Conditions: Clear Cell Renal Cell Carcinoma
Keywords: ccRCC MGCD516 Antineoplastic Agents Immunologic factors nivolumab Tyrosine Kinase Inhibitor VEGFR TAM RTKs PD-1 PD-L1
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The study will evaluate the clinical activity of sitravatinib in combination with nivolumab in patients with locally-advanced clear cell renal cell carcinoma (ccRCC) in the neoadjuvant setting prior to nephrectomy.

Detailed description:
Sitravatinib is a receptor tyrosine kinase inhibitor (TKI) that targets multiple closely related receptor tyrosine kinase pathways including VEGFR, PDGFR, c-KIT, MET, and the TAM family of receptors (TYRO3, AXL, and MER). Nivolumab is a monoclonal antibody directed against PD-1 and blocks the interaction between PD-1 and its ligands, thereby releasing PD-1-mediated inhibition of T-cell proliferation (including cytotoxic CD8+ T-cells) and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment the efficacy of nivolumab.

Arms:
arm 1: Sitravatinib oral capsule administered daily 2 weeks alone then in combination with nivolumab administered as 240 mg IV every 2 weeks. Total treatment duration: 6-8 weeks prior to planned nephrectomy.

Interventions: intervention 1: Sitravatinib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Sitravatinib oral capsule administered daily for 6-8 weeks in segments 1 and 2. intervention 2: Nivolumab administered as 240 mg IV every 2 weeks for 4-6 weeks in segment 2.

Protocol document:
Prot_000.pdf: 
Protocol Number:  516-002 
 
Official Title:  A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients 
Undergoing Nephrectomy for Locally-Advanced Clear Cell Renal Cell 
Carcinoma 
 
NCT Number:  NCT03680521 
 
Document Date:  16-May-2018 


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CLINICAL RESEARCH PROTOCOL 
DRUG(S): 
Sitravatinib (MGCD516) 
Nivolumab (OPDIVO®) 
 
STUDY NUMBER: 
516-002 
 
PROTOCOL TITLE: 
A Phase 2 Study of Sitravatinib in Combination with 
Nivolumab in Patients Undergoing Nephrectomy for 
Locally-Advanced Clear Cell Renal Cell Carcinoma 
 
IND NUMBER: 
138695 
 
SPONSOR: 
Mirati Therapeutics, Inc. 
9393 Towne Centre Drive, Suite 200 
San Diego, California, 92121, USA 
 
ORIGINAL PROTOCOL 
DATE: 
 
3 April 2018 
VERSION NUMBER: 
V3.0 
 
VERSION DATE: 
16 May 2018 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information and/or trade secrets of Mirati Therapeutics, Inc.  As such, 
this document is protected from unauthorized disclosure or use by confidentiality agreement(s) and/or is 
exempt from public disclosure pursuant to applicable FDA and foreign counterpart regulations. 
 


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DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
(This version not 
submitted to FDA) 
3 April 2018 
NA 
Amendment #1, 
Version 2.0 
(This version 
submitted to FDA 
with the initial IND) 
17 April 2018 
• 
Added guidance regarding patient treatment and study 
discontinuation conditions for patients who develop 
adverse events that prevent subsequent nivolumab 
administration depending on treatment to date. 
• 
Added details to sitravatinib dose modification to manage 
hematological and non-hematological adverse events, 
hypertension (added Table 5), decreased LVEF, and 
increase hepatic transaminases. 
• 
Emphasized that OPDIVO Product Information must be 
consulted to ensure correct action is taken for nivolumab 
dose modification in the management of adverse events. 
• 
Restricted secondary efficacy endpoint to Disease-Free 
Survival (DFS) and modified the frequency and method of 
collection of this endpoint. 
• 
Addressed clerical errors and made minor clarifications. 
Amendment #2, 
Version 3.0 
16 May 2018 
• 
In response to comments from the US Food and Drug 
Administration review, the following changes were made: 
o 
Added a dose de-escalation plan for sitravatinib to 
monitor and limit toxicity of the combination regimen 
in the neoadjuvant setting using the Modified Toxicity 
Probability Interval (mTPI) method. 
o 
Expanded guidance regarding sitravatinib 
discontinuation conditions. 
o 
Added guidance regarding the need to undergo the 
scheduled surgery no later than 8 weeks following 
first dose of study drug, and not to extend the 
pre-operative period for missed doses of either study 
drug. 
• 
Addressed clerical errors and made minor clarifications. 
 
 
 


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STUDY SUMMARY 
Title:  
A Phase 2 Study of Sitravatinib in Combination with Nivolumab in 
Patients Undergoing Nephrectomy for Locally-Advanced Clear Cell 
Renal Cell Carcinoma 
Rationale:  
Renal cell carcinomas (RCCs), which originate within the renal 
cortex, are responsible for 80% to 85% of all primary renal 
neoplasms.  In the United States, RCC is the 6th most common 
cancer in men and the 9th most common cancer in women.  An 
estimated 63,340 new cases and 14,970 deaths are expected in 2018.  
Incidence rates of RCC have been rising, with most of the increases 
occurring in early-stage tumors.  Clear cell RCC (ccRCC) is the 
most common RCC histologic type, comprising 70-85% of all 
RCCs, and is overwhelmingly a nonhereditary (sporadic) cancer.  At 
the time of diagnosis, approximately 25% of patients with ccRCC have 
locally-advanced disease.  Locally-advanced tumors are managed 
with radical or partial nephrectomy with curative intent.  Between 
40% and 60% of such patients can be cured with such an 
aggressive surgical approach.  However, given the relatively high 
rate of recurrence and the poor prognosis of metastatic ccRCC 
despite recent advances with immunotherapy and other targeted 
therapies, there remains an unmet medical need for patients with 
locally advanced RCC. 
ccRCC is characterized by two important features.  First, ccRCC is 
often associated with inactivating mutations of the von Hippel-
Lindau (VHL) tumor suppressor gene, which leads to upregulation 
of hypoxia-inducible factors (HIF) and to downstream upregulation 
of vascular endothelial growth factor (VEGF), resulting in increased 
angiogenesis.  VHL inactivation also leads to overexpression of 
receptor tyrosine kinases MET and AXL, known to be important in 
the pathogenesis and resistance to standard anti-angiogenic therapies 
for RCC.  Second, it is often susceptible to immune regulation.  
These two features have led to the use of several active agents that 
either target the VEGF receptor (VEGFR) pathway (e.g., sunitinib, 
pazopanib) or modulate immune response (e.g., interferon-alpha 
[IFN-α], interleukin-2 [IL-2], nivolumab).  Here, we postulate that 
the combination of sitravatinib, an inhibitor of VEGFR and other 
related kinases, and nivolumab, a Programmed Cell Death Protein 1 
(PD-1) inhibitor, is not only active due to each component, but that 
the addition of sitravatinib can further enhance the immune effects 
from nivolumab. 
Sitravatinib is a receptor tyrosine kinase inhibitor (TKI) that targets 
multiple closely related receptor tyrosine kinase pathways including 


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VEGFR, PDGF receptor (PDGFR), c-KIT, MET, and the TAM 
family of receptors (TYRO3, AXL, and MER).  In an ongoing Phase 
1/1b study of sitravatinib, clinical activity has been observed in 
patients with ccRCC, putatively due to sitravatinib’s potent 
inhibition of VEGFR2 and inhibition of MET and AXL; which may 
mediate resistance to VEGFR inhibitors, and in patients with 
qualifying genetic alterations selected based on sitravatinib’s target 
profile. 
Nivolumab is a monoclonal antibody directed against PD-1 and 
blocks the interaction between PD-1 and its ligands, thereby 
releasing PD-1-mediated inhibition of T-cell proliferation (including 
cytotoxic CD8+ T-cells) and cytokine production.  It has been 
evaluated in ccRCC after anti-angiogenic therapy in the Phase 3 
CheckMate 025 trial, where patients treated with nivolumab at a 
dose level of 3 mg/kg every 2 weeks demonstrated a median OS of 
25.0 months compared to 19.6 months for patients treated with 
everolimus, a mammalian target of rapamycin (mTOR) inhibitor, 
with a hazard ratio (HR) of 0.73 (98.5% CI: 0.57, 0.93; p=0.002).  
Nivolumab has been approved for use in this treatment setting. 
Together, sitravatinib and nivolumab may cooperate to elicit greater 
anti-tumor activity than either agent alone, as sitravatinib is 
predicted to enhance several steps in the cancer immunity cycle that 
may augment the efficacy of nivolumab.  First, the anti-tumor 
activity of sitravatinib may promote the release of tumor antigens.  
Second, inhibition of the split kinase receptors VEGFR and KIT 
may decrease the number of regulatory T-cells (Tregs) and myeloid-
derived suppressor cells (MDSCs), thus promoting the expansion 
and migration of anti-tumor cytotoxic T-cells, and their infiltration 
into tumor tissue.  Third, sitravatinib may reverse the 
immunosuppressive effects within the tumor microenvironment 
(TME) that are mediated by the TAM receptors through inhibition of 
MERTK (resulting in an increased number of the proinflammatory 
M1-polarized macrophages, proinflammatory cytokine release, and 
enhanced CD8+ T-cell activation), and through inhibition of AXL 
(predicted to increase the Toll-like receptor dependent inflammatory 
response in dendritic cells).  Moreover, inhibition of MERTK and 
AXL may result in increased natural killer (NK) cell activity by 
releasing the negative feedback regulatory mechanism and may 
complement PD-1/PD-L1 checkpoint inhibition to augment the host 
anti-cancer immune response.  Finally, inhibition of MET may 
enhance the anti-tumor response by restoring antigen-presenting cell 
(APC) function and reducing or eliminating MDSCs within the 
TME. 


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Thus, the combination of sitravatinib and nivolumab is a rational 
approach for patients with ccRCC with effects at several steps in the 
immunity cycle.  This combination has been shown to be safe and 
tolerable in an ongoing Phase 2 Study (MRTX-500) in second-line 
patients with metastatic non-small cell lung cancer (NSCLC).  The 
recommended Phase 2 dose for this combination is 120 mg orally 
daily of sitravatinib and 240 mg of nivolumab (flat dose) 
administered IV Q2W. 
Neoadjuvant, or preoperative, therapy can lead to primary tumor 
downsizing or downstaging, which may decrease intra-operative and 
peri-operative morbidity and potentially allow for less extensive 
surgery or less invasive approaches.  In addition, in 
locally-advanced RCC, neoadjuvant therapy can potentially control 
micrometastatic disease present at the time of surgery.  Neoadjuvant 
targeted therapies have been investigated in several Phase 2 trials in 
both locally-advanced and metastatic ccRCC and have demonstrated 
reduction of primary tumor burden prior to surgery.  Neoadjuvant 
axitinib, a VEGFR TKI, administered for 12 weeks is clinically 
active and reasonably well tolerated in the neoadjuvant setting in 
patients with locally-advanced ccRCC (28% median reduction of 
primary renal tumor diameter, with all patients experiencing tumor 
reduction and with a partial response [PR] rate of 46%).  Similarly, 
neoadjuvant sunitinib, a VEGFR and PDGFR TKI, administered for 
8 weeks is safe and feasible in the neoadjuvant setting in patients 
with either locally-advanced or metastatic ccRCC, and active, 
demonstrating a 21% median reduction of primary renal tumor 
diameter, with all patients experiencing tumor reduction and 29% 
achieving a PR. 
In summary, in addition to sitravatinib’s potent inhibition of VEGFR 
and inhibition of MET and AXL (which potentially mediate 
resistance to VEGFR inhibitors), sitravatinib may act synergistically 
with immune checkpoint inhibitors such as nivolumab in immune 
activation in ccRCC.  Treatment of ccRCC with sitravatinib may 
produce rapid tumor cell death and release of tumor associated 
antigens as well as enhance tumor antigen presentation, inhibit 
immunosuppressive cell types and prime and activate anti-tumor 
T-cell responses.  Here, we evaluate the clinical activity of this 
combination as neoadjuvant treatment of ccRCC and assess correlative 
immune effects. 
Target 
Population: 
Patients with locally-advanced clear cell renal cell carcinoma 
(ccRCC) who are candidates for nephrectomy. 


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Number in 
Primary Trial: 
Approximately 25 patients with locally-advanced RCC who are 
candidates for nephrectomy in order to accrue 18 clinical activity 
evaluable patients with clear cell histology. 
Primary 
Objective:  
• To evaluate the preoperative clinical activity of the combination 
of sitravatinib and nivolumab in patients with locally-advanced 
ccRCC undergoing nephrectomy. 
Secondary 
Objectives: 
• To evaluate the safety and tolerability of the combination 
regimen in the selected population. 
• To characterize the baseline tumor-related immune profile in 
patients with RCC. 
• To determine the immune effects of sitravatinib and the 
combination regimen in patients with ccRCC. 
• To evaluate the pharmacokinetics (PK) of sitravatinib 
administered daily alone and in combination with nivolumab in 
patients with ccRCC. 
• To characterize the time to surgery. 
• To evaluate secondary efficacy endpoints with the combination 
regimen in the selected population. 
Exploratory 
Objective:  
• To evaluate changes in gene expression and the T-cell repertoire 
in response to therapy in patients with ccRCC. 
Primary 
Endpoint: 
• Percentage of patients achieving a point in time objective 
response (either complete or partial response [CR or PR]) prior 
to surgery. 
Secondary 
Endpoints: 
• Safety characterized by type, incidence, severity, timing, 
seriousness and relationship to study treatment of adverse event 
(AEs) and laboratory abnormalities. 
• Descriptive characterization of immune cell populations in the 
tumor and/or peripheral blood at baseline. 
• Temporal changes in PD-L1 expression, selected cytokines and 
immune cell populations in the tumor and/or peripheral blood 
(including myeloid-derived suppressor cells [MDSCs], 
regulatory T-cells [Tregs], CD4+ [helper] and CD8+ [cytotoxic] 
T-cells, and the ratio of Type1:Type 2 tumor-associated 
macrophages). 


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• Blood plasma concentration of sitravatinib. 
• Time-to-surgery. 
• Disease Free-Survival (DFS). 
Exploratory 
Endpoint: 
• Gene expression and T-cell receptor sequencing. 
Study Design: 
This study (516-002) is an open-label, non-randomized, preoperative 
window of opportunity Phase 2 study of sitravatinib and nivolumab 
in the neoadjuvant setting for the treatment of patients with 
locally-advanced clear cell renal cell carcinoma (ccRCC) 
undergoing nephrectomy.  Approximately 25 patients with a clinical 
diagnosis of locally-advanced renal cancer will be enrolled into the 
study in order to identify a total of 18 clinical activity evaluable 
patients with clear cell histology and detect the primary endpoint of 
percentage of patients with ccRCC achieving a point in time 
objective response (either CR or PR) prior to surgery with the 
combination treatment. 
Prior to Start of Treatment:  All enrolled patients will have met all 
entry criteria and have completed baseline procedures and will be 
scheduled to undergo an initial diagnostic tumor biopsy of their 
renal lesion.  Patients with a histology other than ccRCC will 
proceed to their End of Study (EOS) visit following the histology 
results, with no treatment with study drugs and no follow-up.   
Subjects with a clear cell histology will proceed to the study 
combination treatment which will be conducted in 2 sequential 
preoperative treatment segments. 
Segment 1 (2 weeks) consists of a 2-week treatment with 
single-agent sitravatinib.  Sitravatinib will be administered at a dose 
of 120 mg orally once daily (QD), on a continuous daily dosing 
regimen.  After completion of the 2-week dosing period, patients 
will undergo a renal biopsy. 
Segment 2 (4-6 weeks) consist of combination treatment with 
sitravatinib and nivolumab for at least 4 weeks (and up to a 
maximum of 6 weeks to allow for flexibility with the scheduling of 
the nephrectomy).  Sitravatinib will be administered at a dose of 
120 mg orally QD, on a continuous daily dosing regimen for this 
entire segment.  Nivolumab will be administered, in accordance with 
approved labeling, by intravenous (IV) infusion, 240 mg Q2W 
(namely, on D15, D29, and potentially D43).  Patients will receive 


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the nivolumab injection on D43 only if their surgery is expected to 
occur more than a week from that date.  Patients will be subject to a 
2-day preoperative hold of all study drugs prior to surgery (ensuring 
that the last dose of any study drug is administered a minimum of 72 
hours prior to surgery).Surgery:  After completion of neoadjuvant 
therapy and the ~2-day pre-operative period, patients will undergo 
nephrectomy.  Patients will have their End of Study (EOS) visit 
following surgery, with no further study drug administration.  
Patients will be followed for disease-free survival for up to 3 years 
or more until either death, disease recurrence or loss to follow-up.  
Of note, patients should be scheduled to undergo surgery no later 
than 8 weeks following their first dose of study drug, and the 
preoperative period (including Segments 1 and 2) should not be 
extended in order to take missed doses of either study drug. 
Figure 1: 
Study Schema 
 
 
Statistical 
Considerations: 
The primary endpoint of this study is percentage of patients with 
ccRCC achieving a point in time objective response (either CR or 
PR) prior to surgery with the combination treatment of sitravatinib 
and nivolumab.  Objective responses will be assessed in accordance 
with RECIST 1.1.  With currently available treatments, the 
percentage of patients with a point in time objective response prior 
to surgery is assumed to be 5% (p0); thus, this rate is considered 
uninteresting.  The target percentage of patients with a point in time 
objective response prior to surgery using sitravatinib and nivolumab 
in this study is assumed to be 30% (p1).  Controlling for a Type 1 
error (α) of 0.05, and using an exact test (two-sided), with 18 
clinical activity evaluable patients, we have 80% power to rule out a 


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percentage of patients with a point in time objective response prior 
to surgery of 5% assuming percentage of patients with a point in 
time objective response prior to surgery of 30%.  Additional 
subjects may be enrolled for a total of 12 subjects with complete 
tumor tissue collection (collected from initial and mid-study 
biopsies and surgical sample). 
In addition, a plan for possible dose de-escalation will be 
implemented.  Decisions regarding dose de-escalation will be made 
using the Modified Toxicity Probability Interval (mTPI) method to 
set rules on dose de-escalation in the first 6 patients and then on an 
ongoing basis.  Assuming a maximum toxicity level of no more 
than 20% at the tolerated dose, the dose of sitravatinib will be 
decreased if more than 2 patients with toxicity are observed in the 
first 6 patients.  Specific treatment-related adverse events will be 
used to determine the number of patients with toxicity. 


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Table 1 
Schedule of Assessments 
Study Assessments 
Screening 
Initial 
Biopsy1 
Neoadjuvant Tx 
(6-82 wks) 
Preop 
Rebaseline 
Surgery 
EOS/ 
Withdrawal4 
Long-term 
Follow-Up 
D-28 to Initial 
Biopsy 
D-4 (±3) 
D1 
D143 
(±1) 
D15 
(±2) 
D29 
(±2) 
D432 
(±2) 
≤3 dys of 
Surgery 
 
 
 
Informed Consent5 
X 
 
 
 
 
 
 
 
 
 
 
Collection of Tumor Tissue6 
 
X 
 
X 
 
 
 
 
X 
 
 
Medical History, Disease History, 
Prior Therapy 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam7 including Vital Signs 
& ECOG PS 
X 
 
 
 
 
 
 
 
 
X 
 
Abbreviated Physical Exam8 
including Vital Signs 
 
 
X 
 
X 
X 
(X) 
X 
 
 
 
Hematology and Serum Chemistry9,10 
X 
X 
X 
 
X 
X 
(X) 
X 
 
X 
 
Coagulation and Urinalysis9,10 
X 
 
As clinically indicated 
Coagulation 
only 
As clinically indicated 
 
Thyroid Function Test9,10 
X 
 
 
 
 
 
 
X 
 
X 
 
Pharmacokinetic, Pharmacodynamic, 
and Baseline ctDNA Blood Samples, 
and Triplicate 12-Lead ECG11 
See Table 2 
 
See Table 2 
 
 
 
Single 12-Lead ECG11 
X 
As clinically indicated 
X 
 
Echocardiogram 
X 
 
 
 
 
X 
 
X 
 
 
 
Disease Assessment12 
X 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Test13 
X 
As clinically indicated 
 
Sitravatinib Dispensing and/or 
Reconciliation 
 
 
X 
 
 
X 
 
Preop hold for 
2 dys from 
Surgery16 
Surgery 
Hold 
 
 
Nivolumab Administration 
 
 
 
 
X 
X 
(X) 
 
 
AEs14 and Concomitant Medications 
SAEs only 
Throughout 
 
Long-Term Follow-Up15 
 
 
 
 
 
 
 
 
 
 
X 
The Schedule of Assessments provides an overview of the protocol visits and procedures.  Refer to Section 7 for detailed information on each assessment.  
Additional, unplanned assessments should be performed as clinically indicated, including for the purpose of fully evaluating AEs (adverse events). 


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1  
On the Initial Biopsy Visit, laboratory blood assessments completed in the previous week do not need to be repeated.  The Initial Biopsy will preferably be scheduled for D-4 (±3); 
however, to allow flexibility for logistical reasons, this period can include up to 2 weeks from D1 (including D-14). 
2  
Neoadjuvant therapy will be administered for at least 6 weeks (unless treatment discontinuation is warranted), and up to a maximum of 8 weeks, to allow for flexibility with the 
scheduling of the nephrectomy (surgery).  Consequently, nivolumab will be administered as neoadjuvant therapy for at least 2 injections, and up to a maximum of 3 injections.  The 
third injection will only be administered if the subject’s planned day of Surgery is at least one week after D43 and further treatment is not contraindicated [e.g., interruptions for 
adverse events (AEs)].  Assessments that occur in the 2 weeks that are meant to allow flexibility for the scheduling of the surgery are indicated in ( ).  
3  
D14 visit (±1), which has for purpose the mid-study biopsy, must occur prior to first nivolumab injection on D15 (±2). 
4  
End of Study (EOS)/Withdrawal: Laboratory blood assessments completed in the previous 4 weeks do not need to be repeated.  EOS visit must occur at least 28 days after last dose of 
study drug or surgery, whichever occurs last. 
5  
Informed Consent: May be performed within 28 days prior to the first dose of sitravatinib therapy on D1 and must be completed prior to initiation of any study specific assessments. 
6  
Collection of Tumor Tissue: Tumor tissue will be collected from initial and mid-study biopsies and surgical sample.  Fresh tumor biopsies are to be collected on study; archival tissue will 
not be accepted as an alternative.  The tumor biopsy collected on the Initial Biopsy Visit will confirm the histology of the renal cancer.  Tumor tissue will be collected and used to assess 
immune effects through tissue biomarkers prior to and during and following treatment.  Parameters may include, but are not limited to, quantification of tissue immune cell populations by 
flow cytometry including T-cell subpopulations (CD8+, CD8+/Ki67+ and regulatory T-cells [Tregs]), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs) and macrophages; 
immunohistochemistry and/or immunofluorescence for assessment of PD L1 status and characterization of immune cell populations; tumor gene expression analysis; and DNA sequencing 
to assess T-cell clonality.  In addition, next generation sequencing (NGS) analyses for tumor mutations and tumor mutation burden may be assessed using tissue from the surgical sample. 
7  
Physical Examinations: A complete physical examination required at Screening and EOS/Withdrawal only.  Height will be recorded at screening only.  All other evaluations will be 
symptom-directed, abbreviated evaluations.  Vital signs include weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
8  
Abbreviated Physical Exam includes vital signs (weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated) and symptom-directed evaluation. 
9  
Selected D1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.   
10  
Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 7) will be performed by local laboratories.   
11  
Pharmacokinetic (PK) Blood Samples: Blood samples for PK measurements will be collected as outlined in Table 2. 
Pharmacodynamic Blood Samples: Blood samples will be collected for the assessment of immune effects through circulating biomarkers prior to and during and following treatment as 
outlined in Table 2.  Parameters may include, but are not limited to, quantification of circulating immune cell populations by flow cytometry including T-cell subpopulations (CD4+, 
CD4+/Ki67+, CD8+, CD8+/Ki67+ and Tregs), NK cells, and MDSCs; blood levels of selected cytokines and chemokines including IFN-γ, IL-1ß, IL-6, IL-8, IL-12, IL-18 and CXCL10 
(IP-10); and DNA sequencing to assess T-cell clonality.   
Baseline ctDNA Blood Samples: NGS analyses for tumor mutations and tumor mutation burden may be assessed at baseline using ctDNA as outlined in Table 2. 
12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 2.  In addition, single ECGs are to be performed as clinically indicated.  Assessments will include 
an evaluation of RR, QT, and QTc intervals.  In case RR interval cannot be machine-read, ventricular heart rate should be reported instead. 
12  
Disease Assessments will occur at the following times: 
a) 
during screening (within 28 days of D1), 
b) 
preoperatively (within 1 week prior to the surgery). 
At screening/baseline, assessments are to include evaluation of any superficial lesions, Computed Tomography Scan (CT) with contrast or X-ray (radiography) of the chest, Magnetic 
Resonance Imaging (MRI) with and without gadolinium or CT abdomen, as well as, if clinically indicated, MRI of the brain and a chest x-ray.  The subsequent disease assessment 
should include all sites of disease identified at baseline or suspected to have developed.  More detailed guidance on exceptional circumstances is provided in the protocol. 
13  
Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at screening will be required.  The 
informed consent process must include discussion of the risks associated with pregnancy and adequate contraception methods.  Additional pregnancy testing may be necessary if 
required by local practices or regulations, or if potential pregnancy is suspected. 
14  
Adverse Events: SAEs (serious adverse events) will be reported from the time of informed consent until at least 28 days after the last administration of sitravatinib or nivolumab.  Ongoing 
SAEs should be followed until resolution or stabilization to a chronic condition.  AEs will be reported from the day of the initial biopsy until at least 28 days after last dose of study drug. 
15  
Long Term Follow-up: Survival status will be collected by review of medical records or telephone contact with the patient or treating healthcare professional approximately every 6 months 
from EOS visit for up to 3 years or more until death, disease recurrence or loss to follow-up.  Disease recurrence will be based on imaging assessments performed off study per standard of 
care after nephrectomy. 
16          2-day preoperative hold such that the last dose of any drug is administered a minimum of 72 hours prior to surgery. 


