE rate>30%)>=0.7 and the 
study committee and the PI will decide whether to modify or discontinue the study. The 
stopping boundary for toxicity is given in the following table: 
Number of SAEs >= 
in Number of Patients = 
2 
3-5 
3 
6-8 
4 
9-11 
5 
12-14 
6 
15-17 
7 
18-20 
8 
21-23 
9 
24-26 


Nivolumab and Axitinib Phase II Study  
48 
  
 
 
  
 
 
 
10 
27-29 
11 
30-31 
 
We simulate the operating characteristics under various assumed true toxicity rate (see the 
following table): 
 
Scenario 
True Prob. 
of SAE 
Prob. of 
Early 
Stopping 
Average 
Num. of 
Patients 
Average 
Num. of 
SAE 
1 
0.1 
0.10 
28 
3 
2 
0.2 
0.37 
22 
4 
3 
0.3 
0.71 
14 
4 
4 
0.4 
0.93 
8 
3 
 
Regarding the analysis of safety, we will consider a toxicity event to be an adverse event 
(evaluated by CTCAE 5.0) that is possibly, probably, or definitely related to treatment.  The 
maximum grade of toxicity for each category of interest will be recorded for each patient and 
the summary results will be tabulated by category and grade.  
If one Grade 5 event or two Grade 4 events for AEs considered at least possibly related to 
combination study therapy (possibly attributed to each drug) occur, the trial will be halted to 
accrual and a thorough safety analysis will be conducted prior to enrolling new patients. 
 
6.3 
Sample Size and Accrual 
The null hypothesis that the true ORR is 10% will be tested versus a one-sided alternative of 
25% or higher, using Simon’s minimax two-stage design.  In the first stage, 16 patients will be 
accrued. If there are <2 responses, the study will be stopped and alternative doses of axitinib 
considered. If at least 2 responses are observed, 15 additional patients will be enrolled in the 
2nd stage. The combination therapy will be regarded as worthy of further study if ≥6 responses 
are observed in both stages. Total sample size is 31 patients. This design has a type I error rate 
of 0.08 with a power of 0.81 when the true response rate is 0.25. Secondary endpoints of this 
study are PFS, OS and safety. Survival endpoints (PFS and OS) will be estimated with the 
Kaplan-Meier method, and compared between marker value groups with the log-rank test. We 
will also perform extensive correlative analysis (flow, IHC, metabolic analyses). 
The accrual rate of the trial is estimated to be 1-2 patients/month, therefore, we will be able to 
finish the accrual of the study in approximately 24 months.  


Nivolumab and Axitinib Phase II Study  
49 
  
 
 
  
 
 
 
6.4 
Statistical Analysis Plan 
6.4.1 Analysis Sets 
DLT evaluable patients are study-eligible patients (i.e., those meeting all of the protocol 
inclusion/exclusion criteria) who have finished one cycle of the regimen without a DLT, and 
those who received at least one dose of the regimen and experienced DLT in the first cycle.  
 
Response evaluable patients are study-eligible patients (i.e., those meeting all of the protocol 
inclusion/exclusion criteria) who have received the regimen and stayed on study long enough 
for at least one follow-up of response. Patients who didn’t come back for scan but clinically 
progressed will also be considered as evaluable for response, and the best response for these 
patients is progressive disease. 
 
Safety population - all study eligible patients who received any dose of the study drug will be 
included in the safety population.  
 
Efficacy population - the data from all treated patients will be used in the intent to treat 
analyses of tumor response and survival (progression-free and overall). Patients who 
complete at least one cycle of the treatment will be included in the per-protocol analysis of 
bioactivity endpoint. Patients who are considered non-compliant are not evaluable for the 
per-protocol analysis of the primary efficacy endpoint, but still evaluable for safety analysis, 
so they will be replaced for the primary efficacy analysis.  
  