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Table 2: 
Schedule of Pharmacokinetic, Pharmacodynamic, Baseline ctDNA, and Triplicate ECG Assessments 
 
Screening 
Neoadjuvant Tx 
Preop Rebaseline 
 
D-28 to Initial 
Biopsy 
D1 
D15 (± 2) 
D29 (± 2)  
D43 (± 2)  
≤ 3 dys of Surgery  
Collection Time and 
Allowable Window 
 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 min) 
4 hour 
(2-6 hour) 
Pre-dose 
(-2-0 hour) 
Pre-dose 
(-2-0 hour) 
Pre-dose 
(-2-0 hour) 
 
PK Blood Samples1,2,3 
 
X 
X 
X 
X 
 
X (whichever visit occurs first) 
Flow Cytometry Blood 
Samples3,4 
X 
>2 dys from D1 
X 
 
 
X 
X 
X (whichever visit occurs first) 
Protein and Cytokine 
Biomarkers Blood 
Samples3,4 
 
X 
 
 
X 
X 
X (whichever visit occurs first) 
TCR Sequencing 
Blood Samples3,4 
 
X 
 
 
 
 
 
X 
Baseline ctDNA Blood 
Samples4,5 
X 
 
 
 
 
 
 
 
Triplicate ECG6 
 
X 
X 
 
X 
 
 
 
1  Unscheduled PK blood samples should be drawn in association with two kinds of safety events: 1) as soon as possible after a Serious Adverse Event (SAE), 
and 2) at a clinic visit at least one week following a dose modification of sitravatinib. 
2  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede nivolumab infusion. 
3  Pharmacokinetic, pharmacodynamic, and baseline ctDNA blood samples should be collected as detailed in the study Lab Manual and in the study kit. 
4  Blood for Pharmacodynamics: Immune effects will be evaluated through circulating prior to and during and following treatment.  Blood samples will be 
collected for the assessment of parameters that may include, but are not limited to, quantification of circulating immune cell populations by flow cytometry 
including T-cell subpopulations (CD4+, CD4+/Ki67+, CD8+, CD8+/Ki67+ and Tregs), NK cells, and MDSCs; blood levels of selected cytokines and 
chemokines including IFN-γ, IL-1ß, IL-6, IL-8, IL-12, IL-18 and CXCL10 (IP-10); and DNA sequencing to assess T-cell clonality.   
5  Baseline ctDNA Blood Samples: NGS analyses for tumor mutations and tumor mutation burden may be assessed at baseline using ctDNA. 
6  ECGs should be taken in triplicate, each reading approximately 2 minutes apart.  On D1 only, two sets of triplicate ECGs should be done within 1 hour prior 
to dosing (e.g., at 30-minute intervals) to firmly establish the baseline for the patient.  In general, ECGs should be performed prior (within -30 to -5 minutes) 
to the respective PK blood collection. 
• 
Example for D1 pre-dose ECG/PK assessments: ~ -1.0 hour (Triplicate ECGs); ~ -30 minutes (Triplicate ECGs); ~ -15 minutes (Vitals/PK). 
• 
Example for all other pre-dose ECG/PK assessments: ~ -30 minutes (Triplicate ECGs); ~ -15 minutes (Vitals/PK). 
Assessments will include evaluation of RR, QT and QTc intervals.  In case RR interval cannot be machine-read, ventricular heart rate should be reported 
instead. 


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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
DOCUMENT HISTORY ..................................................................................................2 
STUDY SUMMARY ..........................................................................................................3 
TABLE OF CONTENTS ................................................................................................13 
TABLE OF TABLES .......................................................................................................16 
TABLE OF FIGURES .....................................................................................................16 
LIST OF ABBREVIATIONS .........................................................................................18 
LIST OF ABBREVIATIONS (CONTINUED) .............................................................19 
LIST OF ABBREVIATIONS (CONTINUED) .............................................................20 
LIST OF ABBREVIATIONS (CONTINUED) .............................................................21 
LIST OF ABBREVIATIONS (CONTINUED) .............................................................22 
1 
INTRODUCTION AND RATIONALE .................................................................23 
1.1 
Background ..........................................................................................................23 
1.1.1 
Renal Cell Carcinoma....................................................................................23 
1.1.2 
Sitravatinib .....................................................................................................23 
1.1.3 
Nivolumab .......................................................................................................23 
1.1.4 
Potentially Synergistic Effects ......................................................................24 
1.1.5 
Neoadjuvant Setting in Locally-Advanced ccRCC .....................................25 
1.2 
Sitravatinib Background .....................................................................................27 
1.2.1 
Sitravatinib Drug Substance .........................................................................27 
1.2.2 
Sitravatinib Non-Clinical Data .....................................................................28 
1.2.3 
Sitravatinib Clinical Data..............................................................................29 
1.2.3.1 
Sitravatinib Pharmacokinetics ...............................................................29 
1.2.3.2 
Sitravatinib Clinical Safety .....................................................................29 
1.2.3.3 
Sitravatinib Clinical Efficacy ..................................................................31 
1.3 
Nivolumab Background ......................................................................................31 
1.3.1 
Nivolumab Drug Substance ..........................................................................31 
1.3.2 
Nivolumab Non-Clinical Data .......................................................................31 
1.3.3 
Nivolumab Clinical Data ...............................................................................31 
1.3.3.1 
Nivolumab Pharmacokinetics .................................................................32 
1.3.3.2 
Nivolumab Anti-Drug Antibodies ..........................................................32 
1.3.3.3 
Nivolumab Adverse Reactions Common in Clinical Trials .................32 
1.3.3.4 
Nivolumab Immune-Related Adverse Events .......................................33 
1.4 
Combination Safety of Sitravatinib and Nivolumab ........................................33 
1.4.1 
Potential for Drug-Drug Interactions ..........................................................33 
1.4.2 
Evaluation of Potential for Increased Toxicities with Combination 
Use of Sitravatinib and Nivolumab ..............................................................34 
2 
STUDY OBJECTIVES ............................................................................................35 
2.1 
Objectives..............................................................................................................35 
2.1.1 
Primary Objective ..........................................................................................35 
2.1.2 
Secondary Objectives.....................................................................................35 
2.1.3 
Exploratory Objective ...................................................................................35 
2.2 
Endpoints ..............................................................................................................36 
2.2.1 
Primary Endpoint ..........................................................................................36 


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2.2.2 
Secondary Endpoints .....................................................................................36 
2.2.3 
Exploratory Endpoints ..................................................................................36 
3 
STUDY DESIGN ......................................................................................................36 
4 
SUBJECT SELECTION AND ENROLLMENT ..................................................38 
4.1 
Inclusion Criteria .................................................................................................38 
4.2 
Exclusion Criteria ................................................................................................39 
4.3 
Life Style Guidelines ............................................................................................41 
4.4 
Enrollment into Study .........................................................................................41 
5 
STUDY TREATMENT ............................................................................................42 
5.1 
Sitravatinib Study Drug ......................................................................................42 
5.1.1 
Sitravatinib Formulation, Packaging and Storage .....................................42 
5.1.2 
Sitravatinib Preparation, Dispensing, Administration and 
Accountability ................................................................................................42 
5.1.3 
Sitravatinib Dose Modification and Discontinuation .................................43 
5.2 
Nivolumab Study Drug ........................................................................................44 
5.2.1 
Formulation and Packaging ..........................................................................44 
5.2.2 
Preparation and Dispensing ..........................................................................44 
5.2.3 
Administration ...............................................................................................45 
5.2.4 
Dose Modification ..........................................................................................45 
5.3 
Management of Adverse Events .........................................................................45 
5.3.1 
Sitravatinib-Related Adverse Events ...........................................................46 
5.3.1.1 
General Management of Non-Hematological Toxicities ......................46 
5.3.1.2 
General Management of Hematological Toxicities ...............................47 
5.3.1.3 
Management of Selected Adverse Events ..............................................47 
5.3.2 
Nivolumab-Related Adverse Events .............................................................49 
5.3.3 
Management in Event of Immune-Related Adverse Events ......................50 
5.3.3.1 
Diarrhea/Colitis ........................................................................................50 
5.3.3.2 
Increased Transaminases ........................................................................50 
5.3.3.3 
Management of Hy’s Law Cases ............................................................51 
5.4 
Medication Error .................................................................................................51 
5.5 
Concomitant Therapies .......................................................................................51 
5.5.1 
Concomitant Medication(s) ...........................................................................51 
5.5.2 
Concomitant Surgery or Radiation Therapy ..............................................53 
5.5.3 
Other Anticancer or Experimental Therapy ...............................................53 
6 
STUDY ASSESSMENTS .........................................................................................53 
6.1 
Screening ...............................................................................................................53 
6.2 
Study Period .........................................................................................................53 
6.3 
End of Study (EOS) Assessment .........................................................................53 
6.4 
Long-Term Follow-up .........................................................................................54 
6.5 
Patient Discontinuation/Withdrawal .................................................................54 
7 
PROCEDURES .........................................................................................................54 
7.1 
Efficacy..................................................................................................................55 
7.2 
Safety Assessments ...............................................................................................56 
7.2.1 
Medical History ..............................................................................................56 
7.2.2 
Physical Examination and Vital Signs .........................................................56 
7.2.3 
Laboratory Safety Assessments ....................................................................56 


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7.2.4 
Electrocardiogram (ECG) .............................................................................57 
7.2.5 
Echocardiogram (ECHO) .............................................................................57 
7.3 
Laboratory Studies ..............................................................................................57 
7.3.1 
Pharmacokinetic Evaluation .........................................................................58 
7.3.2 
Pharmacodynamic Evaluation in Blood ......................................................58 
7.3.3 
Pharmacodynamic Evaluation in Tumor Tissue ........................................58 
7.3.4 
Circulating and Tissue Tumor DNA ............................................................59 
8 
ADVERSE EVENT REPORTING .........................................................................59 
8.1 
Sponsor Medical Monitor Personnel ..................................................................59 
8.2 
Adverse Events .....................................................................................................59 
8.2.1 
Laboratory Abnormalities ............................................................................60 
8.2.1.1 
Hy’s Law ...................................................................................................60 
8.2.2 
Severity Assessment .......................................................................................61 
8.2.3 
Causality .........................................................................................................61 
8.3 
Serious Adverse Events .......................................................................................61 
8.3.1 
Definition of a Serious Adverse Event .........................................................61 
8.3.2 
Exposure During Pregnancy .........................................................................63 
8.4 
Reporting of Serious Adverse Events and Adverse Events ..............................63 
8.4.1 
Reporting Period ............................................................................................63 
8.4.2 
Reporting Requirements ...............................................................................64 
9 
STATISTICS .............................................................................................................64 
9.1 
Statistical Design ..................................................................................................65 
9.1.1 
Hypothesis and Sample Size ..........................................................................65 
9.1.2 
Dose De-escalation Plan .................................................................................65 
9.2 
Data Handling ......................................................................................................66 
9.3 
Analysis Populations ............................................................................................66 
9.3.1 
Clinical Activity Evaluable Population ........................................................66 
9.3.2 
Safety Population ...........................................................................................66 
9.3.3 
Pharmacokinetic Evaluable Population .......................................................66 
9.3.4 
Pharmacodynamic Evaluable Population....................................................66 
9.4 
Efficacy Endpoint Definitions and Analyses .....................................................67 
9.4.1 
Percentage of Patients Achieving a Point in Time Objective 
Response (either CR or PR) Prior to Surgery .............................................67 
9.4.2 
Disease-Free Survival (DFS) .........................................................................67 
9.5 
Safety Data Presentations and Summaries ........................................................68 
9.5.1 
Prior and Concomitant Medications ............................................................68 
9.5.2 
Adverse Events ...............................................................................................68 
9.5.3 
Clinical and Laboratory Assessments ..........................................................68 
9.5.4 
Patient Demographics, Baseline Characteristics and Disposition .............68 
9.5.5 
Analysis of Study Treatment Dosing ............................................................69 
9.5.6 
Time-to-Surgery .............................................................................................69 
9.6 
Other Study Endpoints ........................................................................................69 
9.6.1 
Pharmacokinetic Analysis .............................................................................69 
9.6.2 
Pharmacodynamic and Exploratory Analysis.............................................69 
9.7 
Interim Analysis ...................................................................................................69 
9.8 
Data Monitoring Committee ...............................................................................69 


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10 ETHICS AND RESPONSIBILITIES .....................................................................70 
10.1 
Ethical Conduct of the Study ..............................................................................70 
10.2 
Obligations of Investigators ................................................................................70 
10.3 
Institutional Review Board/Ethics Committee/Research Ethics Board .........70 
10.4 
Informed Consent Form ......................................................................................71 
10.5 
Confidentiality ......................................................................................................71 
10.6 
Reporting of Serious Breaches of the Protocol or ICH GCP ...........................71 
11 RECORDS MANAGEMENT..................................................................................72 
11.1 
Source Documentation.........................................................................................72 
11.2 
Study Files and Records Retention ....................................................................72 
12 QUALITY CONTROL AND QUALITY ASSURANCE ......................................72 
12.1 
Monitoring Procedures ........................................................................................72 
12.2 
Auditing and Inspection Procedures ..................................................................72 
13 CHANGES IN STUDY CONDUCT .......................................................................73 
13.1 
Protocol Amendments .........................................................................................73 
13.2 
Protocol Deviations ..............................................................................................73 
14 END OF TRIAL ........................................................................................................73 
14.1 
End of Trial in a European Union Member State ............................................73 
14.2 
End of Trial in all other Participating Countries .............................................74 
14.3 
Premature Termination.......................................................................................74 
15 STUDY REPORT AND PUBLICATION POLICY ..............................................74 
16 REFERENCES .........................................................................................................75 
Appendix 1. ECOG PERFORMANCE STATUS .........................................................80 
Appendix 2. MEDICATIONS TO BE AVOIDED OR USED WITH 
CAUTION DURING STUDY TREATMENT .......................................................81 
Appendix 3. ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES ...........................................................................................................83 
Appendix 4. DOSE DE-ESCALATION DECISION TABLE USING the mtpi 
method .......................................................................................................................88 
 
TABLE OF TABLES 
Table 1 Schedule of Assessments .................................................................................10 
Table 2: Schedule of Pharmacokinetic, Pharmacodynamic, Baseline ctDNA, 
and Triplicate ECG Assessments ...................................................................12 
Table 3: Sitravatinib Sequential Dose Reductions for Individual Patients...............44 
Table 4: Sitravatinib Dose Modifications – Non-Hematological Drug-
Related Toxicities1 ...........................................................................................46 
Table 5: Sitravatinib Dose Modification for Increased Blood Pressure ....................48 
Table 6: Sitravatinib Dose Modification for Increased Hepatic 
Transaminase ...................................................................................................51 
Table 7: Laboratory Safety Parameters .......................................................................56 
 
TABLE OF FIGURES 
Figure 1: 
Study Schema .............................................................................................8 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
APC 
Antigen-Presenting Cell  
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration  
AUC0-24 
Area Under the Plasma Concentration Versus Time Curve from Time 0 to 24 Hours 
AUC0-24,ss 
Area Under the Plasma Concentration Versus Time Curve from Time 0 to 24 Hours, 
Steady State 
BCRP 
Breast Cancer Resistance Protein 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Cav,ss 
Average Steady-State Plasma Drug Concentration During Multiple-Dose 
Administration 
ccRCC 
Clear Cell Renal Cell Carcinoma 
CD4+/8+ 
Cluster of Differentiation 4-Positive/8-Positive 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CIT 
Checkpoint Inhibitor Therapy 
Cmax 
Maximum Plasma Concentration 
CO2 
Carbon Dioxide 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor Cell DNA 
CV% 
% Coefficient of Variation 
CXCL 
Chemokine (C-X-C) Ligand 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 


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LIST OF ABBREVIATIONS (CONTINUED) 
DDR2 
Discoidin Domain Receptor 2 
DFS 
Disease-Free Survival 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
dys 
Days 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECL 
Electrochemiluminescent  
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
Epidermal Growth Factor Receptor 
EIU 
Exposure In-Utero 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FLT3 
Fms-Related Tyrosine Kinase 3 
FNA 
Fine Needle Aspirates 
FOB 
Functional Observation Battery 
g 
Gram 
GCP 
Good Clinical Practice 
HDPE 
High-Density Polyethlyene 
hERG 
human Ether-a-go-go Related Gene 
Hg 
Mercury 
HGF 
Hepatocyte Growth Factor 
HIF 
Hypoxia-Inducible Factor 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
hr 
Hour 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-α/γ 
Interferon-Alpha/Gamma 
IgG4 
Immunoglobulin G4 
IL-1ß/2/6/8/12/18 
Interleukin-1 Beta/2/6/8/12/18 
ILD 
Interstitial Lung Disease 


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LIST OF ABBREVIATIONS (CONTINUED) 
IND 
Investigational New Drug 
INR 
International Normalized Ration 
IP-10 
Interferon Gamma-Induced Protein 10 
irAEs 
Immune-Related Adverse Events 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MSC 
Mesenchymal Stem Cell 
mTOR 
Mammalian Target of Rapamycin 
mTPI 
Modified Toxicity Probability Interval 
MUGA 
Multigated Acquisition 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NK 
Natural Killer 
NSCLC 
Non-Small Cell Lung Cancer  
NYHA 
New York Heart Association 
OS 
Overall Survival 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PDGFR 
Platelet-Derived Growth Factor Receptor 
PD-L 
Programmed-Death Ligand 


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LIST OF ABBREVIATIONS (CONTINUED) 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PKAP 
Pharmacokinetic Analysis Plan 
PPE 
Palmar Plantar Erythrodysesthesia 
PR 
Partial Response 
Preop 
Preoperative 
PS 
Performance Status 
PTT 
Partial Thromboplastin Time 
Q2W 
Every 2 Weeks 
QD 
Once Daily 
QTc 
Corrected QT  
RCC 
Renal Cell Carcinoma 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RR Interval 
Inter-beat (R-R) Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SUSAR 
Serious Unexpected Serious Adverse Reaction 
T-cell 
Thymus cell 
t1/2 
Plasma Half-Life 
TAM 
TYRO3, AXL and MER 
TCR 
T-cell Receptor 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TGF-β 
Transforming Growth Factor-Beta 
Th1 
Type 1 T Helper Cells 
TILs 
Tumor Infiltrating Lymphocytes 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Time to Maximum Observed Concentration 


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LIST OF ABBREVIATIONS (CONTINUED) 
TME 
Tumor Microenvironment 
TNF-α 
Tumor Necrosis Factor-Alpha 
Treg 
Regulatory T-cell 
TRK 
Tropomyosin Receptor Kinase 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
USP 
United States Pharmacopeia 
USPI 
United States Package Insert 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR/-2 
Vascular Endothelial Growth Factor Receptor/-2 
VHL 
von Hippel-Lindau 
Vss 
Apparent Volume of Distribution at Steady State 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
μM 
Micromolar 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Background 
1.1.1 
Renal Cell Carcinoma 
Renal cell carcinomas (RCCs), which originate within the renal cortex, are responsible 
for 80% to 85% of all primary renal neoplasms (Garfield-2018).  In the United States, 
RCC is the 6th most common cancer in men and the 9th most common cancer in women 
(Siegel-2018).  An estimated 63,340 new cases and 14,970 deaths are expected in 2018 
(American Cancer Society-2018).  Incidence rates of RCC have been rising, with most of 
the increases occurring in early-stage tumors (Garfield-2018).  Clear cell RCC (ccRCC) 
is the most common RCC histologic type, representing between 70% and 85% of all 
RCCs, and is overwhelmingly a nonhereditary (sporadic) cancer (Muglia-2015; 
Escudier-2014).  ccRCC is characterized by two important features.  First, approximately 
50% of sporadic ccRCC is associated with inactivating mutations of the von 
Hippel-Lindau (VHL) tumor suppressor gene, which leads to upregulation of 
hypoxia-inducible factors (HIF) and to downstream upregulation of vascular endothelial 
growth factor (VEGF), resulting in increased angiogenesis (Rini-2005; Cohen-2012; 
Fischer-2015).  VHL inactivation also leads to overexpression of receptor tyrosine 
kinases MET and AXL, which have been implicated in RCC pathogenesis, prognosis, 
and resistance to standard anti-angiogenic therapies (Tannir-2017).  Second, ccRCC is 
often susceptible to immune regulation (Cho-2017).  These two features have led to the 
use of several active agents that either target the VEGF receptor (VEGFR) pathway 
(e.g., sunitinib, pazopanib) or modulate immune response (e.g., interferon-alpha [IFN-α], 
interleukin-2 [IL-2], nivolumab) (Rini-2016).  Here, we postulate that the combination of 
sitravatinib, an inhibitor of VEGFR and other related kinases, and nivolumab, a 
Programmed Cell Death Protein 1 (PD-1) inhibitor, is not only active due to each 
component, but that the addition of sitravatinib can further enhance the immune effects 
from nivolumab. 
1.1.2 
Sitravatinib 
Sitravatinib is a receptor tyrosine kinase inhibitor (TKI) that targets multiple closely 
related receptor tyrosine kinase pathways including VEGFR, platelet-derived growth 
factor receptor (PDGFR), c-KIT, c-MET, and the TAM family of receptors (TYRO3, 
AXL and MER). 
In an ongoing Phase 1/1b study of sitravatinib, clinical activity has been observed in 
patients with ccRCC, putatively due to sitravatinib’s potent inhibition of VEGFR2 and 
inhibition of MET and AXL, which may mediate resistance to VEGFR inhibitors, and in 
patients with qualifying genetic alterations selected based on sitravatinib’s target profile. 
1.1.3 
Nivolumab 
Nivolumab is a monoclonal antibody directed against the Programmed Cell Death Protein 
1 (PD-1), an inhibitory receptor expressed on activated T-cells, and blocks the interaction 


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between PD-1 and its ligands, thereby releasing PD-1-mediated inhibition of T-cell 
proliferation (including cytotoxic CD8+ T-cells) and cytokine production. 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor expressed on 
T cells, inhibits T-cell proliferation and cytokine production and helps to regulate normal 
immune tolerance.  The PD-1 receptor along with the ligands PD-L1 and PD-L2 
constitute an immune checkpoint pathway that inhibits T-cell activation when engaged 
(Mellman-2011; Topalian-2015).  PD-L1 functions to limit collateral damage to normal 
tissues after an immune response has been triggered.  Upregulation of PD-1 ligands is 
utilized by tumors to help evade detection and elimination by the host immune system 
tumor response. 
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated 
clinical activity across a range of cancer types, including RCC (Motzer-2015; 
Sharma-2016; Sharma-2017; Rosenberg-2016; Patel-2018; Massard-2016; 
Bellmunt-2017; Apolo-2017; Balar-2017a; Balar-2017b).  In ccRCC, nivolumab was 
investigated in patients previously treated with anti-angiogenic therapy in the Phase 3 
CheckMate 025 trial at a dose level of 3 mg/kg every 2 weeks.  Nivolumab treatment was 
associated with a median OS of 25.0 months compared to 19.6 months for patients treated 
with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, with a hazard ratio 
(HR) of 0.73 (98.5% CI: 0.57, 0.93; p=0.002).  Nivolumab has been approved for use in 
this treatment setting (Motzer-2015). 
1.1.4 
Potentially Synergistic Effects 
Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity 
than either agent alone, as sitravatinib is predicted to inhibit multiple targets that enhance 
several steps in the cancer immunity cycle which may in turn augment the efficacy of 
nivolumab. 
First, the anti-tumor activity of sitravatinib may promote the release of tumor antigens. 
Second, inhibition of the split kinase receptors may further enhance anti-tumor 
immunoreactivity by depletion of the populations of two key cellular mediators of 
suppression of anti-tumor immunity (Farsaci-2012; Kujawski-2010; Ozao-Choy-2009).  
Specifically, inhibition of VEGFR2 may decrease the number of regulatory T-cells 
(Tregs) within the tumor microenvironment (TME) (Terme-2013; Finke-2008), and 
inhibition of the KIT and VEGFR family members may decrease the number of 
myeloid-derived suppressor cells (MDSCs) (Garton-2017; Kao-2011; Ko-2009; 
Pan-2008; Ozao-Choy-2009).  Depletion of these two populations may promote the 
expansion and migration of anti-tumor cytotoxic T-cells, and their infiltration into tumor 
tissue.  
Several studies support the potential role of these two cell types in creating an 
immunosuppressive TME that allows tumors to evade an immune response.  Resistance 
to antiangiogenic therapy has been attributed to the action of Tregs in the TME, which 
prevent tumors from mounting an active immune response despite tumor infiltration by 


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CD4+ and CD8+ cells (Liu-2015).  Additionally, increases in circulating MDSCs have 
been found to be the most predominant change in the peripheral blood of untreated 
ccRCC patients prior to nephrectomy, with elevations nearly 2 to 5-fold above the 
average levels measured in healthy volunteers (Gustafson-2015; Najjar-2017), and 
intratumoral and peritumoral presence of MDSCs is an independent prognostic factor for 
decreased survival in a cohort of 375 ccRCC patients (Gustafson-2015).  TKI treatment 
before nephrectomy in patients with ccRCC has been found to increase tumor-infiltrating 
lymphocyte (TIL) expansion associated with depletion of intratumoral MDSCs, providing 
evidence to support the functional link between the two (Guislain-2015).  In addition to 
the potential effects of VEGFR2 inhibition to modulate subsets of immune cells, 
VEGFR2 inhibition may have other key effects, including increased tumor perfusion that 
may facilitate trafficking of TILs into the tumor and upregulation of PD-L1 expression 
(Liu-2015) which may facilitate tumor targeting by nivolumab. 
Third, sitravatinib may reverse the immunosuppressive effects within the TME that are 
mediated by the TAM receptors through inhibition of MERTK, resulting in an increased 
number of M1- versus M2-polarized macrophages and release of IL-12, IL-6 and TNF-α 
which enhance CD8+ T-cell activation, and through the inhibition of AXL, which is 
predicted to increase the Toll-like receptor dependent inflammatory response in dendritic 
cells (Lemke-2008; Camenisch-1999).  Also, inhibition of MERTK and AXL may result 
in increased natural killer (NK) cell activity by releasing the negative feedback regulatory 
mechanism (Paolino-2014) and may complement PD-1/PD-L1 checkpoint inhibition to 
augment the host anti-cancer immune response. 
Finally, inhibition of MET may enhance the anti-tumor response by restoring 
antigen-presenting cell (APC) function and reducing or eliminating MDSCs within the 
TME (Chen-2014; Yen-2013; Okunishi-2005; Singhal-2011; Benkhoucha-2010). 
Thus, the combination of sitravatinib and nivolumab is a rational approach for patients 
with ccRCC with effects at several steps in the immunity cycle, including the potential 
for sitravatinib to inhibit several immune cell types that normally function to suppress 
immune responses and underlie resistance to checkpoint blockade (Vanneman-2012), 
including Tregs, myeloid-derived suppressor cells (MDSCs), and M2-polarized 
macrophages. 
This combination has been shown to be safe and tolerable in an ongoing Phase 2 Study 
(MRTX-500) in second-line metastatic non-small cell lung cancer (NSCLC) patients, 
where the recommended Phase 2 dose for this combination has been established as 
120 mg orally daily of sitravatinib and 240 mg of nivolumab (flat dose) administered IV 
every 2 weeks (Q2W). 
1.1.5 
Neoadjuvant Setting in Locally-Advanced ccRCC 
At the time of diagnosis, approximately 25% of patients with ccRCC have 
locally-advanced disease (Errarte-2016).  Radical or partial nephrectomy with curative 
intent remains a keystone in the treatment of localized RCC (Rini-2009; Choueiri-2011).  
Patients with localized ccRCC are typically treated with surgical resection, with a 5-year 


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survival rate dependent on the disease stage, ranging from 81% for Stage I to 53% for 
Stage III (American Cancer Society-2017).  However, there is a relatively high rate of 
recurrence (Escudier-2014).  Although adjuvant therapy with sunitinib may improve 
disease-free survival in patients with locally-advanced ccRCC (Ravaud-2016; 
Motzer-2017), the benefit is modest, and given the poor prognosis of metastatic ccRCC 
despite recent advances with immunotherapy and other targeted therapies 
(Incorvaia-2016), there remains an unmet medical need for patients with 
locally-advanced ccRCC. 
Neoadjuvant, or preoperative, therapy can lead to primary tumor downsizing or 
downstaging, which may decrease intra-operative and peri-operative morbidity and 
potentially allow for less extensive surgery or less invasive approaches (Sciarra-2012).  
In addition, in locally-advanced RCC, neoadjuvant therapy can potentially control 
micrometastatic disease present at the time of surgery.  Notably, aggressive solid tumor 
mouse models have revealed a survival benefit with short courses of neoadjuvant over 
adjuvant PD-1 blockade (Liu-2016). 
Multiple clinical trials have or are evaluating the role of targeted agents in the 
neoadjuvant setting (Choueiri-2011).  In Phase 2 trials in both locally-advanced and 
metastatic ccRCC, neoadjuvant therapy has been associated with a reduction of primary 
tumor burden prior to surgery.  Neoadjuvant axitinib, a VEGFR TKI, administered for 
12 weeks is clinically active and reasonably well-tolerated in the neoadjuvant setting in 
patients with locally-advanced ccRCC (28% median reduction of primary renal tumor 
diameter, with all patients experiencing tumor reduction and with a partial response [PR] 
rate of 46%) (Karam-2014).  Similarly, neoadjuvant sunitinib, a VEGFR and PDGFR 
TKI, administered for 8 weeks, is safe and feasible in the neoadjuvant setting in patients 
with locally-advanced or metastatic ccRCC, and active, demonstrating a 21% median 
reduction of primary renal tumor diameter, with all patients experiencing tumor reduction 
and 29% with a PR (Silberstein-2010). 
Similarly, neoadjuvant immune checkpoint inhibitors are being investigated in two 
ongoing Phase 2 studies of perioperative nivolumab in non-metastatic ccRCC patients 
which have shown preliminary feasibility and safety with no surgical delays or 
complications (Harshman-2017).  And a Phase 3 randomized study comparing 
perioperative nivolumab to observation in patients with localized RCC undergoing 
nephrectomy is currently under way (Harshman-2017). 
In summary, in addition to sitravatinib’s potent inhibition of VEGFR and inhibition of 
MET and AXL (which potentially mediate resistance to VEGFR inhibitors), sitravatinib 
may act synergistically with immune checkpoint inhibitors such as nivolumab to augment 
immune activity in ccRCC.  Treatment of ccRCC with sitravatinib may produce rapid 
tumor cell death and release of tumor associated antigens as well as enhance tumor 
antigen presentation, inhibit immunosuppressive cell types and prime and activate 
anti-tumor T-cell responses. 
This study (516-002) will evaluate the clinical activity of this combination as neoadjuvant 
treatment of ccRCC and assess correlative immune effects.  Nivolumab will be 


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administered in accordance with approved labeling, by IV infusion, 240 mg Q2W.  
Sitravatinib will be administered in accordance with findings of the prior nivolumab 
combination study (MRTX-500), orally, at a dose of 120 mg QD.  Non-clinical studies 
indicate that the 120 mg dose of sitravatinib should, based on degree of inhibition using 
cellular assays, achieve the plasma exposure required for inhibition of VEGF, TAM, KIT 
and MET receptors, necessary to achieve anti-tumor efficacy in the combination setting. 
1.2 
Sitravatinib Background 
Sitravatinib (MGCD516) is an orally available, potent small molecule inhibitor of a 
closely related spectrum of receptor tyrosine kinases including MET, AXL, MERTK, 
VEGFR family, PDGFR family, KIT, fms-related tyrosine kinase 3 (FLT3), TRK family, 
RET, DDR2, and selected EPH family members.  Receptor tyrosine kinases are key 
regulators of signaling pathways leading to cell growth, survival, and migration 
(Blume-Jensen-2001).  These kinases are dysregulated in many cancers through 
overexpression, genetic alteration or co expression with high affinity ligands 
(Blume-Jensen-2001).  Multiple sitravatinib receptor tyrosine kinase targets are 
genetically altered in a variety of cancers and act as oncogenic drivers, promoting cancer 
development and progression.  In addition to the immunostimulatory effects of AXL and 
MET inhibition, sitravatinib may further condition the TME in favor of anti-tumor 
activity by its immunomodulatory effects mediated through VEGFR and KIT inhibition.  
Preclinical data with sitravatinib indicate that it can increase expression of PD-L1 on 
tumor cells in vitro and in vivo.  Pilot studies in syngeneic mouse tumor models also 
suggest that sitravatinib increases the proliferation and fraction of systemic/spleen CD4+ 
and CD8+ T lymphocytes and reduces the number of systemic MDSCs.  Additional 
studies to investigate the effects of sitravatinib in the TME are ongoing or planned. 
Background information in addition to that presented below is available in the 
Sitravatinib (MGCD516) Investigator’s Brochure. 
1.2.1 
Sitravatinib Drug Substance 
The chemical structure and chemical formulation of sitravatinib (MGCD516) is as 
follows: 
MGCD516 Free Base 
N
S
O
N
H
N
F
H
N
NH
O
O
O
F
 
 
Chemical Formula:  
C33H29F2N5O4S  
Molecular Weight:  
629.68 g/mol 


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1.2.2 
Sitravatinib Non-Clinical Data 
Sitravatinib demonstrated potent, concentration-dependent inhibition of the kinase 
activity of MET, AXL, MERTK, VEGFR family, PDGFR family, KIT, FLT3, TRK 
family, RET, DDR2, and selected EPH family members in biochemical assays and 
inhibited phosphorylation and kinase dependent function in cell-based assays.  
Sitravatinib also inhibited oncogenic functions associated with target receptor tyrosine 
kinases including MET-dependent cell viability and migration and endothelial tube 
formation and angiogenesis.  Consistent with this anti-tumor and anti-angiogenic 
mechanism of action, sitravatinib demonstrated anti-tumor efficacy over a broad 
spectrum of human tumor xenograft models including robust cytoreductive anti-tumor 
activity in a subset of models exhibiting genetic alterations in receptor tyrosine kinase 
targets including MET, RET, FLT3 and others.   
In vitro results from the hERG (human ether-a-go-go related gene) assay demonstrate an 
IC50 of 0.6 μM on the potassium current, which far exceeds exposures observed 
clinically.  There were no adverse effects on the cardiovascular system, including no 
effect on the QTc interval, when sitravatinib was administered to dogs at doses up to 
4 mg/kg (mean 6 hr concentration of 0.072 μg/mL).  Minor increases in vascular 
pressures were observed during the dog cardiovascular study; however, these were mild 
and considered of limited biological consequence.  Assessment of the neurological 
functional observation battery (FOB) and respiratory evaluations (tidal volume, 
respiration rate, and minute volume) in rats did not reveal any sitravatinib-related effects 
at doses up to 25 mg/kg.   
In a bidirectional permeability study with Caco-2 cell lines, MGCD516 is classified as a 
highly permeable compound, and not a substrate of P-glycoprotein (P-gp) and Breast 
Cancer Resistance Protein (BCRP).  A P-gp and BCRP inhibition study using Caco-2 
cells suggested that MGCD516 is a significant inhibitor of P-gp and BCRP with IC50 
value of 0.838 and 1.51 µM, respectively, these values are much higher than the systemic 
steady state exposure levels observed clinically. 
Using an ultra-centrifugation technique sitravatinib was 98.6% bound to human plasma 
proteins. 
MGCD516 was evaluated for cytochrome P450 (CYP)-mediated metabolism using 
human liver microsomes and recombinant human enzymes.  Results suggest that multiple 
enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, 
CYP2E1, and CYP3A4 are involved in the metabolism of MGCD516.   
The effect of treating primary cultures of cryopreserved human hepatocytes with 
MGCD516 on the expression of CYP enzymes was investigated.  Overall, treatment of 
cultured human hepatocytes with up to 30 µM MGCD516 caused little or no increase 
(< 2.0-fold change or < 20% of the positive control) in CYP1A2 activity, CYP1A2 
mRNA (messenger ribonucleic acid) levels, or CYP3A4 activity.  However, MGCD516 
(up to 3 and 10 µM) caused concentration dependent increases (> 2-fold change and 


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> 20% of the positive control) in CYP2B6 activity, CYP2B6 mRNA levels, and CYP3A4 
mRNA levels in one or more human hepatocyte cultures.   
There was little or no evidence of direct inhibition of CYP1A2, CYP2A6 or CYP2E1 by 
MGCD516 or of time- or metabolism-dependent inhibition of any of the CYP enzymes 
evaluated.  Under the experimental conditions examined, MGCD516 demonstrated direct 
inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (as measured by 
testosterone 6β-hydoxylation and midazolam 1´-hydroxylation) with IC50 (half maximal 
inhibitory concentration) values of 2.9 μM, 11 μM, 10 μM, 1.9 μM, 11 μM and 0.81 μM, 
respectively.  In addition, approximate 50% direct inhibition was observed for CYP2B6 
at the highest concentration of MGCD516 evaluated (20 μM); thus, the IC50 value was 
reported as greater than 20 μM.   
Because the potency for MGCD516 against its intended clinical targets is generally less 
than 0.1 μM, it may be unlikely that concentrations required for robust direct systemic 
inhibition/induction of the tested CYPs will be achieved at projected clinical dose and 
exposure levels.   
1.2.3 
Sitravatinib Clinical Data 
1.2.3.1 
Sitravatinib Pharmacokinetics 
After single dose administration, sitravatinib reaches peak concentration in a median time 
of 3 to 9 hours.  Exposure parameters (maximum concentration [Cmax] and area under the 
curve [AUC]) are dose proportional with doses up to 200 mg.  Mean elimination half-life 
varies between 40 and 52 hours after oral administration.  Drug accumulation is observed 
after multiple dose administration; mean accumulation ratios across the seven dose levels 
(10 mg to 200 mg QD) vary between 1.9 and 4.1 for Cmax and 2.4 and 5.6 for AUC0-24.  
Based on current data following administration of 150 mg once daily to patients, the 
steady state mean Cmax, Cave,ss and AUC0-24,ss values are 114 ng/mL, 94 ng/mL and 
2.26 μg.h/mL, respectively. 
1.2.3.2 
Sitravatinib Clinical Safety 
Sitravatinib monotherapy and sitravatinib in combination with nivolumab are being 
evaluated as part of the clinical development program.  
Study 516-001 is a Phase 1/1b clinical trial of sitravatinib as monotherapy in patients 
with advanced solid tumor diseases.  The Phase 1 dose-escalation study evaluated dose 
levels between 10 mg and 200 mg daily.  The Phase 1b expansion included patients 
having tumors with selected histological diagnoses and/or molecular markers solid 
tumors.  As of 26 June 2017, among the 86 patients treated at a higher dose of 150 mg 
QD and for whom safety data were available, treatment-related adverse events reported in 
≥ 10% of patients in this Phase1/1b study include fatigue (44%), diarrhea (35%), 
hypertension (34%), nausea (24%), decreased appetite (22%), vomiting (22%), decreased 
weight (17%), palmar-plantar erythrodysesthesia (13%), and hypothyroidism (12%).  
Dose-limiting toxicity (DLT) was reported in four patients who developed palmar-plantar 


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erythrodysesthesia, neuropathy, mucositis, or fatigue.  Grade 3 adverse events (AEs) 
reported as related to treatment in more than one patient included hypertension (19%); 
diarrhea (11%); pulmonary embolism, increased lipase, and fatigue (5% each); 
palmer-plantar erythrodysesthesia, decreased ejection fraction, left ventricular 
dysfunction, mucosal inflammation, and hyponatremia (2% each).  Grade 4 AEs reported 
as related to treatment in 1 patient each (1%) included febrile neutropenia, hypotension 
and tachycardia.  Treatment-related serious adverse events (SAEs) were reported in 
12 patients (14%) and included diarrhea (4%); pulmonary embolism, hypertension and 
fatigue (2% each); back pain, cardiac failure, ejection fraction decreased, febrile 
neutropenia, hiccups, hypertension, hypoalbuminemia, hypokalemia, hypotension, left 
ventricular dysfunction, odynophagia, oropharyngeal pain, pancreatitis, rash follicular 
and tachycardia (1% each).  Twenty-six deaths were reported in this study, with the 
primary cause of death being the disease under study (n=17), unknown (n=5), hypoxic 
respiratory failure, respiratory failure, GI bleed or sepsis (n=1 each). 
Study MRTX-500 evaluates sitravatinib in combination with the PD-1 inhibitor 
nivolumab in patients with advanced or metastatic non-squamous NSCLC who have 
experienced disease progression either on or after prior treatment with a checkpoint 
inhibitor therapy (CIT-experienced) or after treatment with a platinum-based doublet 
chemotherapy (CIT-naïve).  The primary objective is to evaluate the clinical activity of 
nivolumab in combination with sitravatinib.  The study began with a lead-in evaluation of 
sitravatinib in combination with nivolumab administered by intravenous (IV) infusion, 
240 mg every 2 weeks.  Sitravatinib is administered orally, once daily in cycles of 
28 days.  No protocol defined dose-limiting toxicities (DLTs) were reported in the first 
6 evaluable patients treated at 120 mg QD, which was selected as the recommended 
Phase 2 dose.  The Phase 2 portion of the study uses a Predictive Probability Design 
(Lee-2008) for each treatment arm and stratum.  For patients who are CIT-experienced, 
enrollment is stratified by prior outcome of treatment with a checkpoint inhibitor: those 
with clinical benefit or no clinical benefit to prior checkpoint inhibitor therapy.  Patients 
who are CIT-naïve are stratified according to their PD-L1 status: no/low PD-L1 
expression or high PD-L1 expression.  Sitravatinib is administered orally, 120 mg once 
daily in cycles of 28 days and nivolumab is administered by IV infusion, 240 mg every 
2 weeks.  As of 26 June 2017, among the 10 patients for whom safety data are available, 
sitravatinib-related AEs reported in ≥20% include fatigue (50%), diarrhea (40%), 
aspartate aminotransferase (AST) increase (30%), palmar-plantar erythrodysesthesia 
(30%), dysphonia (30%), lipase increase (20%), weight decrease (20%), nausea (20%), 
vomiting (20%), decreased appetite (20%), hyponatremia (20%), hypertension (20%) and 
hypothyroidism (20%).  One patient experienced SAEs of pulmonary embolism and 
deep-vein thrombosis attributed to sitravatinib treatment.  No immune-related AEs 
(irAEs) or patient deaths have been reported.  The study has met the criterion for 
expansion to Stage 2 of patient enrollment and is ongoing.  
Non-clinical toxicology studies as well as clinical safety data from the Phase 1/1b and 
Phase 2 studies suggest that AEs associated with sitravatinib are similar to those observed 
with other small molecule inhibitors of the VEGFR pathway.   


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Based on reported clinical experience with sitravatinib and similar agents, and 
non-clinical data with sitravatinib, guidance to the Investigator is provided for selected 
AEs in Section 5.3. 
1.2.3.3 
Sitravatinib Clinical Efficacy 
Efficacy results are awaited from both the Phase 1b segment of Study 516-001, and 
Study MRTX-500. 
1.3 
Nivolumab Background 
Nivolumab (OPDIVO®) is a human monoclonal antibody that blocks the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.  Nivolumab is an immunoglobulin G4 
(IgG4) kappa immunoglobulin.   
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T-cells, 
inhibits T-cell proliferation and cytokine production.  Upregulation of PD-1 ligands 
occurs in some tumors and signaling through this pathway can contribute to inhibition of 
active T-cell immune surveillance of tumors.  Nivolumab is a human IgG4 monoclonal 
antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and 
PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including 
the anti-tumor immune response.  In syngeneic mouse tumor models, blocking PD-1 
activity resulted in decreased tumor growth. 
Background information in addition to that presented below is available in the OPDIVO® 
US Prescribing Information (USPI OPDIVO [nivolumab]). 
1.3.1 
Nivolumab Drug Substance 
Generic Name: 
Nivolumab 
Other Name:  
OPDIVO® 
Molecular Weight:  
146 kDa 
1.3.2 
Nivolumab Non-Clinical Data 
The non-clinical experience is described in the OPDIVO® US Prescribing Information 
(USPI OPDIVO [nivolumab]).   
1.3.3 
Nivolumab Clinical Data 
The following reports information included in the OPDIVO® US Prescribing Information 
(USPI OPDIVO [nivolumab]) dated March 2018.  Refer to the current Prescribing 
Information for updates during the conduct of this clinical trial. 


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1.3.3.1 
Nivolumab Pharmacokinetics 
The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 
20 mg/kg administered as a single dose or as multiple doses of OPDIVO® every 2 or 
3 weeks.  The geometric mean (% coefficient of variation [CV%]) clearance (CL) is 
8.2 mL/h (53.9%), geometric mean volume of distribution at steady state (Vss) is 6.8 L 
(27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%).  Steady-state 
concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg 
every 2 weeks, and systemic accumulation was approximately 3.7-fold.  The exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg 
administered every 2 weeks. 
The population PK analysis suggested that the following factors had no clinically 
important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 
160 kg), gender, race, baseline lactate dehydrogenase (LDH), PD-L1 expression, tumor 
type, tumor size, renal impairment, and mild hepatic impairment. 
The effect of renal impairment on the clearance of nivolumab was evaluated by a 
population PK analysis in patients with mild (estimated Glomerular Filtration Rate (eGFR) 
60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or 
severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment.  No clinically important 
differences in the clearance of nivolumab were found between patients with renal 
impairment and patients with normal renal function. 
The effect of hepatic impairment on the clearance of nivolumab was evaluated by 
population PK analyses in patients with mild hepatic impairment (total bilirubin n less 
than or equal to the upper limit of normal (ULN) and AST greater than ULN or total 
bilirubin less than 1 to 1.5 times ULN and any AST; n=92).  No clinically important 
differences in the clearance of nivolumab were found between patients with mild hepatic 
impairment and patients with normal hepatic function.  Nivolumab has not been studied 
in patients with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) 
or severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST). 
1.3.3.2 
Nivolumab Anti-Drug Antibodies 
Of 2085 patients who were treated with OPDIVO®, as a single agent, 3 mg/kg every 
2 weeks and evaluable for the presence of anti-nivolumab antibodies, 233 patients 
(11.2%) tested positive for treatment-emergent anti-nivolumab antibodies by an 
electrochemiluminescent (ECL) assay and 15 patients (0.7%) had neutralizing antibodies 
against nivolumab.  There was no evidence of altered pharmacokinetic profile or 
increased incidence of infusion reactions with anti-nivolumab antibody development. 
1.3.3.3 
Nivolumab Adverse Reactions Common in Clinical Trials 
Refer to the current OPDIVO® US Prescribing Information (USPI OPDIVO 
[nivolumab]), Highlights of Prescribing Information and Section 6.1 for information 
concerning adverse reactions occurring in clinical trials.  As of March 2018, the most 


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common adverse reactions (≥20%) in patients administered OPDIVO® as a single agent 
were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, 
dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract 
infection, pyrexia, headache, and abdominal pain. 
1.3.3.4 
Nivolumab Immune-Related Adverse Events 
Refer to the current OPDIVO® US Prescribing Information (USPI OPDIVO 
[nivolumab]), Section 5, for information concerning irAEs occurring during treatment 
with nivolumab.  As of March 2018, the OPDIVO® US Prescribing Information 
(USPI OPDIVO [nivolumab]) includes warnings and precautions for a range of irAEs 
documented in patients across cancer indications, including, pneumonitis, colitis, 
hepatitis, endocrinopathies (such as hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus), nephritis and renal dysfunction, rash, 
encephalitis, other rarer irAEs, and infusion reactions. 
1.4 
Combination Safety of Sitravatinib and Nivolumab 
1.4.1 
Potential for Drug-Drug Interactions 
Sitravatinib administered in combination with nivolumab is unlikely to result in clinically 
relevant drug-drug interactions (DDI) based on absorption, metabolism, elimination or 
protein binding.  Nivolumab is a mAb and is intravenously administered, whereas 
sitravatinib is a small molecule therapeutic administered orally; no absorption 
interactions are expected.   
No studies on the metabolism of nivolumab have been reported in vitro or in humans.  
Like most therapeutic proteins, nivolumab is not expected to be metabolized by liver 
CYP or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or 
other metabolizing enzymes in terms of inhibition or induction. 
MGCD516 inhibits P-gp and BCRP transporters at high concentrations and, as a result, 
sensitive substrates and substrates with narrow therapeutic index for P-gp and BCRP 
transporters may be used, but with caution during study drug treatment.  Similarly, 
preclinical results suggest that multiple enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 
2C9, 2D6, 2E1, and 3A4 are involved in the metabolism of sitravatinib with a low risk of 
one enzyme contributing to metabolism in a disproportionate manner.  Therefore, 
sensitive substrates and substrates with narrow therapeutic index for indicated CYP 
enzymes may be used, but with caution during study drug treatment.  Finally, QTc 
prolongation with sitravatinib is under evaluation, though no signal has been detected 
from the ongoing sitravatinib clinical trials.  Prior to results of such evaluation, drugs 
with a known risk of torsades de pointes should be avoided during study drug treatment, 
whereas drugs with conditional risk of torsades de pointes may be used, but with caution 
during study drug treatment.  Full details of the medications or substances to be avoided 
or used with caution during study drug treatment are outlined in Appendix 2. 


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1.4.2 
Evaluation of Potential for Increased Toxicities with Combination 
Use of Sitravatinib and Nivolumab 
Frequent AEs, such as fatigue, musculoskeletal pain, decreased appetite, cough, and 
constipation, which are non-specific and typical of cancer treatment regimens have been 
observed with nivolumab and sitravatinib monotherapy.  Potential exists for these AEs to 
be observed with increased severity or frequency during use of the combined agents.  
Management of these effects in patients receiving cancer therapy is well precedented.  
More importantly, irAEs of Special Interest based on observed safety events using 
nivolumab monotherapy include pneumonitis, colitis, hepatitis, endocrinopathy, 
nephritis/renal dysfunction, rash, and encephalitis.  While sitravatinib may have 
immunostimulatory effects, autoimmune adverse effects have not been reported in 
clinical trials of this investigational study agent, including to date in combination with 
nivolumab, nor are they recognized as class effects for this agent.  However, the potential 
for sitravatinib to exacerbate or promote these AEs when administered in combination 
with nivolumab should be borne in mind.  AE incidence data presented below are as 
reported in the OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) 
dated March 2018 and the Sitravatinib Investigator’s Brochure dated September 2017.  
Updates to these data during the conduct of this clinical trial will be found in the current 
OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) and current 
Sitravatinib Investigator’s Brochure. 
A clinically relevant overlap in toxicity may arise between the immune-related colitis 
attributed to nivolumab and the non-specific, most often mild to moderate diarrhea 
observed with sitravatinib.  Immune-related colitis has been reported in 2.9% (58/1994) 
of patients treated with nivolumab, with a median time to onset of 5.3 months (range: 
2 days to 20.9 months).  Diarrhea has been reported in approximately 35% of patients 
treated with sitravatinib, most often beginning within the first month of the start of 
treatment.  Diarrhea (including colitis, enterocolitis, and gastroenteritis) of any grade has 
been reported with single-agent nivolumab to occur at approximately 25% of advanced 
RCC patients treated at 3 mg/kg Q2W in the CheckMate 025 clinical trial 
(USPI OPDIVO [nivolumab]; Motzer-2015).  The time to onset may be helpful in 
distinguishing diarrhea that may be attributed to autoimmune effects versus non-specific 
toxicity. 
Tyrosine kinase inhibitors in general, and MET inhibitors in particular, have been 
associated with non-specific, most often mild to moderate elevation in aspartate and 
alanine transaminases (AST and ALT).  Mild to moderate elevations in liver 
transaminases have also been observed in less than 10% of patient treated with 
sitravatinib.  The elevations observed with sitravatinib generally occur within the first 
28 days of treatment and resolve with interruption of treatment.  In patients receiving 
nivolumab as a single agent, immune-mediated hepatitis occurred in 1.8% (35/1994) of 
patients; the median time to onset was 3.3 months (range: 6 days to 9 months). 
Nivolumab can cause autoimmune thyroid disorders including hypothyroidism, 
thyroiditis resulting in hypothyroidism, and hyperthyroidism.  In patients receiving 


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nivolumab as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism 
occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months (range: 
1 day to 16.6 months).  On the other hand, hyperthyroidism occurred in 2.7% (54/1994) 
of patients receiving nivolumab as a single agent; the median time to onset was 
1.5 months (range: 1 day to 14.2 months).  Hypothyroidism has been reported in 
approximately 12% (10/86) of subjects treated with sitravatinib. 
A clinically relevant overlap in toxicity may arise between the immune-related rash 
attributed to nivolumab and the non-specific, most often mild (Grade 1) rash observed 
with sitravatinib.  Rash, described as dermatitis, acneiform dermatitis, erythematous rash, 
generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema 
multiforme, and erythema, of any grade has been reported in 28% of advanced RCC 
patients treated with nivolumab.  Rash has been reported in 9% (8/86) of patients treated 
with sitravatinib. 
2 STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objective 
To evaluate the preoperative clinical activity of the combination of sitravatinib and 
nivolumab in patients with locally-advanced ccRCC undergoing nephrectomy. 
2.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of the combination regimen in the selected 
population. 
• To characterize the baseline tumor-related immune profile in patients with RCC. 
• To determine the immune effects of sitravatinib and the combination regimen in 
patients with ccRCC. 
• To evaluate the pharmacokinetics (PK) of sitravatinib administered alone and in 
combination with nivolumab in patients with ccRCC. 
• To characterize the time to surgery. 
• To evaluate secondary efficacy endpoints with the combination regimen in the 
selected population. 
2.1.3 
Exploratory Objective 
• To evaluate changes in gene expression and the T-cell repertoire in response to 
therapy in patients with ccRCC. 