6.4.2 Analysis of ORR (Primary) 
Overall response rate (ORR) will be estimated by the percentage of patients who achieve CR, 
PR or SD by RECIST criteria (detailed in Sections 5.1.2.5 and 9.2), with corresponding exact 
95% confidence limits being reported. The difference between marker value groups will be 
examined with Fisher’s exact tests.  
6.4.3 Safety Analysis (Secondary) 
We will consider a toxicity event to be an adverse event (evaluated by CTCAE 5.0) that is 
possibly, probably, or definitely related to treatment.  The maximum grade of toxicity for each 
category of interest will be recorded for each patient and the summary results will be tabulated 
by category and grade.  
All adverse events occurring up to 28 days after the last intake of study medication will be 
recorded. These adverse events will be reported as listings and summarized as frequency tables 
by treatment group and the body system. Additional presentations will include summaries by 
severity and relationship to trial treatment. 
Withdrawals of patients from study medication will be reported as listings and summary tables. 
All summaries and listings of adverse events and laboratory data will be based on the safety 
population. 


Nivolumab and Axitinib Phase II Study  
50 
  
 
 
  
 
 
 
6.4.4 Analysis of PFS and OS (Secondary) 
PFS will be measured from the initial date of treatment to the date of documented progression, 
or the date of death (in the absence of progression), whichever occurs first. OS will be 
measured from the initial date of treatment to the recorded date of death. 
 
PFS and OS will be estimated by the Kaplan-Meier method. The corresponding median 
survival times (with 95% confidence intervals) will be determined, as will the cumulative 
percentage of patients remaining progression-free (and the cumulative percentage-alive) at 
selected time points after initial treatment (e.g., 3, 6,12, 18 months). Log-rank test will be used 
to compare the PFS and OS between subgroups when event number permitted.  
6.4.5 Correlative Translational Assays (Secondary) 
Multiple lab outcomes will be compared between baseline and on treatment to examine the 
change in TME, metabolic profiling and cell hypoxia. These will also be compared between 
baseline and the value at the progression for progressors. All these pre vs post comparisons 
will be done with paired t-tests or Wilcoxon signed rank tests where appropriate.  The change 
from pre- to post- treatment will be compared between subgroups (such as between responders 
and non-responders) with two sample t-test or Wilcoxon rank sum test where appropriate. The 
association of clinical response with tumor metabolism and with T cell function will be 
explored with logistic regressions. The association of survival endpoints (DOR, PFS, OS) with 
tumor metabolism and with T cell function will be explored with Cox proportional hazards 
models.  
7.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
7.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by BMS and Pfizer as summarized in Table 8. 
Table 9:  Product Descriptions 
Product Name & Potency 
Dosage Form 
Nivolumab 100 mg/10ml vial  
Solution for Injection 
Axitinib 5 mg  
Tablets 
 


Nivolumab and Axitinib Phase II Study  
51 
  
 
 
  
 
 
 
Pimonidazole (FDA IND# 73,095) is not used with therapeutic intent, and has a non-hazardous 
designation. It has been widely used for in-vivo evaluation of intratumor hypoxia, and patients 
will take PO pimonidazole before each on-treatment biopsy: thus, patients undergoing biopsy 
will take 2 doses total, each dose 12 weeks apart. A single dose of 0.5 gm/m2 of pimonidazole 
used for tumor hypoxia measurement in humans is equivalent to approximately 13 mg/kg and, 
therefore, far below the dose of 300 mg/kg/day for 10 days that is near the threshold for liver 
damage for primates. Pimonidazole is not toxic to hypoxic cells at the concentrations used for 
hypoxia marking in humans (See Material Safety Data Sheet).  
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
7.2 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
7.3 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
7.4 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from BMS and Pfizer or designee, the amount dispensed to and returned by the subjects and 
the amount remaining at the conclusion of the trial. Upon completion or termination of the 
study, all unused and/or partially used investigational product will be destroyed at the site per 
institutional policy. It is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept  
8.0 ADMINISTRATIVE AND REGULATORY DETAILS  
 