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2.2 
Endpoints 
2.2.1 
Primary Endpoint 
Percentage of patients achieving a point in time objective response (either CR or PR) 
prior to surgery. 
2.2.2 
Secondary Endpoints 
• Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of adverse events (AEs) and laboratory abnormalities. 
• Descriptive characterization of immune cell populations in the tumor and/or 
peripheral blood at baseline. 
• Temporal changes in PD-L1 expression, selected cytokines and immune cell 
populations in the tumor and/or peripheral blood (including myeloid-derived 
suppressor cells [MDSCs], regulatory T-cells [Tregs], CD4+ [helper] and CD8+ 
[cytotoxic] T-cells, and the ratio of Type1:Type 2 tumor-associated macrophages). 
• Blood plasma concentration of sitravatinib. 
• Time-to-surgery. 
• Disease free-survival (DFS). 
2.2.3 
Exploratory Endpoints 
• Gene expression and T-cell receptor sequencing. 
3 STUDY DESIGN 
Study 516-002 is an open-label, non-randomized, preoperative window of opportunity 
Phase 2 study of sitravatinib and nivolumab in the neoadjuvant setting for the treatment 
of patients with locally-advanced ccRCC undergoing nephrectomy.  The study will enroll 
approximately 25 subjects with imaging results consistent with a clinical diagnosis of 
locally-advanced renal cancer in order to identify and treat with the study drug treatment 
18 clinical activity evaluable patients with ccRCC.  Study drug treatment which will be 
conducted in 2 sequential preoperative treatment segments.  During the first segment, 
patients will receive single-agent sitravatinib for 2 weeks, followed by a renal biopsy.  
Patients will then begin the second segment, consisting of combination treatment with 
sitravatinib and nivolumab for at least 4 weeks (and up to a maximum of 6 weeks to 
allow for flexibility with the scheduling of the planned nephrectomy).  This segment will 
be followed by planned surgical resection by way of standard-of-care partial or radical 
nephrectomy.  Patients will be followed for survival.  The primary objective is to evaluate 
the clinical activity of the combination regimen using percentage of patients with ccRCC 
achieving a point in time objective response (either CR or PR) prior to surgery with the 


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combination treatment of sitravatinib and nivolumab.  Objective responses will be 
assessed in accordance with RECIST 1.1.  Secondary objectives include evaluation of 
safety and determination of immune effects of the combination treatment, along with PK 
of sitravatinib.  The Schedule of Assessments to be performed in the study is presented in 
Table 1.  The schedule for collection of PK/PD and ECG assessment time points are 
presented in Table 2. 
Prior to Start of Treatment:  All enrolled patients will have met all entry criteria and 
have completed baseline procedures including disease assessments and blood collection 
for baseline immune characteristics, and will be scheduled to undergo an initial 
diagnostic tumor biopsy of their renal lesion.  Patients with a histology other than ccRCC 
will proceed to their End of Study (EOS) visit following the histology results, with no 
treatment with study drugs.  Subjects with a clear cell histology will proceed to the study 
drug treatment which will be conducted in 2 sequential preoperative treatment segments 
as described below. 
Segment 1 (2 weeks) consists of a 2-week treatment with single-agent sitravatinib.  
Sitravatinib will be administered at a dose of 120 mg orally QD, on a continuous daily 
dosing regimen.  After completion of the 2-week dosing period, patients will undergo a 
renal biopsy. 
Segment 2 (4-6 weeks) consist of combination treatment with sitravatinib and nivolumab 
for at least 4 weeks (and up to a maximum of 6 weeks to allow for flexibility with the 
scheduling of the nephrectomy).  Sitravatinib will be administered at a dose of 120 mg 
orally daily, on a continuous daily dosing regimen for this entire segment.  Nivolumab 
will be administered, in accordance with approved labeling, by IV infusion, 240 mg every 
Q2W (namely, on D15, D29, and potentially D43).  Patients will receive the nivolumab 
injection on D43 only if their surgery is expected to occur more than a week from that 
date.  Patients will be subject to a 2-day preoperative hold of all study drugs prior to 
surgery (such that the last dose of any drug is administered a minimum of 72 hours prior 
to surgery). 
Of note, patients should be scheduled to undergo surgery no later than 8 weeks following 
their first dose of study drug, and the preoperative period (including Segments 1 and 2) 
should not be extended in order to take missed doses of either study drug. 
Guidance for AE management and associated nivolumab treatment modifications are 
provided in product labeling.  Guidelines for sitravatinib administration and dose 
reduction in the event of toxicity are provided in Section 5.1. 
After completion of neoadjuvant therapy, patients will undergo planned nephrectomy.  
Patients will have their EOS visit following surgery, with no further study drug 
administration.  Patients will be followed for disease-free survival for up to 3 years or 
more until either death, disease recurrence or loss to follow-up. 
Further detail on sample collection and analyses are presented in Section 7.3 and the 
Study Laboratory Manual.  The study will collect blood and tumor tissue collections as 


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described in the Schedule of Assessments (Table 1) depicted and the study schema in 
Figure 1.  Protocol guidance of special interest is listed below.   
• Freshly biopsied tumor tissue collection at pre-treatment is required for study 
drug treatment.  Similarly, the on-treatment mid-study tumor biopsy on D14 is 
highly desirable for all treated patients.  Archival samples cannot be submitted in 
lieu of pre-treatment samples.  All attempts should be made to biopsy the same 
lesion on the mid-study biopsy as the initial biopsy. 
• Tumor gene expression in freshly biopsied tumor samples will be determined 
using next generation sequencing performed by a central laboratory.  For patients 
in whom tumor tissue has previously been tested using next generation 
sequencing, presence of specific tumor gene mutations and estimation of total 
mutation burden will be collected in the case report form (CRF). 
4 SUBJECT SELECTION AND ENROLLMENT 
Patient eligibility must be reviewed and documented by an appropriately qualified 
member of the Investigator’s study team before patients are included in the study.  No 
exceptions to the patient eligibility requirements will be granted by the Sponsor. 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Imaging results consistent with locally-advanced renal cell carcinoma (RCC) 
without evidence of metastatic disease with absence of adjacent organ invasion or 
retroperitoneal adenopathy (cT2-T3b, N0, M0).  Retroperitoneal lymph nodes 
≤ 1cm in size each are considered N0. 
2. Candidate for partial or complete nephrectomy that extirpates all tumor tissue as 
part of treatment plan. 
3. Measurable disease as per RECIST version 1.1 (refer to Appendix 3).   
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 
(refer to Appendix 1). 
5. Adequate bone marrow and organ function demonstrated by:  
a. Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 × 109/L); 
b. Platelet count ≥ 100 × 109/L (≥ 100,000 per mm3); 
c. ALT and AST ≤ 2.5 × ULN; 


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d. Serum bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert 
Syndrome; 
e. Serum creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) ≥ 50 mL/min 
(using the Cockcroft-Gault formula or following local institutional standards). 
6. ≥ 18 years of age. 
7. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP 
agrees to use contraception while participating in this study, and for a period of 
6 months following termination of study treatment. 
8. Completed informed consent process, including signing Institutional Review 
Board/Ethics Committee/Research Ethics Board (IRB/EC/REB) approved 
informed consent form. 
9. Willing to comply with clinical trial instructions and requirements. 
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Prior systemic anti-tumor treatment for RCC. 
2. Patients who are receiving any other investigational agents. 
3. Clinical status indicating that immediate surgery (within 6 weeks) is warranted 
regardless of whether neoadjuvant therapy is to be administered, as assessed by 
the treating surgeon. 
4. Inability to undergo baseline tumor biopsy.  
5. Active or prior documented autoimmune disease: 
a. Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis); 
b. Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis 
which required steroid treatment, or any evidence of clinically active 
interstitial lung disease; 
c. Other active or prior, documented autoimmune disease within the past 2 years.  
NOTE: Patients with Type I diabetes, vitiligo, Grave’s disease, residual 
hypothyroidism due to autoimmune condition only requiring hormone 
replacement, or psoriasis not requiring systemic treatment (within the past 2 
years) are not excluded. 
6. Active or prior immunocompromising conditions: 


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a. Current or prior use of immunosuppressive medication within 28 days before 
the first dose of study treatment, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are 
not to exceed 10 mg/day of prednisone, or an equivalent dose of another 
corticosteroid; 
b. Known acute or chronic human immunodeficiency virus (HIV); 
c. History of primary immunodeficiency; 
d. History of allogeneic transplant. 
7. Known acute or chronic hepatitis B or hepatitis C. 
8. History of hypersensitivity to study treatment excipient. 
9. History of severe hypersensitivity reaction to any monoclonal antibody. 
10. Use of live vaccines against infectious disease (e.g., varicella) within 28 days of 
initiation of study therapy; killed vaccinations (e.g., influenza) are allowed at any 
appropriate time before and during the study. 
11. Uncontrolled arterial hypertension (> 150 mm Hg systolic or > 100 mm Hg 
diastolic) on multiple observations despite standard of care treatment. 
12. History of stroke or transient ischemic attack within the previous 6 months. 
13. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris; 
b. Congestive heart failure ≥ NYHA (New York Heart Association Functional 
Classification) Class 3; 
c. QTc > 480 milliseconds; 
d. Left ventricular ejection fraction (LVEF) ≤ 40%. 
14. Concomitant medication known to cause prolonged QT which cannot be 
discontinued or changed to a different medication prior to enrollment (refer to 
Appendix 2). 
15. Known or suspected presence of another malignancy that could be mistaken for 
the malignancy under study during disease assessments. 
16. Pregnancy.  WOCBP must have a negative serum or urine pregnancy test 
documented within the screening period prior start of study drug. 


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17. Breast-feeding or planning to breast feed during the study or within 6 months 
after study treatment. 
18. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or 
uncontrolled infection, or other medical history, including laboratory results, 
which, in the Investigator’s opinion, would be likely to interfere with the patient’s 
participation in the study, or with the interpretation of the results. 
4.3 
Life Style Guidelines 
Patients who are biologically capable of having children and sexually active must agree 
to use an acceptable method of contraception for the duration of the treatment period and 
for at least 6 months after the last dose of study treatment.  The Investigator will counsel 
the patient on selection of contraception method and instruct the patient in its consistent 
and correct use.  Examples of acceptable forms of contraception include: 
1. Oral, inserted, injected or implanted hormonal methods of contraception, provided 
it has been used for an adequate period of time to ensure effectiveness; 
2. Correctly placed copper containing intrauterine device (IUD); 
3. Male condom or female condom used WITH a spermicide; 
4. Male sterilization with confirmed absence of sperm in the post-vasectomy 
ejaculate; 
5. Bilateral tubal ligation or bilateral salpingectomy. 
The Investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.   
Note: Women are considered post-menopausal and/or not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
6 months ago.  In case of any ambiguity, the reproductive status of the woman should be 
confirmed by hormone level assessment. 
4.4 
Enrollment into Study 
Following completion of the informed consent process and review of all screening 
procedures, patient eligibility will be confirmed by appropriately qualified staff at the 
investigational site.  Patients will be enrolled by entry into a patient registration log 
provided by the Sponsor and maintained by the study site and completion of the patient 
registration procedure detailed in the Site Operations Manual.  Each patient will be 
assigned a sequential number by site.  The patient number must be used on all 
documentation and correspondence with the Sponsor and Contract Research Organization 
(CRO). 


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5 STUDY TREATMENT 
5.1 
Sitravatinib Study Drug 
5.1.1 
Sitravatinib Formulation, Packaging and Storage 
Sitravatinib will be provided by the Sponsor as 10 mg and 40 mg unit dose strength 
capsules.  The composition of the drug product consists of a blend of MGCD516 free 
base drug substance, microcrystalline cellulose (Avicel® PH302), colloidal silicon 
dioxide (Aerosil® 200) and polysorbate 80 (Tween® 80).  The blend is filled into Size 1 
Light Blue Opaque (10 mg strength) or Swedish Orange Opaque (40 mg strength) hard 
gelatin capsules. 
Sitravatinib drug product is packaged in 30-count, high-density polyethylene (HDPE), 
white opaque, round 60 cc bottles.  A tamper-proof heat induction seal and a 
child-resistant closure are used.  The provided bottles may be labeled for specific patient 
use and given to the patient if the capsule count is the needed number. 
Sitravatinib medication labels comply with the legal requirements of the United States 
and will be printed in the languages required in the countries in which the study is 
conducted 
Investigational clinical trial material should be stored in an area that is secure, with 
limited access and monitored for temperature using a calibrated thermostat or 
thermometer.  Sitravatinib capsules should be stored under the conditions stated on the 
container labels and the Pharmacy Study Manual.  Refer to the Pharmacy Study Manual 
for details. 
5.1.2 
Sitravatinib Preparation, Dispensing, Administration and 
Accountability 
Only qualified personnel who are familiar with procedures that minimize undue exposure 
to them and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents. 
Study site personnel will dispense sitravatinib capsules on D1 and D29 of the study.  
Sufficient supply will be provided at each visit and extra capsules may be provided to 
cover an additional 2 days in case of delayed clinic visits or lost capsules.  Study capsules 
will be dispensed in HDPE bottles provided by the Sponsor.   
Sitravatinib capsules will be administered at a dose of 120 mg orally QD, on a continuous 
daily dosing regimen.  Depending on safety observations, the sitravatinib dose may be 
reduced following Table 3. 
The following guidelines should be followed for sitravatinib administration: 
• Dosing in the morning is preferred; 


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• Capsules should be taken on an empty stomach (at least 2-hour fast before each 
dose and no food for a minimum of 1 hour after each dose);  
• Capsules should be taken with at least 200 mL (1 cup) of water; 
• Patients should swallow the capsules whole and not chew them; 
• If vomiting occurs after dosing, sitravatinib doses should not be replaced.   
On days when sitravatinib and nivolumab dosing are both scheduled, the daily dose of 
sitravatinib should precede nivolumab infusion for logistical reasons.  This order of 
dosing is of most interest on days when blood sampling is scheduled for sitravatinib PK. 
All sitravatinib study treatment supplies will be accounted for in the drug accountability 
inventory forms supplied by the Sponsor or using locally approved forms that include all 
required information.  The drug accountability inventory forms must identify the study 
drug, including batch or lot numbers and account for its disposition on a 
patient-by-patient basis, including specific dates and quantities.  The forms must be 
signed by the individual who dispensed the drug. 
Patients will be asked to record their daily dosing on Sponsor provided diary cards and 
report any missed doses or lost doses at the next clinic visit.  On the back of each Sponsor 
provided diary card, written dosing instructions for sitravatinib capsules are provided 
(e.g., fasting instructions, take with water, etc.).  Patients should be told to bring study 
treatment bottle(s) (empty or not) and completed dosing diaries with them to the clinic 
visit for a compliance check and capsule count.  Study site personnel will retain the 
bottle(s) until a monitor has completed reconciliation and retain dosing diaries with site 
study files, unless institutional policy prohibits such practice, in which case reconciliation 
should be carried by study staff and properly documented.   
At the end of the study, all unused sitravatinib drug supplies must be destroyed in 
accordance with local Standard Operating Procedure provided to the Sponsor for the Trial 
Master File, or returned to the Sponsor or its appointed agent, as directed by the Sponsor. 
5.1.3 
Sitravatinib Dose Modification and Discontinuation 
This protocol provides guidance for dose modification of sitravatinib (i.e., interruption, 
dose reduction or discontinuation) for AEs attributed to sitravatinib.  For AEs due to 
nivolumab, see the current OPDIVO® US Prescribing Information (USPI OPDIVO 
[nivolumab]) and Section 5.2.4 for dose modifications. 
Based on available safety and pharmacokinetic data from an ongoing Phase 1b trial in 
patients with various solid tumors and an ongoing Phase 2 trial in combination with 
nivolumab in patients with NSCLC, the dose and regimen recommended is 120 mg 
sitravatinib administered daily.  If unacceptable toxicity is observed, the starting dose 
may be decreased during the study using the dose de-escalation rules described in Section 
9.1.2 and the dose levels indicated in Table 3. 


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Guidelines for sitravatinib dose modifications to be implemented to manage adverse 
events are described in Section 5.3.  Available dose levels for sitravatinib are outlined in 
Table 3.  Once the dose has been reduced, re-escalation is generally not recommended 
but may be considered on a case-by-case basis.  If the administration of sitravatinib is 
interrupted for reasons other than toxicity, then treatment with the study drug may be 
resumed at the same dose. 
Table 3: 
Sitravatinib Sequential Dose Reductions for Individual Patients 
120 mg once daily 
80 mg once daily 
60 mg once daily 
Dose reduction below 60 mg QD may be undertaken after discussion with the Sponsor.  
If treatment with sitravatinib is withheld for ≥ 14 consecutive days, then permanent 
discontinuation from the study should be considered.  If after receiving sitravatinib but 
prior to any nivolumab dosing, patients develop toxicities that prevent the first nivolumab 
administration, then permanent discontinuation from study should be considered.  In 
contrast, patients who have already received nivolumab and who develop AEs (regardless 
of causality) preventing subsequent nivolumab administration may remain on study 
receiving sitravatinib alone. 
5.2 
Nivolumab Study Drug  
Nivolumab will be obtained from commercial sources and managed in accordance with 
the OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]).  The following 
reports information and guidance included in the OPDIVO® US Prescribing Information 
dated March 2018.  Refer to the current Prescribing Information for updates during the 
conduct of this clinical trial. 
5.2.1 
Formulation and Packaging 
OPDIVO® is a sterile, preservative-free, non-pyrogenic liquid.  OPDIVO® injection for 
IV infusion is supplied in single-dose vials.  Each mL of OPDIVO® solution contains 
nivolumab 10 mg.  Refer to the OPDIVO® US Prescribing Information (USPI OPDIVO 
[nivolumab]) for further detail. 
5.2.2 
Preparation and Dispensing 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration.  OPDIVO® is a clear to opalescent, colorless to pale-yellow solution.  
Discard the vial if the solution is cloudy, discolored or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles.  Do not shake the 
vial. 
• Withdraw the required volume of OPDIVO® and transfer into an IV container. 


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• Dilute OPDIVO® with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL.  The total volume of infusion must not exceed 
160 mL. 
• Mix diluted solution by gentle inversion.  Do not shake. 
• Discard partially used vials or empty vials of OPDIVO®. 
The product does not contain a preservative.  After preparation, store the OPDIVO® 
infusion either: 
• at room temperature for no more than 8 hours from the time of preparation.  This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion; or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
the time of infusion preparation. 
Do not freeze. 
5.2.3 
Administration 
The recommended dose of OPDIVO® is 240 mg administered as an IV infusion over 
30 minutes Q2W (namely, on D15, D29, and potentially D43).  Administer the 
OPDIVO® infusion through an IV line containing a sterile, non-pyrogenic, low protein 
binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).  Flush the IV line at 
end of infusion. 
5.2.4 
Dose Modification 
Required dose modifications (i.e., interruption, dose reduction or discontinuation) for 
nivolumab should be performed per the current OPDIVO® US Prescribing Information 
(USPI OPDIVO [nivolumab]) Section 2.10 and Section 5, in addition to potential dose 
modifications for sitravatinib in accordance to Section 5.1.3 and Section 5.3.  
If after receiving sitravatinib but prior to any nivolumab dosing, patients develop 
toxicities that prevent the first nivolumab administration, then permanent discontinuation 
from study should be considered.  In contrast, patients who have already received 
nivolumab and who develop AEs (regardless of causality) preventing subsequent 
nivolumab administration may remain on study receiving sitravatinib alone. 
5.3 
Management of Adverse Events 
Management of AEs due to nivolumab should be performed in accordance with the 
current OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) and 
Section 5.3.2.  This protocol provides guidance for dose modification of sitravatinib 


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(i.e., interruption, dose reduction or discontinuation) for AEs attributed to sitravatinib 
(Section 5.1.3). 
5.3.1 
Sitravatinib-Related Adverse Events 
5.3.1.1 
General Management of Non-Hematological Toxicities 
In general, prolonged (> 1 week) non-hematological Grade 2 adverse events that are 
assessed to be causally related to sitravatinib should be managed by dose reduction of 
sitravatinib.  Exceptions, whereby patients can continue at the same dose, include lab 
abnormalities; nausea, vomiting or diarrhea that is manageable with supportive care; and 
any Grade 2 toxicity whose maximal severity is Grade 2 in NCI CTCAE, Version 5.0. 
Non-hematological toxicities ≥ Grade 3 and considered to be sitravatinib-related should 
be managed with permanent discontinuation of sitravatinib as outlined in Table 4.  For 
Grade 3 toxicities of nausea, vomiting, diarrhea, and lab abnormalities that are adequately 
managed by routine supportive care (such as anti-emetics, anti-diarrheals or electrolyte 
supplementation) and persist ≤72 hours, Grade 3 fatigue lasting ≤ 8 days, or Grade 3 
amylase or lipase elevation, sitravatinib treatment may be interrupted until resolution of 
toxicity to ≤ Grade 1 or to baseline value and subsequently resumed at the same dose. 
Table 4: 
Sitravatinib Dose Modifications – Non-Hematological Drug-
Related Toxicities1 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1, or Grade 2 (≤ 1 week) 
Investigator discretion2 
Prolonged Grade 2 (> 1 week) 
Investigator discretion2 
Decrease by 1 dose level3 
Grade 3 or 4 
Discontinue sitravatinib2,4 Discontinue sitravatinib2,4 
1  Special cases for adverse events of special interest for sitravatinib are presented in Section 5.3.1.3. 
2  The current OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) must be consulted to 
determine appropriate dose modifications for nivolumab. 
3  Patients may instead continue at the same dose for the following prolonged Grade 2 adverse events: 
a. 
Grade 2 nausea, vomiting or diarrhea that is manageable with supportive care; 
b. Grade 2 electrolyte abnormality that is not clinically complicated and resolves spontaneously or 
with conventional medical treatment; 
c. 
Grade 2 fatigue; 
d. Grade 2 amylase or lipase elevation (that is not associated with symptoms or clinical 
manifestations of pancreatitis). 
e. 
Any Grade 2 adverse event whose maximal severity is Grade 2 in NCI CTCAE, Version 5.0. 
4  Patients may instead hold sitravatinib until toxicity ≤ Grade 1 or returns to baseline and subsequently 
resume at the same dose in the following cases: 
a. 
Grade 3 nausea, vomiting or diarrhea that is manageable with supportive care and persists for ≤ 72 
hours; 
b. Grade 3 electrolyte abnormality that is not clinically complicated and resolves spontaneously or 
with conventional medical treatment within 72 hours; 
c. 
Grade 3 fatigue that persists for ≤ 8 days; 
d. Grade 3 amylase or lipase elevation that is not associated with symptoms or clinical 
manifestations of pancreatitis. 


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5.3.1.2 
General Management of Hematological Toxicities 
Hematological toxicities are not a frequent cause of treatment interruption or 
discontinuation of sitravatinib treatment.   
In general, prolonged (> 1 week) hematological Grade 2 toxicities that are considered to 
be causally related to sitravatinib should be managed by dose reduction of sitravatinib. 
Observed ≥ Grade 3 hematological events that are considered to be causally related to 
sitravatinib should initially be managed using treatment interruption.  In addition, dose 
reduction of sitravatinib should be implemented in the following cases: 
• Grade 4 neutropenia persisting for ≥ 8 days; or 
• Grade 3 thrombocytopenia with bleeding. 
Conversely, permanent discontinuation of sitravatinib should be implemented in the 
following cases: 
• Grade 3 or 4 febrile neutropenia; or 
• Grade 4 thrombocytopenia of any duration. 
5.3.1.3 
Management of Selected Adverse Events 
The following are guidelines for management of potential AEs more specific to treatment 
with sitravatinib or agents in the same class of cancer treatment. 
5.3.1.3.1 
Hypertension 
Hypertension, including Grade 3 events, has been reported with sitravatinib.  
Dihydropyridine calcium channel blockers such as nifedipine, amlodipine, and 
nicardipine may be considered if anti-hypertensive therapy is required, and should be 
considered for patients with Grade 3 hypertension without clinically significant increases 
in blood pressure (BP) (see Table 5).  On the other hand, in cases of Grade 3 
hypertension with clinically significant increases in blood pressure (see Table 5), 
temporary suspension of sitravatinib dosing is recommended until blood pressure is 
controlled.  Treatment with sitravatinib may resume at the same or a lower dose at the 
discretion of the Investigator.  If significant hypertension recurs, options include change 
in medical management of the patient, reduction of sitravatinib dose, or discontinuation 
of study treatment, at the discretion of the Investigator.  In the event of Grade 4 
hypertension, sitravatinib should be permanently discontinued (see Table 5). 


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Table 5: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 or 2 hypertension 
As per Table 4 
Grade 3 hypertension without clinically 
significant increases in BP as defined below 
Investigator discretion. Consider 
anti-hypertensives per Section 5.3.1.3.1 
Grade 3 hypertension with clinically 
significant increases in BP defined as either 
an increase of ≥ 30 mmHg in systolic BP to 
≥ 180 mmHg or increase of ≥ 20 mmHg in 
diastolic BP to ≥ 110 mmHg, confirmed 
with repeated testing after at least 5 minutes 
Hold until 
≤ Grade 2 or return 
to baseline 
Investigator 
discretion 
Grade 4 hypertension 
Discontinue 
sitravatinib 
Discontinue 
sitravatinib 
5.3.1.3.2 
Palmar-Plantar Erythrodysesthesia 
Palmar plantar erythrodysesthesia (PPE) has been reported as a dose-limiting toxicity in 
the Phase 1 study of sitravatinib.  Measures that can be taken to manage PPE include 
avoidance of exposure of hands and feet to hot water when washing dishes or bathing, or 
to other sources of heat, avoidance of activities that cause unnecessary force or friction 
(rubbing) on the hands or feet, avoiding contact with harsh chemicals such as cleaning 
products, use of tools or household items that result in pressure on the hands, such as 
garden tools, knives, and screwdrivers, and wearing of loose fitting, well-ventilated shoes 
and clothes.  Treatment may include use of topical moisturizing agents, topical 
anesthetics or topical anti-inflammatory medications such as corticosteroid creams.  In 
more severe cases, dose interruption and reduction may be warranted.  In the event of 
Grade ≥ 3 palmar-plantar erythrodysesthesia, sitravatinib should be permanently 
discontinued. 
5.3.1.3.3 
Diarrhea 
Immune-mediated etiology (e.g., immune-mediated colitis) should be considered (see 
Section 5.3.3.1 for management of immune-mediated diarrhea/colitis).  
Diarrhea has been reported with sitravatinib treatment, though the mechanism remains 
unclear, as with other small molecule receptor TKIs.  Patients should be counseled that 
diarrhea is a possible side effect and advised to take loperamide or a similar medication 
as needed if diarrhea develops.  Any patients developing dehydration or clinically 
significant electrolyte abnormalities should interrupt treatment, but treatment may be 
restarted once diarrhea is controlled.  


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5.3.1.3.4 
Hemorrhagic Events 
The risk of hemorrhagic events with sitravatinib is unknown; however, such events have 
been reported with inhibitors of VEGFR.  Patients with active hemoptysis or 
gastrointestinal bleeding should not take sitravatinib, and suspension of treatment is 
recommended for patients developing clinically significant bleeding.  In the event of 
Grade ≥ 3 hemorrhage, sitravatinib should be permanently discontinued. 
5.3.1.3.5 
Thrombotic Events 
Though thrombotic events (e.g., pulmonary embolism) have been reported with 
sitravatinib and with inhibitors of VEGFR, the risk of such events with sitravatinib is 
unknown.  Precautions should be taken in patients with recent, clinically significant 
thrombotic events, and treatment should be discontinued in the event of Grade ≥ 2 
thrombotic events including thrombosis, pulmonary embolism, myocardial infarction, 
cerebrovascular accident and thromboembolic event. 
5.3.1.3.6 
Thyroid Dysfunction Other than Immune-Mediated 
Hypothyroidism and increases in thyroid-stimulating hormone (TSH) have been reported 
in patients taking sitravatinib.  Patients diagnosed with hypothyroidism should be treated 
with thyroid replacement and may continue treatment with sitravatinib at the 
Investigator’s discretion. 
5.3.1.3.7 
Decreased Left Ventricular Ejection Fraction 
Decreased LVEF has been reported with sitravatinib.  In addition, decreases of LVEF to 
< 50% on-study were observed in patients undergoing scheduled multigated acquisition 
(MUGA) scans or echocardiograms.  Discontinuation should be considered in the event 
of treatment-related, Grade ≥ 2 decreased ejection fraction and for patients requiring 
acute hospitalization for treatment of CHF. 
5.3.1.3.8 
Proteinuria 
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
inhibitors of the VEGFR pathway.  Patients who develop ≥ 2+ proteinuria should 
undergo 24-hour urine collection for assessment of urine protein; treatment with 
sitravatinib should be discontinued in the presence of ≥ 2 g of proteinuria/24 hours and 
may restart when protein levels decrease to less than 2 g/24 hours.  Patients who develop 
nephrotic syndrome should be withdrawn from treatment with sitravatinib. 
5.3.2 
Nivolumab-Related Adverse Events 
Refer to the OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) 
Section 2.10 and Section 5 for guidance concerning management of AEs, including 
immune-related AEs, during treatment with nivolumab. 


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5.3.3 
Management in Event of Immune-Related Adverse Events 
Sitravatinib has not been associated with irAEs.  However, the potential exists for 
sitravatinib to contribute to irAEs associated with nivolumab treatment.  In the event of a 
Grade 2 irAE during study treatment, administration of sitravatinib and nivolumab should 
be interrupted until the event stabilizes to Grade ≤ 1 (consistent with guidance provided 
in the OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab])).  At the 
time of resumption of sitravatinib dosing, a dose reduction may be implemented at the 
discretion of the Investigator. 
In general, patients should permanently discontinue nivolumab in the presence of any 
Grade 3 or 4 irAEs.  Sitravatinib may be resumed at the same or lower dose at the 
discretion of the Investigator until the event stabilizes to Grade ≤ 1. 
5.3.3.1 
Diarrhea/Colitis 
The management of diarrhea should be guided by clinical judgment and an assessment of 
the most likely causative etiology, with special consideration given to the potential for 
immune-mediated colitis.  The presence of abdominal pain, mucus or blood in the stool 
or peritoneal signs should raise the index of suspicion for immune-mediated colitis, as 
these features are generally not observed with sitravatinib treatment-associated diarrhea.  
The diarrhea observed with sitravatinib generally improves within several days of 
interrupting study medication, with close observation may help establish the most likely 
causality.  However, if any features of the clinical presentation, including timing of 
presentation, failure to improve with dose interruption, laboratory or radiologic tests 
suggests the presence of immune-mediated colitis, all study medications should be 
withheld and treatment with immuno-suppressive therapy initiated as detailed in the 
OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]). 
5.3.3.2 
Increased Transaminases 
The management of increases in AST and ALT should be guided by the clinical judgment 
of the Investigator, including an assessment of the most likely causative etiology, with 
special consideration given to the potential for immune-mediated hepatitis.  Increased 
transaminases should be evaluated to determine whether confounding factors exist, such 
as viral infection, metastatic lesions or biliary obstruction. 
For cases where transaminase increases are not likely to be immune-mediated, treatment 
management decisions should be made using Investigator discretion in consideration of 
clinical factors.  Recommended treatment modifications for sitravatinib are provided in 
Table 6.  However, if any features of the clinical presentation, including timing of 
presentation, failure to improve with dose interruption, laboratory or radiologic tests 
suggests the presence of immune-mediated hepatitis, all study medications should be 
withheld and treatment with immuno-suppressive therapy initiated as detailed in the 
OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]). 


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Table 6: 
Sitravatinib Dose Modification for Increased Hepatic 
Transaminase 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 (> ULN – 3.0 × ULN) 
May be implemented at Investigator and patient 
discretion 
Grade 2 (> 3.0 – 5.0 × ULN)  
Not required1 
Decrease by 1 dose level1 
Grade 3/4 (> 5.0 × ULN)  
Discontinue sitravatinib1 
Discontinue sitravatinib1 
1  The current OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) (and Section 5.3.3, 
in case the event is deemed to be an irAE) must be consulted to determine appropriate dose 
modifications for nivolumab. 
5.3.3.3 
Management of Hy’s Law Cases 
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 × ULN, 
bilirubin ≥ 2 × ULN but without concurrent increases in alkaline phosphatase (i.e., 
alkaline phosphatase < 2 × ULN), that is not attributable to liver metastases or biliary 
obstruction, sitravatinib and nivolumab should be permanently discontinued and steroids 
administered. 
5.4 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (e.g., a dose that is not planned in the study).  
Medication errors occurring during the conduct of this study will be documented as AEs 
(regardless of whether clinical signs or symptoms are observed) and if serious 
consequences are observed, will be reported on SAE forms.  In all cases of medication 
error, the sponsor should be notified immediately. 
There is currently no specific treatment in the event of an overdose of sitravatinib or 
nivolumab.  The Investigator will use clinical judgment to treat any overdose. 
5.5 
Concomitant Therapies 
5.5.1 
Concomitant Medication(s) 
Concomitant medications must be locally approved and used at doses and regimens that 
are considered standard-of-care for the treated indication.  Treatment for co-morbidities, 
disease signs and symptoms and treatment-emergent adverse events (TEAEs) should be 
provided as necessary in the judgment of the Investigator.  Patients may continue to use 
any ongoing medications not prohibited by the inclusion/exclusion criteria or treatment 
plan. 


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Antibiotics and analgesics: These drugs should be used as needed. Patients with 
neutropenic fever or infection should be treated promptly (therapeutic colony-stimulating 
factors should be used in accordance with ASCO guidelines). 
Anti-diarrheals:  In general, patients should be counseled that diarrhea is a possible side 
effect of the study treatments and advised to take loperamide or a similar medication as 
needed if diarrhea develops.   
Anti-emetics:  Patients may be premedicated for nausea and vomiting.  Recommended 
anti-emetic agents include granisetron 1 mg as premedication, and then granisetron 
and/or prochlorperazine as needed. 
Gastric Acid Medications:  Solubility of sitravatinib is maximal at low pH.  Proton 
pump inhibitors and H2-antagonists should be avoided during treatment on study but are 
not exclusionary.  Switch from use of proton pump inhibitors or H2 antagonists to use of 
antacids is preferred.  Use of antacids should be avoided 4 hours before and 2 hours after 
administration of sitravatinib. 
Immunosuppressive Medications:  Use of immunosuppressive mediations should be 
limited to the extent possible to allow testing of the immune-stimulatory mechanisms 
proposed in this clinical trial.  Immunosuppressive medications should be used as needed 
to manage irAEs and the extent required to manage comorbidities and symptoms of 
disease.   
Vaccines:  Live attenuated vaccines within 28 days of nivolumab dosing are to be 
avoided.  Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
Medications with potential for drug-drug interactions: Full details of the medications 
to be avoided or used with caution during study drug treatment are outlined in 
Appendix 2. 
Sitravatinib inhibits P-gp and BCRP transporters at high concentrations and, as a result, 
sensitive substrates and substrates with narrow therapeutic index for P-gp and BCRP 
transporters should be used with caution during study drug treatment.  Similarly, 
preclinical results suggest that multiple enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 
2C9, 2D6, 2E1, and 3A4 are involved in the metabolism of sitravatinib with a low risk of 
one enzyme contributing to metabolism in a disproportionate manner.  Therefore, 
sensitive substrates and substrates with narrow therapeutic index for indicated CYP 
enzymes should be used with caution during study drug treatment.  Finally, QTc 
prolongation with sitravatinib is under evaluation, though no signal has been detected 
from the ongoing sitravatinib clinical trials.  Prior to results of such evaluation, drugs 
with a known risk of torsades de pointes should be avoided during study drug treatment, 
whereas drugs with conditional risk of torsades de pointes may be used, but with caution 
during study drug treatment. 


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5.5.2 
Concomitant Surgery or Radiation Therapy 
The study involves a planned surgical intervention in the form of partial or radical 
nephrectomy following the combination treatment.   
The use of any radiation or earlier-than-planned surgery to manage cancer lesions during 
study drug treatment can jeopardize assessment of the primary objective of the study, 
evaluation of disease status.  Therefore, the use of these treatments during study drug 
treatment is discouraged.  However, they may be used in cases where these treatments are 
deemed medically necessary.  In these cases, patients should discontinue study drug 
treatment, if possible at least 2 days prior to the treatment.  These patients will not resume 
study drug treatment.  If patients receive a medically necessary, earlier-than-planned 
surgery involving tumor tissue collection from the patient’s renal tumor (e.g., earlier than 
planned partial or radical nephrectomy), efforts should be made to collect tumor tissue 
samples from the surgical sample.  Patients with earlier-than-planned surgery or radiation 
while on study should proceed to their EOS visit (at least 28 days after last dose) without 
resuming dosing. 
5.5.3 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the 
study treatment period, including chemotherapy, biological response modifiers, hormone 
therapies or immunotherapy.  No other investigational drug may be used during treatment 
on this protocol.  Concurrent participation in another therapeutic clinical trial is not 
allowed. 
6 STUDY ASSESSMENTS  
6.1 
Screening 
Voluntary, written, dated, and signed informed consent must be obtained before any 
study specific procedures are performed.  Patients who completed the informed consent 
process but did not enroll on the study will be considered as screen failures.  Limited 
information will be recorded in the CRF for these patients. 
6.2 
Study Period 
For details on procedures during the study, see Schedule of Assessments (Table 1). 
6.3 
End of Study (EOS) Assessment 
All patients will be followed for AEs and SAEs for at least 28 days after the last dose of 
study drug treatment or surgery, whichever occurs last.  See the Schedule of Assessments 
(Table 1) for evaluations to be performed at the EOS visit. 


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6.4 
Long-Term Follow-up 
Patient disease-free survival may be followed by review of medical records or telephone 
contact with the patient or treating healthcare professional approximately every 6 months 
from EOS visit for up to 3 years or more until death, disease recurrence or loss to 
follow-up. 
6.5 
Patient Discontinuation/Withdrawal 
Patients may discontinue from study treatment or from the study at any time at their own 
request, or they may be discontinued at any time at the discretion of the Investigator or 
Sponsor for safety, behavioral reasons, or the inability of the patient to comply with the 
protocol required schedule of study visits or procedures at a given study site.   
Criteria that may be used to discontinue patients from receipt of study medication will 
include, but will not be limited to: 
• Objective disease progression as determined by the Investigator; 
• Global deterioration of health status requiring discontinuation; 
• Adverse event (AE) (see Section 5.3); 
• Significant protocol violation; 
• Loss to follow-up; 
• Refusal for further treatment; 
• Study termination by Sponsor; 
• Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient.  At least 2 attempts should be made to contact the patient, and each attempt 
should be recorded in the source documents.  In any circumstance, every effort should be 
made to document patient outcome, if possible.  The Investigator should inquire about the 
reason for withdrawal, request that the patient returns for a final visit, and if applicable, 
follow-up with the patient regarding any unresolved AEs. 
If the patient withdraws consent, no further evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before the withdrawal. 
7 PROCEDURES 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that there may be circumstances 


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outside of the control of the Investigator that may make it unfeasible to perform a 
protocol-specified assessment.  In these cases, the Investigator will take all steps 
necessary to ensure the safety and well-being of the patient.  When a protocol required 
test cannot be performed, the Investigator will document in the source document and 
CRF the reason and any corrective and preventive actions which he/she has taken to 
ensure that normal processes are adhered to as soon as possible.  The study team will be 
informed of these incidents in a timely fashion. 
7.1 
Efficacy 
All patients enrolled in the study are to be evaluated for disease activity as outlined in the 
Schedule of Assessments (Table 1).  All known and suspected sites of disease should be 
evaluated at each assessment.  Screening/baseline tumor assessments should include CT 
or X-ray (radiography) of the chest, and CT or MRI of abdomen, and, if clinically 
indicated, whole body bone scan and CT with contrast or MRI of the brain and evaluation 
of any superficial lesions.  The subsequent, on-study disease assessment will include 
imaging of all known and suspected sites of disease and obtained in the preoperative 
setting, namely at the Preoperative Rebaseline visit (which should generally occur within 
3 days of the planned partial or radical nephrectomy).  The allowable windows for 
assessments are 4 weeks prior to first study treatment for screening/baseline assessments 
and within 1 week of the planned partial or radical nephrectomy for the on-study disease 
assessment. 
CT scans should be performed with contrast agents unless contraindicated for medical 
reasons.  If IV contrast is medically contraindicated, the imaging modality to be used 
(either CT without contrast or MRI) should be the modality which best evaluates the 
disease, and the choice should be determined by the Investigator in conjunction with the 
local radiologist.  Depending on the adequacy for evaluation of disease, a combination of 
CT without contrast and MRI should most often be used.  CT without contrast is 
preferred for evaluation of lesions in lung parenchyma.  Chest X-ray is also acceptable.  
MRI is not adequate for evaluation of lung parenchyma but should also be performed to 
evaluate all other aspects of the chest.  MRI of the abdomen should substitute for CT with 
contrast unless the method does not adequately depict the individual’s disease, in which 
case CT without contrast is preferred.  
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer-2009).  
Appendix 3 provides guidance in using the response criteria.  The appendix includes a 
clarification that based on the single on-study disease assessment, RECIST 1.1 will be 
used in the determination of the single point in time objective response to treatment.  
Because only one post-treatment imaging assessment is expected, objective responses 
will not be confirmed by repeated imaging. 
The Investigator’s assessment of disease response and progression will be the basis for 
patient management. 
Secondary efficacy endpoint will include long-term follow-up for Disease Free-Survival 
(DFS) and will be collected by review of medical records or telephone contact with the 


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patient or treating healthcare professional approximately every 6 months from EOS visit 
for up to 3 years or more until death, disease recurrence or loss to follow-up.  Disease 
recurrence will be based on imaging assessments performed off study per standard of 
care after nephrectomy.  After sufficient data for the primary endpoint is collected in this 
study, the electronic study database may be locked, and the collection of the long-term 
survival status may be reported through a different mechanism (rather than using the 
electronic database). 
7.2 
Safety Assessments 
7.2.1 
Medical History 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present at 
baseline will be recorded in the CRF as AEs beginning on D1 of study treatment and 
onward throughout the study.  The actual date of onset should be recorded in all cases.   
7.2.2 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and 
EOS Visits only.  During study treatment, symptom directed physical examinations will 
be performed.   
Vital signs to be assessed include weight, body temperature, blood pressure, and pulse 
rate.  Height will be recorded at screening only.  On days when both vital signs and PK 
sampling are scheduled, the vital signs should be assessed prior to blood sampling.   
Clinically significant findings noted during screening will be reflected on the medical 
history CRF, while those noted during study treatment will be collected on the AE CRFs.   
7.2.3 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, coagulation, and chemistry parameters presented in Table 7. 
Laboratory tests will be drawn at the time points described in the Schedule of 
Assessments (Table 1) and analyzed at local laboratories.  Additional laboratory tests 
may be performed per standard of care, at the Investigator's discretion for the purpose of 
planning treatment administration, dose modification, following AEs, or as clinically 
indicated. 
Table 7: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
Alkaline phosphatase 


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Hematology Panel 
Blood Chemistry Panel 
Neutrophil count 
Total bilirubin 
Lymphocyte count 
Lipase 
 
Amylase 
Coagulation 
Sodium 
International normalized ratio (INR) 
Potassium 
Partial thromboplastin time (PTT) 
Chloride 
 
Bicarbonate 
Urinalysis (dip stick) 
Blood urea nitrogen (BUN) 
Blood 
Creatinine 
Protein 
Albumin 
 
Total calcium 
Thyroid Function Test 
Magnesium 
Thyroid-stimulating hormone (TSH) 
Phosphate 
 
Uric acid 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test 
will be performed at screening.  Pregnancy tests will also be done whenever pregnancy is 
suspected during the study.  Additional pregnancy testing may be necessary if required by 
local practices or regulations.   
7.2.4 
Electrocardiogram (ECG)  
Single and triplicate ECGs are to be performed as outlined in the Schedule of 
Assessments (Table 1 and Table 2).  It is preferable that the machine used has a capacity 
to calculate standard intervals automatically.  In addition, QTc will be calculated 
manually using Fridericia’s formula.  Assessments reported by automated read as QTc 
prolongation are advised to be over-read by a cardiologist to ensure accuracy of 
interpretation. 
7.2.5 
Echocardiogram (ECHO) 
Echocardiograms will be performed at screening, and thereafter as in the Schedule of 
Assessments (Table 1).   
7.3 
Laboratory Studies 
Full details on sample collection, processing, storage and shipment are presented in the 
Study Laboratory Manual. 


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7.3.1 
Pharmacokinetic Evaluation 
The PK of sitravatinib will be determined using blood samples collected at specified time 
points prior to and following study treatment dosing.  Every effort will be made to collect 
these PK samples at the exact nominal times relative to dosing.  A variation window is 
allowed for each time point as outlined in Table 2.  The actual time of each sample 
collection will be recorded on the source document and CRF.   
All plasma samples will be stored frozen and shipped on dry ice according to instructions 
provided.  Analysis of samples will be performed using specific validated bioanalytical 
methods.  Full details on sample collection, processing, storage and shipment will be 
provided in the Study Laboratory Manual. 
7.3.2 
Pharmacodynamic Evaluation in Blood 
Immune effects will be evaluated through circulating prior to and during and following 
treatment as outlined in Table 2.  Blood samples will be collected for the assessment of 
parameters that may include, but are not limited to, quantification of circulating immune 
cell populations by flow cytometry including T-cell subpopulations (CD4+, 
CD4+/Ki67+, CD8+, CD8+/Ki67+ and Tregs), NK cells, and MDSCs; blood levels of 
selected cytokines and chemokines including IFN-γ, IL-1ß, IL-6, IL-8, IL-12, IL-18 and 
CXCL10 (IP-10); and DNA sequencing to assess T-cell clonality.  Full details on sample 
collection, processing, storage and shipment will be provided in the Study Laboratory 
Manual. 
7.3.3 
Pharmacodynamic Evaluation in Tumor Tissue 
Tumor tissue will be collected from initial and mid-study biopsies and surgical sample.  
Fresh tumor biopsies are to be collected on study; archival tissue will not be accepted as 
an alternative.  Tumor tissue will be collected and used to assess immune effects through 
tissue biomarkers prior to and during and following treatment.  Parameters may include, 
but are not limited to, quantification of tissue immune cell populations by flow cytometry 
including T-cell subpopulations (CD8+, CD8+/Ki67+ and Tregs), NK cells, MDSCs, and 
macrophages; immunohistochemistry and/or immunofluorescence for assessment of 
PD-L1 status and characterization of immune cell populations; tumor gene expression 
analysis; and DNA sequencing to assess T-cell clonality.  In addition, next generation 
sequencing (NGS) analyses for tumor mutations and tumor mutation burden may be 
assessed using tumor tissue from the surgical sample.  For patients whose tumor tissue 
has previously been tested using NGS, presence of specific tumor gene mutations and 
estimation of total mutation burden will be collected in the CRF. 
Samples should be of acceptable quality and quantity for analysis.  Samples should be 
collected via a core needle of 18 gauge or larger with sufficient passes or be collected by 
an incisional or excisional tumor biopsy.  Samples from fine needle aspirates (FNA) are 
not appropriate for study evaluations.  Further guidance on sample preparation, handling 
and submission can be found in the Study Laboratory Manual. 


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7.3.4 
Circulating and Tissue Tumor DNA 
NGS analyses for tumor mutations and tumor mutation burden will be assessed at using 
baseline circulating tumor cell DNA (ctDNA) blood samples outlined in Table 2 and 
using tumor tissue from the surgical sample as outlined in Table 1.  At each ctDNA time 
point, blood samples will be collected into two 10 mL Streck brand Cell-Free DNA 
Blood Collection tubes allowing shipping and stability at ambient temperatures.  Tissue 
samples should be of acceptable quality and quantity for analysis.  Full details on sample 
collection, processing, storage and shipment will be provided in the Study Laboratory 
Manual. 
For patients whose tumor tissue or blood has previously been tested using NGS, presence 
of specific tumor gene mutations and estimation of total mutation burden will be 
collected in the CRF. 
8 ADVERSE EVENT REPORTING 
8.1 
Sponsor Medical Monitor Personnel 
The contact information for the sponsor's Medical Monitor personnel for this trial is 
available in the study contact list located in the Site Operations Manual. 
8.2 
Adverse Events 
An AE is any reaction, side effect or other undesirable medical event that occurs during 
participation in a clinical trial, regardless of treatment group or suspected causal 
relationship to study treatment.  Assessment of AEs will include type, incidence, severity 
(graded by the National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE, Version 5.0]), timing, seriousness, and relatedness to study 
treatment. A treatment-emergent adverse event (TEAE) is an AE that occurs after the first 
dose of any study treatment or any preexisting condition that increases in severity after 
the first dose of study treatment. 
All observed or volunteered AEs will be recorded in source documents and reported in 
the CRF.  The best available medical terminology should be used to describe AEs in 
source documents and CRFs.  Terms describing the diagnosis are preferred over 
individual signs and symptoms of the diagnosis.  If determination of the diagnosis is 
delayed, record signs and symptoms and add the diagnosis as an additional AE when 
available; follow all recorded AEs to resolution.  The actual date of onset should be 
recorded in all cases.  Ongoing AEs that change in attribution or severity should have the 
date of change entered as the “end date” and a new AE record should be opened with the 
changed details.  Examples of AEs include but are not limited to:   
• Signs or symptoms of co-morbidity, illness, or toxicity of study treatment; 
• Signs or symptoms of worsening malignancy under study (disease progression 
assessed by measurement of malignant lesions should not be reported as an AE). 