8.1 DATA SAFETY AND MONITORING PLAN 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet monthly in disease center 


Nivolumab and Axitinib Phase II Study  
52 
  
 
 
  
 
 
 
Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but not 
limited to, the following: 
 
• Serious adverse events 
• Subject safety issues 
• Recruitment issues 
• Accrual 
• Protocol deviations 
• Unanticipated problems 
• Breaches of confidentiality 
 
Minutes from the disease center DSMB meetings are available to those who are unable to 
attend in person. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 5.0. All study treatment associated adverse events 
that are serious, at least possibly related and unexpected will be reported to the IRB. A set of 
Bayesian continuous monitoring stopping rules will be implemented to ensure that the true 
severe adverse event (SAE) rate is controlled under 30% (see section 7). Any modifications 
necessary to ensure subject safety and decisions to continue, or close the trial to accrual are 
also discussed during these meetings. If any literature becomes available which changes the 
risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB will be 
notified in the form of an Unanticipated Problem submission and the study may be terminated.  
 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPCI DSMC 
which also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse 
events). DSMC progress reports, to include a summary of all serious adverse events and 
modifications, and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, 
will be reviewed twice a year rather than monthly. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records.  


Nivolumab and Axitinib Phase II Study  
53 
  
 
 
  
 
 
 
 
8.2 Quality Control and Quality Assurance 
 
The Sponsor-Investigator and the University of Pittsburgh and UPMC will permit direct access of the 
study monitors and appropriate regulatory authorities to the study data and to the corresponding source 
data and documents to verify the accuracy of this data. 
 
8.3 Data Handling and Record Keeping 
 Data recording/case report forms/visit checklists 
A Case Report Form will be completed for each subject enrolled into the clinical study.  
Source Data are the clinical findings and observations, laboratory and test data, and other information 
contained in Source Documents. Source Documents are the original records  including, but not limited 
to, hospital medical records,  physician or office charts, physician or nursing notes, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, x-rays, 
etc. When applicable, information recorded on the CRF shall match the Source Data recorded on the 
Source Documents.  
 
        8.4 Ethics 
Institutional Review Board (IRB) approval 
The Investigator will obtain, from the University of Pittsburgh Institutional Review Board (IRB), 
prospective approval of the clinical protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, and advertisements 
(i.e., directed at potential research subjects) for study recruitment.  
 
The only circumstance in which a deviation from the current IRB-approved clinical protocol/consent 
form(s) may be initiated in the absence of prospective IRB approval is to eliminate an apparent 
immediate hazard to the research subject(s). In such circumstances, the -Investigator will promptly 
notify the University of Pittsburgh IRB of the deviation.  
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 50 and 
21 CFR 56, and in conformance with applicable International Conference on Harmonization (ICH) 
Guidelines on Good Clinical Practice (CGP). 
 
Ethical and scientific conduct of the clinical research study 
The clinical research study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH GCP Guidelines adopted by the FDA; and relevant policies, requirements, and 
regulations of the University of Pittsburgh IRB, University of Pittsburgh and UPMC, Commonwealth 
of Pennsylvania, and applicable federal agencies. 


Nivolumab and Axitinib Phase II Study  
54 
  
 
 
  
 
 
 
9.0 APPENDICES 
9.1 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
9.2 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
9.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.  
*As published int eh European Journal of Cancer (2009) 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
In addition, volumetric analysis will be explored by central review for response assessment.  
 


Nivolumab and Axitinib Phase II Study  
55 
  
 
 
  
 
 
 
1. 
Najjar YG, Menk AV, Sander C, et al. Tumor cell oxidative metabolism as a barrier to 
PD-1 blockade immunotherapy in melanoma. JCI Insight 2019. 
2. 
Varia M. Oral Pimonidazole HCl as Tumor Hypoxia Marker: Report of First Clinical 
Use 
- 
Pharmacokinetics 
and 
Tolerance. 
International 
Journal 
of 
Radiation 
Oncology*Biology*Physics 2009;75:S539-S40. 
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