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• Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); 
• Hypersensitivity; 
• Drug abuse, dependency, overdose, withdrawal or misuse; 
• Signs or symptoms of drug interactions; 
• Extravasation; 
• Exposure during pregnancy or via breastfeeding; 
• Medication error; or 
• Occupational exposure. 
8.2.1 
Laboratory Abnormalities 
An abnormal laboratory test results should be reported as an AE in the CRF only if it is 
associated with one or more of the following:  
• Clinical symptoms; 
• Requires additional tests (beyond repeats), treatment or intervention; 
• Results in change in study treatment dosing; 
• Requires discontinuation from study treatment; and/or 
• Considered by the Investigator or Sponsor to be an AE. 
8.2.1.1 
Hy’s Law 
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN 
concurrent with an increase in total bilirubin to ≥ 2 × ULN but without increase in 
alkaline phosphatase (i.e., alkaline phosphatase < 2 × ULN) meets the criteria for Hy’s 
Law and raises the concern for drug-induced liver injury when no other cause of the 
abnormal laboratory results is identified.  Follow-up investigations and inquiries will be 
initiated promptly by the investigational site to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by 
a disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an 
agent other than the investigational product. 
Cases meeting Hy’s Law should be reported as SAEs.  Both study drugs should be 
permanently discontinued for a Hy’s Law case and steroids administered.   


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8.2.2 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the NCI CTCAE, 
Version 5.0.  Documentation of AE grading in the source documents and CRF should be 
consistent with provided definitions. 
8.2.3 
Causality 
For each AE, the Investigator should determine and document whether there exists a 
reasonable possibility that the study treatment caused or contributed to the AE.  The 
Investigator’s assessment should be recorded in the source document.  The CRF will 
provide the options for attribution to study treatment as “related” and “not related.”  If the 
Investigator's causality assessment is "unknown but not related to investigational 
product," this should be recorded in the CRF as “not related.”  If the Investigator does not 
know whether or not the study treatment is causally-related to the event, reporting for 
study purposes will be as “related” to study treatment.   
Collection of causal relationship for AEs associated with study procedures (e.g., tumor 
biopsy) is provided for separately in the CRF.   
8.3 
Serious Adverse Events 
8.3.1 
Definition of a Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/permanent damage (substantial 
disruption of the ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
• Other: Important medical events that may not result in death, be life-threatening, 
or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such events are: 
− Intensive treatment in an emergency room or at home for allergic 
bronchospasm; 
− Blood dyscrasias or convulsions that do not result in inpatient hospitalization; 


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− Development of drug dependency or drug abuse. 
Progression of the malignancy under study, including any signs or symptoms of 
progression that may require hospitalization, should not be reported as an SAE unless the 
outcome is fatal within the safety reporting period.   
Definition of Terms 
Life-threatening: An AE is life threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death.  For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. 
Hospitalization: In general, hospitalization signifies that the patient has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician's 
office or outpatient setting.  When in doubt as to whether 'hospitalization' occurred or was 
necessary, the AE should be considered serious.  Hospitalization for elective surgery or 
routine clinical procedures that are not the result of AE (e.g., elective surgery for a 
pre-existing condition that has not worsened) need not be considered AEs or SAEs.  If 
anything untoward is reported during the procedure, that occurrence must be reported as 
an AE, either 'serious' or 'non-serious' according to the usual criteria. 
Disability/permanent damage: An AE is disabling or caused permanent damage if it 
resulted in a substantial disruption of a person’s ability to conduct normal life functions, 
e.g., a significant, persistent or permanent change, impairment, damage or disruption in 
body function/structure, physical activities and/or quality of life. 
Adverse Event of Special Interest (AESI): AESIs are of scientific and medical interest 
specific to understanding of the Investigational Product and may require close monitoring 
and rapid communication by the Investigator to the sponsor.  An AESI may be serious or 
non-serious.  The rapid reporting of AESIs allows ongoing surveillance of these events in 
order to characterize and understand them in association with the use of this 
investigational product. 
Immune-related Adverse Events (irAE):  An irAE is defined as an AE that is associated 
with drug exposure and is consistent with an immune-mediated mechanism of action and 
where there is no clear alternate etiology.  Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis.  Appropriate 
efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE. 


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8.3.2 
Exposure During Pregnancy 
Exposure during pregnancy (i.e., exposure in-utero [EIU]) may occur in a female study 
participant, the female partner of a male study participant or study site personnel working 
with the investigational product (e.g., occupational exposure) if: 
• A female becomes or is found to be pregnant during treatment or within 6 months 
after discontinuing treatment or having been directly exposed to the investigational 
product; 
• A male is exposed to the investigational product prior to or around the time of 
conception or during the pregnancy of his partner. 
If exposure in-utero occurs, the Investigator must submit an SAE form and an EIU 
Supplemental Form within 24 hours of awareness of the exposure, regardless of whether 
an AE or SAE has occurred.   
In the event of pregnancy in a female study participant, if the pregnancy is continued, 
study treatment will be immediately discontinued. 
In the event of exposure of the pregnant partner of a male study participant, the study 
participant should be asked to deliver an EIU Pregnant Partner Release of Information 
Form to his partner.  The Investigator must document on the EIU Form that the patient 
was given this letter to provide to his partner. 
Follow-up to obtain pregnancy outcome information is to be conducted for all EIU 
reports.  In the case of a live birth, the health of the neonate should be assessed at the 
time of birth and for up to 3 months after birth.  Further follow-up of birth outcomes will 
be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify 
developmental delays).  In the event the pregnancy is terminated, the reason(s) for 
termination should be reported and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection. 
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), 
an SAE report should be submitted to the Sponsor. 
8.4 
Reporting of Serious Adverse Events and Adverse Events 
8.4.1 
Reporting Period 
The active reporting period for SAEs begins from the time that the patient provides 
informed consent (i.e., prior to undergoing any study-specific procedure or assessment) 
and continues until at least 28 days after last administration of study treatment or surgery, 
whichever occurs last.  All SAEs ongoing 28 days after the last dose should be followed 
until all SAEs have resolved or stabilized to a chronic condition, whichever is later.  If a 
patient begins a subsequent systemic anticancer therapy, the reporting period for new 
SAEs ends at the time the new treatment is started.  Death must be reported if it occurs 


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during the active reporting period for SAEs regardless of whether a subsequent systemic 
anticancer therapy is administered.  SAEs occurring to a patient after the active reporting 
period has ended should be reported to the Sponsor if the Investigator becomes aware of 
them and if the Investigator assesses at least a reasonable possibility of being related to 
drug.  These SAEs should be followed until resolved or stabilized to a chronic condition. 
The reporting period for non-serious AEs begins from the day of first dose of study 
treatment and continues until at least 28 days after last administration of study dug 
treatment or surgery, whichever occurs last.  If a patient begins a subsequent systemic 
anticancer therapy, the AE reporting period ends at the time the new treatment is started. 
8.4.2 
Reporting Requirements 
All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, 
irrespective of the extent of available AE information, by faxing the SAE report to the 
Sponsor’s pharmacovigilance representative designated in the Site Operations Manual.  
The 24-hour timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports and to the initial and follow-up reporting of exposure 
during pregnancy and exposure via breastfeeding.  The need for an expedited report to 
regulatory authorities will be determined by the Sponsor and necessary reporting will be 
performed by the Sponsor.  The Sponsor will notify study Investigators of all Suspected, 
Unexpected (as judged against the Investigator Brochure) Serious Adverse Reaction 
(SUSAR) reports.  The Investigator is responsible for reporting all SUSARs to the 
IRB/EC/REB.   
All AE (including SAEs) must be documented in source documents and reported in the 
CRF.  Please note that the CRF and SAE report forms may collect information in 
somewhat different formats.  Where the requested data overlap in different formats, the 
information should be consistent between the two forms. 
After sufficient data for the primary endpoint is collected in this study, the electronic 
study database may be locked, and the collection of the long-term survival status may be 
recorded through a different mechanism (rather than using the electronic database). 
9 STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained 
by the Sponsor.  The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 


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9.1 
Statistical Design 
9.1.1 
Hypothesis and Sample Size 
With currently available treatments, the percentage of patients with a point in time 
objective response prior to surgery is assumed to be 5% (p0); thus, this rate is considered 
uninteresting.  The target percentage of patients with a point in time objective response 
prior to surgery using sitravatinib and nivolumab in this study is assumed to be 30% (p1).  
Controlling for a Type 1 error (α) of 0.05, and using an exact test (two-sided), with 18 
clinical activity evaluable patients, we have 80% power to rule out a percentage of 
patients with a point in time objective response prior to surgery of 5% assuming 
percentage of patients with a point in time objective response prior to surgery of 30%. 
Assuming a non-evaluable rate between 25%-30% from enrolled patients to clinical 
activity evaluable patients, the study will enroll approximately 25 patients in order to get 
18 clinical activity evaluable patients.  Additional subjects may be enrolled for a total of 
12 subjects with complete tumor tissue collection (collected from initial and mid-study 
biopsies and surgical sample). 
9.1.2 
Dose De-escalation Plan 
The Modified Toxicity Probability Interval (mTPI) method (Ji-2010) will be used to set 
rules on a dose de-escalation plan to monitor and limit toxicity of the combination 
regimen in the neoadjuvant setting.   The first assessment will occur after the first 6 
patients have completed 3 weeks on therapy, or earlier if 2 or more patients with toxicity 
are suspected.  Subsequent assessments will occur at intervals that include up to 6 
additional patients completing the observation period.  Assuming a maximum toxicity 
level of no more than 20% at the tolerated dose, the dose will be decreased if more than 2 
patients with toxicities are observed in the first 6 patients (Refer to Appendix 4 for the 
dose de-escalation table).  For the purposes of decision making for dose de-escalation, 
patients with the following treatment-related adverse events will be used to determine the 
number of patients having toxicity: 
1. Non-hematologic Grade 4 adverse event. 
2. Non-hematologic Grade 3 adverse event with the following exceptions: 
a. Grade 3 nausea, vomiting or diarrhea that is manageable with supportive care 
and persists for ≤ 72 hours; 
b. Grade 3 electrolyte abnormality that is not clinically complicated and resolves 
spontaneously or with conventional medical treatment within 72 hours; 
c. Grade 3 fatigue that persists for ≤ 8 days; 
d. Grade 3 amylase or lipase elevation that is not associated with symptoms or 
clinical manifestations of pancreatitis. 


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3. Surgical delay of greater than 2 weeks and due to toxicity. 
In the proposed plan, there is no dose escalation, and surgical delay will be assessed only 
for those patients who have already undergone surgery. 
9.2 
Data Handling 
Listings of all patient data will be prepared.  Data summaries will be presented in tabular 
and/or graphical format and summarized descriptively, where appropriate.  Further details 
of planned analyses will be described in the SAP. 
For all variables, only the observed data from patients will be used in the statistical 
analyses; there is no plan to estimate missing data.  Patients without a valid clinical 
response assessment will be assigned a best overall response of not evaluable (NE).  Data 
from patients who are lost to follow-up or have missing observations before reaching an 
endpoint in any of the time-to-event analyses will be treated as censored with specific 
rules defined in the SAP. 
9.3 
Analysis Populations 
9.3.1 
Clinical Activity Evaluable Population  
The Clinical Activity Evaluable population will include patients who receive at least one 
dose of each study treatment drug and who have their on-study disease assessment prior 
to surgery.  Patients who discontinue treatment due to AEs or withdrawal of consent prior 
to their on-study disease assessment will not be included in the clinical activity evaluable 
population.  This population will be used to present tumor responses. 
9.3.2 
Safety Population 
The Safety population is defined as all patients who received at least 1 dose of either 
sitravatinib or nivolumab.  The Safety population will be used for all safety analyses. 
9.3.3 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic Evaluable population will consist of all patients who receive 
treatment with sitravatinib and have sufficient concentration-time data to permit 
calculation of PK parameters for sitravatinib.  For patients who are noncompliant with 
respect to administration of sitravatinib, or for patients with incomplete data, a decision 
as to their inclusion in the analysis will be made on a case-by-case basis. 
9.3.4 
Pharmacodynamic Evaluable Population 
The Pharmacodynamic Evaluable population will consist of all patients who receive at 
least 1 dose of either sitravatinib or nivolumab for whom sufficient pharmacodynamic 
data are available. 


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9.4 
Efficacy Endpoint Definitions and Analyses 
9.4.1 
Percentage of Patients Achieving a Point in Time Objective 
Response (either CR or PR) Prior to Surgery  
The primary endpoint of this study is percentage of patients with ccRCC achieving a 
point in time objective response (either CR or PR) prior to surgery with the combination 
treatment of sitravatinib and nivolumab.  Single point in time objective response to 
treatment at the Preoperative Rebaseline visit will be categorized in accordance with 
RECIST 1.1 (Appendix 3). 
Descriptive statistics (frequency and percentage) for CR, PR, and percentage of patients 
with ccRCC achieving a point in time objective response (either CR or PR) prior to 
surgery will be presented.  The exact 95% CI of these response rates will be calculated.  
An exact test for single proportion (two-sided α=5%) will be performed to test H0: 
percentage of patients with ccRCC achieving a point in time objective response (either 
CR or PR) prior to surgery ≤ 5% against H1: percentage of patients with ccRCC 
achieving a point in time objective response (either CR or PR) prior to surgery > 5%.  
Other details will be described in the SAP. 
Additionally, information regarding pathologic complete response (pCR) will be 
collected in the CRF and will be descriptively summarized.  The determination of pCR to 
detect residual disease in kidney and regional lymph nodes will be based on the 
pathology examination of the surgical sample.  pCR is defined as the absence of residual 
invasive disease on evaluation of the complete resected renal specimen and all sampled 
regional lymph nodes following completion of neoadjuvant systemic therapy. 
9.4.2 
Disease-Free Survival (DFS) 
Patient survival may be followed by review of medical records or telephone contact with 
the patient or treating healthcare professional approximately every 6 months from EOS 
visit for up to 3 years or more until death, disease recurrence or loss to follow-up.  
Disease recurrence will be based on imaging assessments performed off study per 
standard of care after nephrectomy.  After sufficient data for the primary endpoint is 
collected in this study, the electronic study database may be locked, and the collection of 
the long-term survival status may be recorded through a different mechanism (rather than 
using the electronic database). 
DFS is defined as the time from date of surgery to disease recurrence or death whichever 
occurs first.  For patients without disease recurrence or death (including those lost to 
follow-up), censoring for the DFS endpoint will be done using the date of the last 
follow-up or the date of surgery (with duration of 1 day), whichever occurs later.  DFS 
will be analyzed using Kaplan-Meier methods. 


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9.5 
Safety Data Presentations and Summaries 
9.5.1 
Prior and Concomitant Medications 
Collected prior and concomitant medications will be coded using the WHO medical 
dictionary; patients who received these medications will be listed and summarized.   
9.5.2 
Adverse Events 
AEs will be classified using the medical dictionary for regulatory activities (MedDRA) 
classification system.  Listings will include the verbatim term, preferred term, and system 
organ class (SOC).  The number of patients with treatment emergent AEs and the 
incidence of TEAEs by SOC and preferred term will be summarized.  TEAEs will be 
summarized by maximum intensity and relationship to study therapy.  Separate 
summaries will be provided for TEAEs, TESAEs, treatment-related AEs, 
treatment-related SAEs, and other significant AEs (e.g., AEs leading to study 
discontinuation). 
9.5.3 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, 
coagulation, and chemistry), vital signs, and 12-lead ECGs. 
Clinical laboratory results will be listed by patient and, as appropriate, summarized 
descriptively, which will include a display of change from baseline.  Selected parameters 
will be presented in shift tables of baseline against worst grade test result.  Laboratory 
values outside of the normal ranges will be identified.  Laboratory values that meet Grade 
3 or 4 criteria according to NCI CTCAE Version 5.0 will be listed and summarized. 
ECG assessments will be evaluated for change of QTc from baseline as an exposure: 
response analysis.  The Investigator’s interpretation of QTc will be used in the clinical 
management of patients.  The study analysis will use the Fridericia formula applied 
programmatically to the ECG data collected in CRFs using the QT interval and either the 
RR interval or the heart rate if the RR interval is not reported.   
Vital signs, ECHO and ECG measurements will be listed for each patient at each visit.  
Descriptive statistics of observed values and changes from baseline will be summarized. 
9.5.4 
Patient Demographics, Baseline Characteristics and Disposition 
Presentations of patient characteristics will include a summary of the following for all 
patients enrolling in the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 


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• Prior therapies/surgeries 
A summary of patient enrollment and disposition will include reasons for study 
discontinuation. 
9.5.5 
Analysis of Study Treatment Dosing 
Study treatment administration will be described in terms of the total number of days 
administered, the median (range) of days administered for each agent separately and for 
the combination, dose intensity, and reasons for the deviations from planned therapy. 
9.5.6 
Time-to-Surgery 
Time-to-surgery will be collected and described by Kaplan-Meier methods.  
Time-to-surgery is defined as the number of calendar days between D1 and the planned 
nephrectomy. 
9.6 
Other Study Endpoints 
9.6.1 
Pharmacokinetic Analysis 
The PK sparse exposure data from this study may be used in the development of 
population PK and PK/PD models.  Pharmacokinetic concentration levels and parameters 
will be determined, listed, and summarized for the PK evaluable population in the 
Pharmacokinetic Analysis Plan (PKAP).  Only samples with acceptable PK (as defined in 
the PKAP) will be included in the summary statistics and a listing of individual data 
points or patients excluded from the analysis will be presented.  Plasma concentrations 
will be listed by patient for the PK Population.  Summary statistics of investigational 
agent concentrations will be reported by Visit Day. 
9.6.2 
Pharmacodynamic and Exploratory Analysis 
No formal statistical analysis of pharmacodynamic endpoints will be performed.  
Pharmacodynamic data from each assay will be listed.  Possible relationships between 
pharmacodynamic variables, PK parameters, safety, and clinical activity may be 
examined if appropriate.   
9.7 
Interim Analysis 
No interim statistical analysis is planned during this study. 
9.8 
Data Monitoring Committee 
No Data Monitoring Committee is planned during this study.  However, the study team 
will monitor adverse events in the study on an ongoing basis to assess whether a lower 
starting dose of sitravatinib is warranted (see section 9.1.2). 


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10 ETHICS AND RESPONSIBILITIES 
10.1 Ethical Conduct of the Study 
This study will be conducted in accordance with International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations 
of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) [International 
Conference on Harmonization (ICH) 1996], and concepts that have their origin in the 
Declaration of Helsinki (World Medical Association 1996, 2008 & 2013).  Specifically, 
this study is based on adequately performed laboratory and animal experimentation; the 
study will be conducted under a protocol reviewed and approved by an IRB/EC/REB; the 
study will be conducted by scientifically and medically qualified persons; the benefits of 
the study are in proportion to the risks; the rights and welfare of the patients will be 
respected; the physicians conducting the study do not find the hazards to outweigh the 
potential benefits; and each patient will give his or her written informed consent before 
any protocol-driven tests or evaluations are performed. 
10.2 Obligations of Investigators 
The Investigator is responsible for complying with the protocol and all applicable 
regulations and guidelines governing clinical research.  Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
All Investigators must provide the sponsor with a current curriculum vitae.  Only 
Investigators and designated Sub-Investigators are permitted to sign CRFs and 
examination findings (e.g., laboratory results or ECGs). 
The Investigator or designee is responsible for informing the patient of all available 
information relevant to his/her safety and obtaining signed, written consent from all 
participating patients.  Additionally, the Investigator is responsible for monitoring patient 
safety and providing periodic and requested reports to the IRB/EC/REB. 
The Investigator is responsible for the accuracy and completeness of all study records 
including CRFs, source documents, and the Site Trial Master File.  The Investigator will 
allow the study monitor, Sponsor, auditor, regulatory agencies, and IRB/EC/REB full 
access to the study and source documents. 
10.3 Institutional Review Board/Ethics Committee/Research Ethics Board 
Prior to the shipment of clinical supplies or initiation of the study, the clinical trial 
protocol along with the informed consent form (ICF), Investigator’s Brochure, and any 
other written information or instructions for the patient must be submitted to the 
IRB/EC/REB for written approval.  The Investigator will provide the Sponsor with a 
copy of the IRB/EC/REB’s written approval, as well as the membership list or a 
compliance statement from the IRB/EC/REB.  The Investigator is responsible for 
notifying the IRB/EC of any Sponsor-approved amendments to the protocol or ICF, 


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SAEs occurring in patients treated at the study site in accordance with local IRB/EC/REB 
practice, and all expedited safety reports from SAEs occurring at other study sites 
participating in the drug development program. 
10.4 Informed Consent Form 
The ICF must contain all elements required by the Food and Drug Administration (FDA) 
under 21 Code of Federal Regulations (CFR) Part 50 and the ICH GCP guidelines (ICH 
E6) in addition to any other elements required by applicable national, state, provincial, 
and local regulations, or institutional policies. 
All patients who choose to participate in the study must provide written consent after 
having had adequate time to consider whether they will participate in the study.  The 
written consent must be obtained prior to any protocol-related procedures that are not part 
of the patient’s normal medical care.  The patient must be advised of his/her right to 
withdraw from the study at any time. 
Written documentation of consent must be recorded in the patient’s source documents, 
study records and CRF indicating the date the consent was signed.  The patient should 
receive a signed copy of the consent form according to GCP guidelines. 
10.5 Confidentiality 
All information generated in this study is considered confidential, is subject to applicable 
privacy rules and regulations, and must not be disclosed to any person or entity not 
directly involved with the study unless prior written consent is gained from the Sponsor 
and otherwise except in accordance with applicable law or regulations.  However, 
authorized regulatory officials, IRB/EC/REB personnel, the Sponsor and its authorized 
representatives (as and to the extent authorized in the patient’s ICF) are allowed access to 
the records. 
Identification of patients in CRFs shall be by study assigned patient numbers only.  If 
required, the patient's full name may be made known to an authorized regulatory agency 
or other authorized official. 
10.6 Reporting of Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction (i.e., clinical hold) imposed by an applicable 
Regulatory Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the 
Sponsor must be informed immediately.  In addition, the Investigator will inform the 
Sponsor immediately of any serious breaches of this protocol or of ICH GCP of which 
the Investigator becomes aware. 


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11 RECORDS MANAGEMENT 
11.1 Source Documentation 
Source documents include hospital or clinical patient charts, pertinent historical medical 
records, laboratory test reports, ECG tracings, pathology reports, radiographs, etc.  All 
source documents must be legible.  Data reported in CRFs and evidence of patient’s 
informed consent must be documented in source documents.   
11.2 Study Files and Records Retention 
A CRF must be completed for each patient for whom informed consent for the study is 
obtained.  The CRFs must be maintained by properly trained and delegated site 
representatives.  The Principal Investigator has responsibility for ensuring the 
authenticity, accuracy, completeness and timeliness of all data collected in the CRF.  
CRFs must be signed by the Principal Investigator or by an authorized Sub-Investigator 
to attest that the information included is true.   
The study site will maintain a Site Trial Master File in accordance with GCPs. 
The Investigator shall retain all records for the longest of the following periods: 
(i) 15 years; (ii) the period of time that conforms to ICH GCP guidelines; (iii) the period 
of time required by applicable law or regulations, or (iv) the period of time specified in 
the Clinical Research Agreement. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring Procedures 
Sponsor appointed Site Monitor(s) must be allowed access to all study records, original 
source documents, and investigational products throughout the duration of the study.  
These personnel are responsible to assess compliance with the protocol, appropriate 
health authority regulations, ICH GCP guidelines, and Sponsor requirements. 
The study monitor is responsible for complying with the monitoring guidelines 
established by the Sponsor for the study, assessing the site’s needs, and liaising with the 
assigned Sponsor staff. 
If the Investigator withdraws from the study and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the Sponsor in writing so 
arrangements can be made to properly store the study materials. 
12.2 Auditing and Inspection Procedures 
The Sponsor’s Quality Assurance representatives, IRB/EC/REB reviewers, or inspectors 
from regulatory agencies may perform an audit or inspection at any time during or after 
completion of the clinical study.  All study-related documentation must be made 
available to the designated auditor.  In addition, representatives of applicable regulatory 


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health authorities may choose to inspect a study.  A Sponsor representative will be 
available to assist in the preparation for such an inspection.   
13 CHANGES IN STUDY CONDUCT 
13.1 Protocol Amendments 
Changes to the study protocol, except those intended to reduce immediate risk to study 
patients, may be made only by the Sponsor.  A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/EC/REB is notified within 5 days.  Any urgent safety measures taken by the 
Investigator to protect the study patients against any immediately life-threatening hazard 
must be reported immediately to the Sponsor. 
Any permanent change to the protocol must be handled as a protocol amendment.  The 
change and the justification will be documented in writing by the Sponsor, as an 
Administrative Letter or amended protocol.  Protocol amendments will be provided with 
a separate document describing each change and rationale.  The written Administrative 
Letter or amendment must be submitted to the IRB/EC/REB and the Investigator must 
await approval before implementing the changes.  The Sponsor will be responsible for 
submitting protocol amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/EC/REB, the Investigator, and/or the Sponsor, the 
amendment to the protocol substantially changes the study design and/or increases the 
potential risk to the patient and/or has an impact on the patient's involvement as a study 
participant, the currently approved written informed consent form will require similar 
modification.  In such cases, informed consents (revised as appropriate to address 
protocol amendments) will be obtained for patients enrolled in the study before continued 
participation. 
13.2 Protocol Deviations 
Prospective permission to deviate from the eligibility criteria for this protocol will not be 
provided by the Sponsor.  Study specified assessments should not be omitted and the 
study treatment regimen should not deviate from protocol specifications.  Minor, 
occasional adjustments in the clinic visit schedule may be necessary for logistical reasons 
(e.g., due to weather conditions) but must not become routine or systematically alter the 
study schedule.  The IRB/EC/REB should be informed of any deviations that may affect 
a patient’s treatment or informed consent, especially those increasing potential risks, 
which must receive prior written approval by the IRB/EC/REB.   
14 END OF TRIAL 
14.1 End of Trial in a European Union Member State  
End of Trial in a Member State of the European Union is defined as the time at which it 
is deemed that sufficient patients have been recruited and completed the study as stated in 


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the regulatory application [i.e., Clinical Trial Application (CTA)] and ethics application 
in the Member State. 
14.2 End of Trial in all other Participating Countries 
End of Trial in all other participating countries is defined as the time at which all patients 
enrolled in the study have completed the last study visit and data from those visits have 
been reviewed by the Investigator or designee. 
14.3 Premature Termination 
Premature termination of this study may occur at any time because of a regulatory 
authority decision, change in opinion of the IRB/EC/REB, drug safety concerns, or at the 
discretion of the Sponsor.  In addition, the Sponsor retains the right to discontinue 
development of sitravatinib at any time.  If termination becomes necessary, the Sponsor 
will inform the appropriate regulatory authorities of the termination and the reason.  The 
Principal Investigator will inform the IRB/EC/REB of the same.  In terminating the 
study, the Sponsor and the Principal Investigator will assure that adequate consideration 
is given to the protection of the patients’ interests. 
15 STUDY REPORT AND PUBLICATION POLICY 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication of study results will be governed by the applicable Clinical Research 
Agreement between the Sponsor and the Study Site and Investigator (as applicable). 


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APPENDIX 1. ECOG PERFORMANCE STATUS  
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair 
5 
Dead 


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APPENDIX 2.  MEDICATIONS TO BE AVOIDED OR USED WITH CAUTION 
DURING STUDY TREATMENT 
Bold font indicates medications that might be relatively commonly used. 
Italic font indicates medications for indications that are exclusionary for the current study 
or would likely result in discontinuation from study treatment with sitravatinib for 
management of a concurrent illness. 
MEDICATIONS THAT SHOULD BE AVOIDED 
Drugs with a Known Risk of Torsades de Pointes 
Amiodarone, anagrelide, arsenic trioxide, astemizole (off US market), azithromycin, 
bepridil (off US market), chloroquine, chlorpromazine, cilostazol, ciprofloxacin, 
cisapride (off US market), citalopram, clarithromycin, cocaine, disopyramide, 
dofetilide, domperidone (not on US market), donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin (off US market), 
grepafloxacin (not on US market), halofantrine (not on US market), haloperidol, 
ibogaine (not on US market), ibutilide, levofloxacin, levomepromazine / 
methotrimeprazine (not on US market), levomethadyl (off US market), levosulpiride 
(not on US market), mesoridazine (off US market), methadone, moxifloxacin, 
ondansetron, oxaliplatin, pentamidine, pimozide, probucol (off US market), 
procainamide, propofol, quinidine, roxithromycin (not on US market), sevoflurane, 
sotalol, sparfloxacin (off US market), sulpiride (not on US market), sultopride (non on 
US market), terfenadine (off US market), terlipressin (not on US market), terodiline 
(not on US market), thioridazine, vandetanib. 
 
 
 


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CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS 
Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and 
BCRP transporters 
Enzyme 
 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, 
posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan. 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan. 
Sensitive Substrates and Substrates with Narrow Therapeutic Index for the 
indicated CYP Enzymes  
Enzyme 
 
CYP2B6 
Bupropion. 
CYP2C8 
Repaglinide. 
CYP2D6 
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, 
nortriptyline, perphenazine, tolterodine, venlafaxine. 
CYP3A 
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, 
everolimus, felodipine, ibrutinib, indinavir, lomitapide, lovastatin, 
lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, ticagrelor, 
tipranavir, tolvaptan, triazolam, vardenafil. 
Drugs with Conditional Risk of Torsades de Pointes 
Amantadine, amisulpride (not on US market), amitriptyline, amphotericin B, 
atazanavir, bendroflumethiazide / bendrofluazide (not on US market), chloral hydrate, 
diphenhydramine, doxepin, esomeprazole, famotidine, fluoxetine, fluvoxamine, 
furosemide / frusemide, galantamine, garenoxacin (not on US market), 
hydrochlorothiazide, hydroxychloroquine, hydroxyzine, indapamide, itraconazole, 
ivabradine, ketoconazole, lansoprazole, loperamide, metoclopramide, metolazone, 
metronidazole, nelfinavir, olanzapine, omeprazole, pantoprazole, paroxetine, 
piperacillin/tazobactam, posaconazole, propafenone, quetiapine, quinine sulfate, 
ranolazine, sertraline, solifenacin, telaprevir, torsemide / torasemide, trazodone, 
voriconazole, ziprasidone. 
 


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APPENDIX 3.  ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES  
RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 guidelines will be used in 
the assessment of the point in time response for the on-study assessment.  Confirmation 
of response will not be used since there is only one on-study assessment. 
Categorizing Lesions at Baseline 
Measurable Lesions 
• Accurately measured in at least one dimension. 
• When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice 
thickness 5-8 mm), measured in the axial plane.  If the slice thickness is greater 
than 5 mm (including any inter-slice gap), the longest diameter must be at least 
twice the slice thickness. 
• Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when 
assessed by CT or MRI. 
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other lesions. 
Non-Measurable Disease 
• Lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) or truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal 
disease, lymphangitic involvement of skin or lung, and abdominal masses 
identified by physical exam that are not measurable by reproducible imaging 
techniques. 
• Bone disease is non-measurable with the exception of soft tissue components that 
can be evaluated by CT or MRI and meet the definition of measurability at 
baseline. 
• Previously irradiated lesions (or those subjected to other local treatment) are 
non-measurable unless it they have progressed since completion of treatment. 
 
 


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Normal Lesions 
• Non-malignant simple cysts should not be recorded either as target or non-target 
disease.  Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above. 
• Lymph nodes with short axis < 10 mm are considered normal and should not be 
followed as disease. 
Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  All required scans must be done within the window 
of time specified in the Schedule of Assessments prior to treatment.  If the baseline 
assessment is inadequate, subsequent statuses generally should be indeterminate. 
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial.  Once selected as a target lesion, a lesion 
remains target throughout the trial. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in 
the case of pathological lymph nodes for which the short axis should be recorded.  The 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions at baseline will be the basis for comparison to look for partial response at 
later assessments. 
• If 2 target lesions coalesce the longest diameter measurement of the coalesced 
mass is used.  If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be 
recorded.  If a target lesion becomes too small to measure, 0 mm should be 
recorded if the lesion is considered to have disappeared; otherwise a default value 
of 5 mm should be recorded. 
• When nodal lesions decrease to < 10 mm (normal), the actual measurement 
should still be recorded. 
 
 


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Non-Target Lesions 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
qualitative evaluations of status will be recorded.  Multiple non-target lesions in one 
organ may be recorded as a single item on the CRF (e.g., ‘multiple liver metastases’). 
Objective Response Status at Each Evaluation 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast.  If not, subsequent objective statuses may be indeterminate. 
Target Disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
< 10 mm).  All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of 
the sum of diameters of all target measurable lesions.  The short diameter is used in 
the sum for target nodes, while the longest diameter is used in the sum for all other 
target lesions.  All target lesions must be assessed. 
• Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target 
lesions must be assessed.  Stable can follow PR only in the rare case that the sum 
increases by less than 20% from the nadir, but enough that a previously documented 
30% decrease no longer holds. 
• Progressive Disease (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy) with a minimum absolute increase of 5 mm. 
• Indeterminate: Progression has not been documented, and  
− one or more target lesions have not been assessed, 
− or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
− or one or more target lesions cannot be measured accurately (e.g., poorly 
visible unless due to being too small to measure), 
− or one or more target lesions were excised or irradiated and have not 
reappeared or increased. 
 
 


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Non-Target Disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
• PD: Unequivocal progression of pre-existing lesions.  Generally, the overall 
tumor burden must increase sufficiently to merit discontinuation of therapy.  In the 
presence SD or PR in target disease, progression due to unequivocal increase in 
non-target disease should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target 
sites were not assessed or assessment methods were inconsistent with those used at 
baseline. 
New Lesions 
 The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion 
is equivocal, for example due to its small size, continued assessment will clarify the 
etiology.  If repeat assessments confirm the lesion, then progression should be recorded 
on the date of the initial assessment.  A lesion identified in an area not previously 
scanned will be considered a new lesion. 
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
Point in Time Objective Response Guide 
Target 
Lesions 
Non-Target 
Lesions 
New Lesion 
Point in Time 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 


516-002 – Phase 2 in Locally-Advanced ccRCC 
Confidential
Sitravatinib (MGCD516) with Nivolumab 
Page 87 of 88
 
 
 
Mirati Therapeutics, Inc. 
 
 
 
 
 
 
 
 
Subjective Progression 
Patients requiring discontinuation of treatment due to worsening health status attributable 
to advancement of the malignancy under study but without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the End of Study CRF as off treatment due to Global Deterioration of Health 
Status. 
 
 


516-002 – Phase 2 in Locally-Advanced ccRCC 
Confidential
Sitravatinib (MGCD516) with Nivolumab 
Page 88 of 88
 
 
 
Mirati Therapeutics, Inc. 
 
 
 
 
 
 
 
 
APPENDIX 4.  DOSE DE-ESCALATION DECISION TABLE USING THE mTPI 
METHOD 
The table below will be used for decision making with regards to potential sitravatinib 
starting dose de-escalation in subsequent patients.  The assessment is based on the 
number of patients with toxicity at a given dose as defined in Section 9.1 and assumes a 
maximum toxicity level of no more than 20% at the tolerated dose.  The letters in 
different colors are computed based on the decision rules under the mTPI method (Ji-
2010) and represent different dose-finding actions which include: S = Stay at the current 
dose; D = De-escalate to the next lower dose; and U = The current dose in unacceptably 
toxic. 
 
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
0 S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
1 DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
2
DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
3
DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
4
DU DU DU DU DU DU D
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
5
DU DU DU DU DU DU DU DU DU S
S
S
S
S
S
S
S
S
S
S
S
6
DU DU DU DU DU DU DU DU DU DU DU S
S
S
S
S
S
S
S
S
7
DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
S
S
S
S
8
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
9
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
10
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
11
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
12
DU DU DU DU DU DU DU DU DU DU DU DU DU DU
13
DU DU DU DU DU DU DU DU DU DU DU DU DU
14
DU DU DU DU DU DU DU DU DU DU DU DU
15
DU DU DU DU DU DU DU DU DU DU DU
16
DU DU DU DU DU DU DU DU DU DU
17
DU DU DU DU DU DU DU DU DU
18
DU DU DU DU DU DU DU DU
19
DU DU DU DU DU DU DU
20
DU DU DU DU DU DU
21
DU DU DU DU DU
22
DU DU DU DU
23
DU DU DU
24
DU DU
25
DU
Number of patients treated at current dose
Number of  toxicities
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
Tolorated Dose = ≤ 20% toxicities
Sample Size = 25
Epsilon1 = 0.05
Epsilon2 = 0.05

SAP_001.pdf: 
Protocol Number:  516-002 
 
Official Title:  A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients 
Undergoing Nephrectomy for Locally-Advanced Clear Cell Renal Cell 
Carcinoma 
 
NCT Number:  NCT03680521 
 
Document Date:  01-Jul-2020 


S p o n s or: Mir ati T h er a p e uti c s, I n c
St ati sti c al A n al y si s Pl a n
Pr ot o c ol n o: 5 1 6- 0 0 2
V er si o n  D at e: 0 1 J ul 2 0 2 0
P R S 0 0 5 T 1 7 G
P a g e 1 of 2 9
Stri ctl y C o nfi d e nti al.  © 2 0 1 7, P R A H e alt h S ci e n c e s. All ri g ht s r e s er v e d.
St ati sti c al A n al y si s Pl a n
S p o n s or:
Mir ati T h er a p e uti c s, I n c
Pr ot o c ol N o:
5 1 6- 0 0 2
P R A Pr oj e ct I d:
M R T 1 6 0 0 2- 5 1 6 0 0 2
V er si o n D at e:
1 6- M a y- 2 0 1 8
V er si o n N o.:
3. 0
Titl e:
A P h a s e 2 St u d y of Sitr a v ati ni b i n C o m bi n ati o n wit h Ni v ol u m a b i n P ati e nt s 
U n d er g oi n g N e p hr e ct o m y f or L o c all y- A d v a n c e d Cl e ar C ell R e n al C ell 
C ar ci n o m a
C R F V er si o n
N o./ D at e:
1. 0/ 2 9- A u g- 2 0 1 8
S A P N o.
Fi n al/ 0 1- J ul- 2 0 2 0
1.  
A p pr o v al s
S p o n s or
S p o n s or N a m e:
Mir ati T h er a p e uti c s, I n c.
 
Si g n at ur e / D at e:
Si g n at ur e/ D at e:
P R A
Si g n at ur e/ D at e:
 
Si g n at ur e/ D at e:
, 6 0 8/ 3 2 5 Ā- 5 9 1 4 6 7 1 Ā.,( Ā % #)*" $) Ȁ'!" $ Ȁ $' % % Ȁ'! $' Ȁ! %* #)" + %* & $*


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Statistical Analysis Plan
Protocol no: 516-002
Version Date: 01 Jul 2020
PRS 005 T 17 G
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Table of Contents
1. 
Approvals .......................................................................................................................................................................... 1 
2. 
Purpose .............................................................................................................................................................................. 4 
3. 
Scope ................................................................................................................................................................................... 4 
4. 
Introduction ..................................................................................................................................................................... 4 
5. 
Study Objectives and Endpoints .............................................................................................................................. 4 
5.1. 
Objectives ..................................................................................................................................................................... 4 
5.1.1. 
Primary Objective ................................................................................................................................................ 4 
5.1.2. 
Secondary Objectives .......................................................................................................................................... 4 
5.1.3. 
Exploratory Objectives....................................................................................................................................... 5 
5.2. 
Endpoints ..................................................................................................................................................................... 5 
5.2.1. 
Primary Endpoint ................................................................................................................................................. 5 
5.2.2. 
Secondary Endpoints .......................................................................................................................................... 5 
5.2.3. 
Exploratory Endpoints ....................................................................................................................................... 5 
6. 
Study Design .................................................................................................................................................................... 5 
6.1. 
Prior to Start of Treatment ................................................................................................................................. 11 
6.2. 
Segment 1 ................................................................................................................................................................... 11 
6.3. 
Segment 2 ................................................................................................................................................................... 11 
6.4. 
Surgery, EOS and Follow-up ............................................................................................................................... 11 
6.5. 
Sitravatinib Dose De-escalation ........................................................................................................................ 13 
6.6. 
Hypothesis and Sample Size Considerations ............................................................................................... 13 
6.7. 
Randomization ......................................................................................................................................................... 13 
7. 
Analysis Populations .................................................................................................................................................. 14 
7.1. 
Screened Population .............................................................................................................................................. 14 
7.2. 
Enrolled Population ............................................................................................................................................... 14 
7.3. 
Clinical Activity Evaluable Population ........................................................................................................... 14 
7.4. 
Safety Population .................................................................................................................................................... 14 
7.5. 
Pharmacokinetic Evaluable Population ......................................................................................................... 14 
7.6. 
Pharmacodynamic Evaluable Population ..................................................................................................... 14 
8. 
Endpoint Definitions................................................................................................................................................... 14 
8.1. 
Efficacy Variables .................................................................................................................................................... 15 
8.1.1. 
Percentage of Patients Achieving a Point-in-time Objective Response Prior to Surgery ..... 15 
8.1.2. 
Disease-Free Survival (DFS) .......................................................................................................................... 15 
8.1.3. 
Time-to-Surgery ................................................................................................................................................. 15 
8.2. 
Study Drug Exposure Variables ........................................................................................................................ 15 
8.2.1. 
Study Treatment Duration ............................................................................................................................. 15 
8.2.2. 
Total Number of Injections of Nivolumab Received ............................................................................ 16 
8.2.3. 
Days on sitravatinib .......................................................................................................................................... 16 
8.2.4. 
Cumulative Dose Received ............................................................................................................................. 16 
8.2.5. 
Dose Intensity ...................................................................................................................................................... 16 
8.3. 
Safety Variables ....................................................................................................................................................... 16 
8.3.1. 
Adverse Events .................................................................................................................................................... 17 
8.3.1.1. 
Baseline Signs and Symptoms .................................................................................................................. 17 
8.3.1.2. 
Treatment-Emergent AEs (TEAEs) ........................................................................................................ 17 
8.3.1.3. 
Adverse Events of Special Interest (AESI) .......................................................................................... 17 
8.3.1.4. 
Immune-related Adverse Event (irAE)................................................................................................. 17 
8.3.2. 
Physical Examinations ..................................................................................................................................... 17 
8.3.3. 
Vital Signs .............................................................................................................................................................. 17 
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8.3.4. 
Clinical Laboratory Assessments ................................................................................................................. 17 
8.3.5. 
Electrocardiograms ........................................................................................................................................... 18 
8.3.6. 
Echocardiograms ................................................................................................................................................ 18 
8.3.7. 
Prior and Concomitant Medications ........................................................................................................... 18 
8.4. 
Other Endpoints ...................................................................................................................................................... 19 
9. 
Data Handling ................................................................................................................................................................ 19 
9.1. 
Missing Dates ............................................................................................................................................................ 19 
9.2. 
Protocol Deviations ................................................................................................................................................ 20 
10. 
Interim Analyses...................................................................................................................................................... 20 
11. 
Statistical Methods ................................................................................................................................................. 20 
11.1. 
Patient Disposition ............................................................................................................................................ 21 
11.2. 
Important Protocol Deviations ..................................................................................................................... 21 
11.3. 
Treatments ............................................................................................................................................................ 21 
11.3.1. 
Prior and Concomitant Medications ........................................................................................................... 21 
11.4. 
Demographic and Baseline Characteristics ............................................................................................. 21 
11.5. 
Medical History ................................................................................................................................................... 21 
11.6. 
Efficacy Analyses ................................................................................................................................................ 22 
11.6.1. 
Primary Variable ................................................................................................................................................ 22 
11.6.2. 
Secondary Variables .......................................................................................................................................... 22 
11.6.2.1. 
Time to Surgery: ............................................................................................................................................ 22 
11.6.2.2. 
DFS: ..................................................................................................................................................................... 22 
11.7. 
Safety Analyses .................................................................................................................................................... 22 
11.7.1. 
Extent of Study Drug Exposure .................................................................................................................... 22 
11.7.2. 
Adverse Events .................................................................................................................................................... 23 
11.7.3. 
Deaths and Serious Adverse Events ........................................................................................................... 24 
11.7.4. 
Laboratory Data .................................................................................................................................................. 24 
11.7.4.1. 
Hematology ...................................................................................................................................................... 25 
11.7.4.2. 
Chemistry .......................................................................................................................................................... 25 
11.7.4.3. 
Urinalysis .......................................................................................................................................................... 25 
11.7.4.4. 
Thyroid .............................................................................................................................................................. 25 
11.7.4.5. 
CTCAE Coding of Laboratory Data ......................................................................................................... 25 
11.7.4.6. 
Hy’s Law ............................................................................................................................................................ 26 
11.7.5. 
Vital Signs .............................................................................................................................................................. 26 
11.7.6. 
Physical Examinations, ECGs, and Other Observations Related to Safety .................................. 26 
11.7.6.1. 
Physical Examination ................................................................................................................................... 26 
11.7.6.2. 
Electrocardiogram ........................................................................................................................................ 26 
11.7.6.3. 
Echocardiogram ............................................................................................................................................. 27 
11.7.6.4. 
Pregnancy Test ............................................................................................................................................... 27 
11.7.6.5. 
Long Term Follow-up .................................................................................................................................. 27 
11.7.6.6. 
Death Report ................................................................................................................................................... 27 
12. 
Validation ................................................................................................................................................................... 27 
13. 
References .................................................................................................................................................................. 27 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 28 
 
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2.
Purpose
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and
analyses of data collected under Mirati Therapeutics, Inc Protocol 516-002.
3.
Scope
This plan is a living document that supplements the study protocol for statistical analysis-related aspects.
The SAP outlines the following:
x
Study objectives and endpoints
x
Study design
x
Analysis populations
x
Endpoint and variable definitions
x
Data handling
x
Data review
x
Statistical methods
Deviations from the statistical analysis plan will be described in the Clinical Study Report (CSR).
4.
Introduction
This SAP describes the statistical methods to be used during the analysis and reporting of data collected 
under Mirati Therapeutics, Inc. Protocol 516-002.
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol dated 16 May 2018 and CRF version 1.0 dated 
29 August 2018. Any further changes to the protocol or CRF may necessitate updates to the SAP.
The SAP will be developed in two stages. An initial SAP will be finalized based on the current protocol 
and CRF, so that programming may be created. Changes following approval of the SAP will be tracked in 
the SAP Change Log. A final version of the SAP, known as the amended SAP, will be issued prior to 
database lock.
Each version of the SAP requires approval by the project manager and the sponsor.
5.
Study Objectives and Endpoints
5.1.
Objectives
5.1.1.Primary Objective
x
To evaluate the preoperative clinical activity of the combination of sitravatinib and nivolumab in 
patients with locally-advanced clear-cell renal cell carcinoma (ccRCC) undergoing nephrectomy.
5.1.2.Secondary Objectives
x
To evaluate the safety and tolerability of the combination regimen in the selected population.
x
To characterize the baseline tumor-related immune profile in patients with RCC.
x
To determine the immune effects of sitravatinib and the combination regimen in patients with 
ccRCC.
x
To evaluate the pharmacokinetics (PK) of sitravatinib administered alone and in combination with 
nivolumab in patients with ccRCC.
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x
To characterize the time to surgery.
x
To evaluate secondary efficacy endpoints with the combination regimen in the selected 
population.
5.1.3.Exploratory Objectives
x
To evaluate changes in gene expression and the T-cell repertoire in response to therapy in 
patients with ccRCC.
5.2.
Endpoints
5.2.1.Primary Endpoint
Percentage of patients achieving a point in time objective response (either CR or PR) prior to surgery.
5.2.2.Secondary Endpoints
x
Safety characterized by type, incidence, severity, timing, seriousness and relationship to study
treatment of adverse events (AEs) and laboratory abnormalities.
x
Descriptive characterization of immune cell populations in the tumor and/or peripheral blood at 
baseline.
x
Temporal changes in PD-L1 expression, selected cytokines and immune cell populations in the 
tumor and/or peripheral blood (including myeloid-derived suppressor cells [MDSCs], regulatory T-
cells [Tregs], CD4+ [helper] and CD8+ [cytotoxic] T-cells, and the ratio of Type1:Type 2 tumor-
associated macrophages).
x
Blood plasma concentration of sitravatinib.
x
Time-to-surgery.
x
Disease free-survival (DFS).
5.2.3.Exploratory Endpoints
x
Gene expression and T-cell receptor sequencing.
6.
Study Design
Study 516-002 is an open-label, non-randomized, preoperative window of opportunity Phase 2 study of 
sitravatinib and nivolumab in the neoadjuvant setting for the treatment of patients with locally-advanced 
clear cell renal cell carcinoma (ccRCC) undergoing nephrectomy. The study will enroll approximately 25 
subjects with imaging results consistent with a clinical diagnosis of locally-advanced renal cancer in order 
to identify and treat with the study drug treatment 18 clinical activity evaluable patients with ccRCC. Study 
drug treatment will be conducted in 2 sequential preoperative treatment segments. During the first 
segment, patients will receive single-agent sitravatinib for 2 weeks, followed by a renal biopsy. Patients 
will then begin the second segment, consisting of combination treatment with sitravatinib and nivolumab 
for at least 4 weeks (and up to a maximum of 6 weeks to allow for flexibility with the scheduling of the 
planned nephrectomy). This segment will be followed by planned surgical resection by way of standard-
of-care partial or radical nephrectomy. Patients will be followed for survival.
The primary objective is to evaluate the clinical activity of the combination regimen using percentage of 
patients with ccRCC achieving a point in time objective response (either CR or PR) prior to surgery with 
the combination treatment of sitravatinib and nivolumab. Objective responses will be assessed in 
accordance with RECIST 1.1. Secondary objectives include evaluation of safety and determination of 
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immune effects of the combination treatment, along with pharmacokinetics (PK) of sitravatinib. The 
Schedule of Assessments to be performed in the study is presented in Table 1. The schedule for 
collection of PK/Pharmacodynamics and ECG assessment time points are presented in Table 2.
Further detail on sample collection and analyses are presented in Section 7.3 of the protocol and the 
Study Laboratory Manual. The study will collect blood and tumor tissue collections as described in the 
Schedule of Assessments (Table 1) depicted and the study schema in Figure 1. Protocol guidance of 
special interest is listed below.
x
Freshly biopsied tumor tissue collection at pre-treatment is required for study drug treatment. 
Similarly, the on-treatment mid-study tumor biopsy on D14 is highly desirable for all treated 
patients. Archival samples cannot be submitted in lieu of pre-treatment samples. All attempts 
should be made to biopsy the same lesion on the mid-study biopsy as the initial biopsy.
x
Tumor gene expression in freshly biopsied tumor samples will be determined using next 
generation sequencing performed by a central laboratory. For patients in whom tumor tissue has
previously been tested using next generation sequencing, presence of specific tumor gene 
mutations and estimation of total mutation burden will be collected in the case report form (CRF).
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Table 1:
Schedule of Assessments
Study Assessments
Screening
Initial 
Biopsy1
Neoadjuvant Tx
(6-82 wks)
Preop 
Rebaseline
Surgery
EOS/
Withdrawal4
Long-term 
Follow-Up
D-28 to 
Initial 
Biopsy
D-4 (±3)
D1
D143
(±1)
D15
(± 2)
D29 
(±2)
D432
(±2)
≤3 dys of 
Surgery
Informed Consent5
X
Collection of Tumor Tissue6
X
X
X
Medical History, Disease History, 
Prior Therapy 
X
Physical Exam7 including Vital Signs 
& ECOG PS
X
X
Abbreviated Physical Exam8
including Vital Signs
X
X
X
(X)
X
Hematology and Serum Chemistry9,10
X
X
X
X
X
(X)
X
X
Coagulation and Urinalysis9,10
X
As clinically indicated
Coagulation 
only
As clinically indicated
Thyroid Function Test9,10
X
X
X
Pharmacokinetic, Pharmacodynamic, 
and Baseline ctDNA Blood Samples, 
and Triplicate 12-Lead ECG11
See Table 2
See Table 2
Single 12-Lead ECG11
X
As clinically indicated
X
Echocardiogram
X
X
X
Disease Assessment12
X
X
Pregnancy Test13
X
As clinically indicated
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Table 1:
Schedule of Assessments (Continued)
Study Assessments
Screening
Initial 
Biopsy1
Neoadjuvant Tx
(6-82 wks)
Preop 
Rebaseline
Surgery
EOS/
Withdrawal4
Long-term 
Follow-Up
D-28 to 
Initial 
Biopsy
D-4 (±3)
D1
D143
(±1)
D15
(± 2)
D29 
(±2)
D432
(±2)
≤3 dys of 
Surgery
Sitravatinib Dispensing and/or 
Reconciliation
X
X
Preop hold for 
2 dys from 
Surgery16
Surgery 
Hold
Nivolumab Administration
X
X
(X)
AEs14 and Concomitant Medications
SAEs only
Throughout
Long-Term Follow-Up15
X
1.
On the Initial Biopsy Visit, laboratory blood assessments completed in the previous week do not need to be repeated. The Initial Biopsy will preferably be 
scheduled for D-4 (±3); however, to allow flexibility for logistical reasons, this period can include up to 2 weeks from D1 (including D-14).
2.
Neoadjuvant therapy will be administered for at least 6 weeks (unless treatment discontinuation is warranted), and up to a maximum of 8 weeks, to allow for 
flexibility with the scheduling of the nephrectomy (surgery). Consequently, nivolumab will be administered as neoadjuvant therapy for at least 2 injections, and up 
to a maximum of 3 injections. The third injection will only be administered if the subject’s planned day of Surgery is at least one week after D43 and further 
treatment is not contraindicated [e.g., interruptions for adverse events (AEs)].
3.
D14 visit (±1), which has for purpose the mid-study biopsy, must occur prior to first nivolumab injection on D15 (±2).
4.
End of Study (EOS)/Withdrawal: Laboratory blood assessments completed in the previous 4 weeks do not need to be repeated. EOS visit must occur at least 28 
days after last dose of study drug or surgery, whichever occurs last.
5.
Informed Consent: May be performed within 28 days prior to the first dose of sitravatinib therapy on D1 and must be completed prior to initiation of any study 
specific assessments.
6.
Collection of Tumor Tissue: Tumor tissue will be collected from initial and mid-study biopsies and surgical sample. Fresh tumor biopsies are to be collected on 
study; archival tissue will not be accepted as an alternative. The tumor biopsy collected on the Initial Biopsy Visit will confirm the histology of the renal cancer. 
Tumor tissue will be collected and used to assess immune effects through tissue biomarkers prior to and during and following treatment. Parameters may include, 
but are not limited to, quantification of tissue immune cell populations by flow cytometry including T-cell subpopulations (CD8+, CD8+/Ki67+ and regulatory T-
cells [Tregs]), natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs) and macrophages; immunohistochemistry and/or immunofluorescence for 
assessment of PD L1 status and characterization of immune cell populations; tumor gene expression analysis; and DNA sequencing to assess T-cell clonality. In 
addition, next generation sequencing (NGS) analyses for tumor mutations and tumor mutation burden may be assessed using tissue from the surgical sample.
7.
Physical Examinations: A complete physical examination required at Screening and EOS/Withdrawal only. Height will be recorded at screening only. All other 
evaluations will be symptom-directed, abbreviated evaluations. Vital signs include weight, temperature, blood pressure, and pulse rate to be assessed prior to 
dosing as indicated.
8.
Abbreviated Physical Exam includes vital signs (weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated) and symptom-
directed evaluation.
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9.
Selected D1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.
10. Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations will be performed by local laboratories.
11. Pharmacokinetic (PK) Blood Samples: Blood samples for PK measurements will be collected as outlined in Table 2.
Pharmacodynamic Blood Samples: Blood samples will be collected for the assessment of immune effects through circulating biomarkers prior to and during and 
following treatment as outlined in Table 2. Parameters may include, but are not limited to, quantification of circulating immune cell populations by flow cytometry 
including T-cell subpopulations (CD4+, CD4+/Ki67+, CD8+, CD8+/Ki67+ and Tregs), NK cells, and MDSCs; blood levels of selected cytokines and chemokines 
including IFN-γ, IL-1ß, IL-6, IL-8, IL-12, IL-18 and CXCL10 (IP-10); and DNA sequencing to assess T-cell clonality.
Baseline ctDNA Blood Samples: NGS analyses for tumor mutations and tumor mutation burden may be assessed at baseline using ctDNA as outlined in Table 2.
12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 2. In addition, single ECGs are to be performed as clinically indicated. 
Assessments will include an evaluation of RR, QT, and QTc intervals. In case RR interval cannot be machine-read, ventricular heart rate should be reported 
instead.
12. Disease Assessments will occur at the following times:
a)
during screening (within 28 days of D1),
b)
preoperatively (within 1 week prior to the surgery).
At screening/baseline, assessments are to include evaluation of any superficial lesions, Computed Tomography Scan (CT) with contrast or X-ray (radiography) of 
the chest, Magnetic Resonance Imaging (MRI) with and without gadolinium or CT abdomen, as well as, if clinically indicated, MRI of the brain and a chest x-ray. 
The subsequent disease assessment should include all sites of disease identified at baseline or suspected to have developed. More detailed guidance on exceptional 
circumstances is provided in the protocol.
13. Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at screening will be 
required. The informed consent process must include discussion of the risks associated with pregnancy and adequate contraception methods. Additional pregnancy 
testing may be necessary if required by local practices or regulations, or if potential pregnancy is suspected.
14. Adverse Events: SAEs (serious adverse events) will be reported from the time of informed consent until at least 28 days after the last administration of sitravatinib 
or nivolumab. Ongoing SAEs should be followed until resolution or stabilization to a chronic condition. AEs will be reported from the day of the initial biopsy until 
at least 28 days after last dose of study drug.
15. Long Term Follow-up: Survival status will be collected by review of medical records or telephone contact with the patient or treating healthcare professional 
approximately every 6 months from EOS visit for up to 3 years or more until death, disease recurrence or loss to follow-up. Disease recurrence will be based on 
imaging assessments performed off study per standard of care after nephrectomy.
16. 2-day preoperative hold such that the last dose of any drug is administered a minimum of 72 hours prior to surgery.
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Table 2:
Schedule of Pharmacokinetic, Pharmacodynamic, Baseline ctDNA, and Triplicate ECG Assessments
Screening
Neoadjuvant Tx
Preop Rebaseline
D-28 to Initial 
Biopsy
D1
D15 (± 2)
D29 (± 2)
D43 (± 2)
≤ 3 dys of Surgery
Collection Time and 
Allowable Window
Pre-dose
(-0.5-0 hour)
30 min
(± 10 min)
4 hour
(2-6 hour)
Pre-dose
(-2-0 hour)
Pre-dose
(-2-0 hour)
Pre-dose
(-2-0 hour)
PK Blood Samples1,2,3
X
X
X
X
X (whichever visit occurs first)
Flow Cytometry Blood 
Samples3,4
X
>2 dys from D1
X
X
X
X (whichever visit occurs first)
Protein and Cytokine 
Biomarkers Blood Samples3,4
X
X
X
X (whichever visit occurs first)
TCR Sequencing Blood 
Samples3,4
X
X
Baseline ctDNA Blood 
Samples4,5
X
Triplicate ECG6
X
X
X
1.
Unscheduled PK blood samples should be drawn in association with two kinds of safety events: 1) as soon as possible after a Serious Adverse Event (SAE), 
and 2) at a clinic visit at least one week following a dose modification of sitravatinib.
2.
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. Sitravatinib dosing and sampling should precede nivolumab infusion.
3.
Pharmacokinetic, pharmacodynamic, and baseline ctDNA blood samples should be collected as detailed in the study Lab Manual and in the study kit.
4.
Blood for Pharmacodynamics: Immune effects will be evaluated through circulating prior to and during and following treatment. Blood samples will be 
collected for the assessment of parameters that may include, but are not limited to, quantification of circulating immune cell populations by flow cytometry 
including T-cell subpopulations (CD4+, CD4+/Ki67+, CD8+, CD8+/Ki67+ and Tregs), NK cells, and MDSCs; blood levels of selected cytokines and 
chemokines including IFN-γ, IL-1ß, IL-6, IL-8, IL-12, IL-18 and CXCL10 (IP-10); and DNA sequencing to assess T-cell clonality.
5.
Baseline ctDNA Blood Samples: NGS analyses for tumor mutations and tumor mutation burden may be assessed at baseline using ctDNA.
6.
ECGs should be taken in triplicate, each reading approximately 2 minutes apart. On D1 only, two sets of triplicate ECGs should be done within 1 hour prior 
to dosing (e.g., at 30-minute intervals) to firmly establish the baseline for the patient. In general, ECGs should be performed prior (within -30 to -5 minutes) 
to the respective PK blood collection.
x
Example for D1 pre-dose ECG/PK assessments: ~ -1.0 hour (Triplicate ECGs); ~ -30 minutes (Triplicate ECGs); ~ -15 minutes (Vitals/PK).
x
Example for all other pre-dose ECG/PK assessments: ~ -30 minutes (Triplicate ECGs); ~ -15 minutes (Vitals/PK).
Assessments will include evaluation of RR, QT and QTc intervals. In case RR interval cannot be machine-read, ventricular heart rate should be reported instead.
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6.1.
Prior to Start of Treatment
All enrolled patients will have met all entry criteria and have completed baseline procedures including 
disease assessments and blood collection for baseline immune characteristics and scheduled to undergo 
an initial diagnostic tumor biopsy of their renal lesion. Patients with a histology other than ccRCC will 
proceed to their End of Study (EOS) visit following the histology results, with no treatment with study 
drugs. Subjects with a clear cell histology will proceed to the study drug treatment which will be 
conducted in 2 sequential preoperative treatment segments as described in the following sections.
6.2.
Segment 1
The first segment of treatment period will consist of a 2-week treatment with single-agent sitravatinib. 
Sitravatinib will be administered at a dose of 120 mg orally QD, on a continuous daily dosing regimen. 
After completion of the 2-week dosing period, patients will undergo a renal biopsy.
6.3.
Segment 2
The second segment of treatment period will consist of a combination treatment with sitravatinib and 
nivolumab for at least 4 weeks (and up to a maximum of 6 weeks to allow for flexibility with the scheduling 
of the nephrectomy). Sitravatinib will be administered at a dose of 120 mg orally daily, on a continuous 
daily dosing regimen for this entire segment. Nivolumab will be administered, in accordance with 
approved labeling, by IV infusion, 240 mg every Q2W (namely, on D15, D29, and potentially D43). 
Patients will receive the nivolumab injection on D43 only if their surgery is expected to occur more than a 
week from that date. Patients will be subject to a 2-day preoperative hold of all study drugs prior to 
surgery (such that the last dose of any drug is administered a minimum of 72 hours prior to surgery).
6.4.
Surgery, EOS and Follow-up
After completion of neoadjuvant therapy, patients will undergo planned nephrectomy. Patients will have 
their EOS visit following surgery, with no further study drug administration. Patients will be followed for 
disease-free survival for up to 3 years or more until either death, disease recurrence or loss to follow-up.
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Figure 1: Study Schema
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6.5.
Sitravatinib Dose De-escalation
Based on available safety and pharmacokinetic data from an ongoing Phase 1b trial in patients with 
various solid tumors and an ongoing Phase 2 trial in combination with nivolumab in patients with NSCLC, 
the starting dose and regimen recommended is 120 mg sitravatinib administered daily. If unacceptable 
toxicity is observed, the starting dose may be decreased during the study. Starting doses in the event of 
dose de-escalation will be clarified in the amended SAP as necessary.
The Modified Toxicity Probability Interval (mTPI) method (Ji-2010) will be used to set rules on a dose 
de-escalation plan to monitor and limit toxicity of the combination regimen in the neoadjuvant setting. The 
first assessment will occur after the first 6 patients have completed 3 weeks on therapy, or earlier if 2 or 
more patients with toxicity are suspected. Subsequent assessments will occur at intervals that include up 
to 6 additional patients completing the observation period. Assuming a maximum toxicity level of no more 
than 20% at the tolerated dose, the dose will be decreased if more than 2 patients with toxicities are 
observed in the first 6 patients (Refer to Appendix 4 of the protocol for the dose de-escalation table). For 
the purposes of decision making for dose de-escalation, patients with the following treatment-related 
adverse events will be used to determine the number of patients having toxicity:
1.
Non-hematologic Grade 4 adverse event.
2.
Non-hematologic Grade 3 adverse event with the following exceptions:
a.
Grade 3 nausea, vomiting or diarrhea that is manageable with supportive care and persists 
for ≤ 72 hours;
b.
Grade 3 electrolyte abnormality that is not clinically complicated and resolves spontaneously 
or with conventional medical treatment within 72 hours;
c.
Grade 3 fatigue that persists for ≤ 8 days;
d.
Grade 3 amylase or lipase elevation that is not associated with symptoms or clinical 
manifestations of pancreatitis.
3.
Surgical delay of greater than 2 weeks and due to toxicity.
Study drug toxicities and dose de-escalations that occur during the study will be recorded and 
documented by the sponsor. In the proposed plan, there is no dose escalation, and surgical delay will be 
assessed only for those patients who have already undergone surgery.
6.6.
Hypothesis and Sample Size Considerations
With currently available treatments, the percentage of patients with a point in time objective response 
prior to surgery is assumed to be 5% (p0); thus, this rate is considered uninteresting. The target 
percentage of patients with a point in time objective response prior to surgery using sitravatinib and 
nivolumab in this study is assumed to be 30% (p1). Controlling for a Type 1 error (α) of 0.05, and using an 
exact test (two-sided), with 18 clinical activity evaluable patients, we have 80% power to rule out a 
percentage of patients with a point in time objective response prior to surgery of 5% assuming percentage 
of patients with a point in time objective response prior to surgery of 30%. 
Assuming a non-evaluable rate between 25%-30% from enrolled patients to clinical activity evaluable 
patients, the study will enroll approximately 25 patients in order to get 18 clinical activity evaluable 
patients. Additional subjects may be enrolled for a total of 12 subjects with complete tumor tissue 
collection (collected from initial and mid-study biopsies and surgical sample).
6.7.
Randomization
Random assignment to treatment arm is not being used in this study. Enrolment decisions will be 
determined by the site where the patient is enrolled as described in Section 6.0.
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7.
Analysis Populations
7.1.
Screened Population
The Screened population is defined as all patients who sign an informed consent for the study. Screen 
failure patients and disposition summaries will be displayed using the Screened Population. .
7.2.
Enrolled Population
The Enrolled population is defined as all patients who sign an informed consent and meet inclusion and 
exclusion criteria. Percentages in the disposition summaries will use the Enrolled Population as the 
denominator.
7.3.
Clinical Activity Evaluable Population
The Clinical Activity Evaluable population will include patients who 1) have measurable disease (per 
RECIST 1.1) at baseline, 2) receive at least one dose of both sitravatinib and nivolumab, 3) have their on-
study disease assessment prior to surgery, and 4) undergo surgery and are deemed disease-free (i.e. 
non-metastatic) after surgery.
This population will be used to present tumor responses.
7.4.
Safety Population
The Safety population is defined as all patients who received at least 1 dose of either sitravatinib or 
nivolumab. The Safety population will be used for all safety analyses including serious adverse events 
(SAE) summaries.
7.5.
Pharmacokinetic Evaluable Population
The Pharmacokinetic Evaluable population will consist of all patients who received treatment with 
sitravatinib and have sufficient concentration-time data to permit calculation of PK parameters for 
sitravatinib. For patients who are noncompliant with respect to administration of sitravatinib, or for patients 
with incomplete data, a decision as to their inclusion in the analysis will be made on a case-by-case 
basis. Details of this analysis will be provided in the PKAP.
7.6.
Pharmacodynamic Evaluable Population
The Pharmacodynamic Evaluable population will consist of all patients who receive at least 1 dose of 
either sitravatinib or nivolumab for whom sufficient pharmacodynamic data are available. Details of this 
analysis will be provided in the PDAP.
8.
Endpoint Definitions
The term “baseline” is defined as the last pre-dose assessment, (includes screening and Study Day 1 
pre-dose assessment which would represent a 29-day window). Unscheduled visits assessments will be 
considered for baseline. If assessment time is missing and there is no way to determine if the assessment 
occurred before or after study drug administration, Study Day 1 assessments will be considered for 
baseline.
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8.1.
Efficacy Variables
With regard to efficacy endpoints, the term “on-study” includes the period from signing of the informed 
consent until End of Study evaluation. 
For the investigator assessment, the date of response or progression will be determined using the latest 
Date of Assessment recorded among the radiologic modalities included for the applicable Time Point 
Assessment.
8.1.1.Percentage of Patients Achieving a Point-in-time Objective 
Response Prior to Surgery
x
Single point in time objective response to treatment at the Preoperative Rebaseline visit will be 
categorized in accordance with RECIST 1.1. The primary endpoint of this study is percentage of 
patients with ccRCC achieving a point in time objective response (either CR or PR) prior to 
surgery with the combination treatment of sitravatinib and nivolumab.
x
Additionally, information regarding pathologic complete response (pCR) will be collected in the 
CRF and will be descriptively summarized. The determination of pCR to detect residual disease
in kidney and regional lymph nodes will be based on the pathology examination of the surgical 
sample. pCR is defined as the absence of residual invasive disease on evaluation of the 
complete resected renal specimen and all sampled regional lymph nodes following completion of 
neoadjuvant systemic therapy.
8.1.2. Disease-Free Survival (DFS)
DFS is defined as the time from date of surgery to disease recurrence or death whichever occurs first.
Disease recurrence will be based on imaging assessments performed off study per standard of care after 
nephrectomy. After sufficient data for the primary endpoint is collected in this study, the electronic study 
database may be locked, and the collection of the long-term survival status may be recorded through a 
different mechanism (rather than using the electronic database) at the site.
DFS (in months) will be calculated as (first event date – surgery date +1)/30.4375.
In cases of staggered surgeries, the surgery date should reflect the latest surgical date in the clinical 
database.
8.1.3. Time-to-Surgery
Time-to-surgery is defined as the number of calendar days between study Day 1 and the planned 
nephrectomy. Only subjects who complete treatment and undergo on-study surgery will be included in 
this analysis.
In cases of staggered surgeries, the surgery date should reflect the earliest surgical date in the clinical 
database.
In addition, delays in days between planned surgery date (at time of study treatment initiation) and actual 
surgery date will be described using descriptive statistics.
8.2.
Study Drug Exposure Variables
8.2.1. Study Treatment Duration
Study treatment duration (weeks) is defined as [(the last dose date – the first dose date +1) / 7].
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8.2.2. Total Number of Injections of Nivolumab Received
Total number of injections of nivolumab 240 mg received is defined as the cumulative number of 
injections of nivolumab received at the 240 mg dose.
8.2.3. Days on sitravatinib
Days on study drug is defined as the total number of days patient received sitravatinib, after subtracting 
for interruptions or drug missed, that is, the [(latest Stop Date - the earliest Start Date captured on the 
Sitravatinib Administration CRF page) – number of days with 0 mg dose + 1] for sitravatinib.
8.2.4. Cumulative Dose Received
x
Cumulative dose received for nivolumab (mg) is defined as the total amount of the study drug a 
patient receives during the study as recorded on the Nivolumab Administration CRF forms. 
Nivolumab is planned to be administered as a 240 mg intravenous infusion over 30 minutes every 
2 weeks only in Segment 2 (starting from Day 15 [±2]). Dose modifications should be accounted 
for in the cumulative dose received calculations.
x
Cumulative dose received for sitravatinib (mg) is defined as the total amount of the study drug a 
patient receives during the study, that is, Sum of [(Stop date – Start date + 1) * Total Dose (mg 
per administration) * Dose Frequency] as recorded on the Sitravatinib Administration CRF forms.
Dose modifications should be accounted for in the cumulative dose received calculations.
8.2.5. Dose Intensity
x
Absolute dose intensity (mg/day) is calculated as cumulative dose received (mg) / Treatment 
duration (days), including dose decreases and interruptions as per physician’s decision. Absolute 
dose intensity should only apply to sitravatinib.
x
Relative dose intensity should apply to both sitravatinib and nivolumab and is defined as:
o
For sitravatinib: [cumulative dose received (mg) / cumulative planned dose (mg)] * 100,
where cumulative planned dose is calculated as the starting daily dose multiplied by the
study treatment duration, which does not take into account dose reduction or interruption.
o
For nivolumab: [total dose administered (mg)] / [rounded, planned total dose (mg)] * 100, 
where the rounded, planned total dose is:

240 mg times (last nivolumab dose date - first nivolumab dose date + 14) divided 
by 14. Then round the number to the nearest multiple of 240.
For example, if the first dose date is 2019-01-01 and last dose date is 2019-01-
17, the planned total dose is 240 mg * (16+14) / 14 = 514.29 mg. And the 
rounded, planned total dose is 480 mg.
x
Compliance is calculated as cumulative dose received (mg) / cumulative planned dose (mg,
including dose reduction and interruptions due to AE). Compliance should only apply to
sitravatinib.
8.3.
Safety Variables
Adverse events (AEs) and laboratory values will be graded according to the NCI CTCAE Version 5.0.
With regards to adverse events, the term “on-study” includes the period from the first dose of study 
treatment until at least 28 days after the last dose of study treatment or surgery, whichever occurs last.
AEs and laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
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8.3.1.Adverse Events
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 21.0 or higher).
Non-serious AEs will be reported from the day of first dose of study treatment until at least 28 days after 
last administration of study dug treatment or surgery, whichever occurs last. Serious adverse events 
(SAEs) are reported from the time that the patient provides informed consent (i.e., prior to undergoing any 
study-specific procedure or assessment) until at least 28 days after last administration of study treatment 
or surgery, whichever occurs last.
8.3.1.1.
Baseline Signs and Symptoms
x
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present prior to Day 1
of study treatment dosing are recorded in the CRF as medical history.
8.3.1.2.
Treatment-Emergent AEs (TEAEs)
x
TEAEs are AEs that begin on or after Day 1 of study treatment and prior to 28 days after last 
dose of study drug or surgery, whichever occurs last, and prior to the initiation of subsequent 
systemic anti-cancer therapy. Baseline signs and symptoms that change attribution or severity 
during the on-study period are TEAEs. Any ongoing TEAEs that changes in attribution or severity 
is captured as a new AE. All AEs will be coded according to the MedDRA Version 21.0 dictionary 
by SOC, PT, and severity grade using NCI CTCAE Version 5.0.
8.3.1.3.
Adverse Events of Special Interest (AESI)
An AESI is defined as an AE of scientific and medical interest specific to understanding of the 
Investigational Product. Preferred terms (PTs) of AESI will be identified by sponsor’s medical director
from potential Standardised MedDRA Queries (SMQs).
8.3.1.4.
Immune-related Adverse Event (irAE)
An irAE is defined as an AE that is associated with drug exposure and is consistent with an immune-
mediated mechanism of action and where there is no clear alternate etiology. irAEs will be identified on 
the adverse events CRF page.
8.3.2. Physical Examinations
A physical examination including all major body systems is mandated at Screening and End of Study 
(EOS) Visits only. During study treatment, symptom-directed physical examinations are performed.
8.3.3. Vital Signs
Vital signs: systolic and diastolic blood pressure, pulse rate, body temperature, height and weight. Height 
will be recorded at screening only.
8.3.4. Clinical Laboratory Assessments
Clinical laboratory parameters to be collected routinely on-study (i.e. from signing of the informed consent 
until End of Study evaluation) are listed in Table 6 below.
Table 6: Laboratory Safety Parameters
Hematology Panel
Blood Chemistry Panel
Hemoglobin
Aspartate aminotransferase (AST)
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Platelet count
Alanine aminotransferase (ALT)
White blood cell count (WBC)
Alkaline phosphatase
Neutrophil count
Total bilirubin
Lymphocyte count
Lipase
Amylase
Coagulation
Sodium
International normalized ratio (INR)
Potassium
Partial thromboplastin time (PTT)
Chloride
Bicarbonate [CO2]
Urinalysis (dip stick)
Blood urea nitrogen (BUN)
Blood
Creatinine
Protein
Albumin
Total calcium
Thyroid Function Test
Magnesium
Thyroid stimulating hormone (TSH)
Phosphate
Uric acid
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test will be 
performed at screening. Pregnancy tests will also be done whenever pregnancy is suspected during the 
study.
8.3.5. Electrocardiograms
Single and triplicate 12-Lead electrocardiogram (ECG) parameters will be collected as shown in Table 1
and Table 2: rhythm, heart rate, QT, RR, and the overall impression. QT interval corrected for heart rate 
by the Fridericia’s formula (QTcF) will be manually calculated in the database.
For each planned visit for which a triplicate ECG is obtained, the average the 3 values will be calculated
and reported. The baseline to be used in the calculation of changes over time will be the mean of the 6 
pre-dose values, i.e., the triplicate values at -1 hour and -0.5 hour predose.
8.3.6. Echocardiograms
Echocardiograms will be performed at screening, and thereafter as shown in Table 1.
8.3.7. Prior and Concomitant Medications
Medications administered to study participants during the on-study period are captured on a log CRF
page. Medications are considered prior medications if they have a start date prior to the date of first dose 
of study medication or a partial start date which indicates the medication was begun prior to the first dose 
of study treatment. Medications with missing start dates will be considered prior medications.
Concomitant medications are defined as medications administered to study participants on or after the 
first dose of study treatment and prior to 28 days after the last dose of study treatment or surgery, 
whichever occurs last. Medications start 29 days after the last dose of study treatment or surgery, 
whichever occurs last, will be considered as post-study meds and will not be summarized or listed. If 
medication with missing start dates but the end date is after first dose of study treatment, it will be 
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considered as concomitant medication as well. A medication can be considered both prior and 
concomitant. Collected prior and concomitant medications will be coded using the World Health 
Organization (WHO) medical dictionary.
8.4.
Other Endpoints
x
Pharmacokinetic evaluations of sitravatinib.
x
Pharmacodynamic evaluation in tumor tissue.
x
Pharmacodynamic evaluation in the blood.
x
Circulating tumor DNA.
9.
Data Handling
9.1.
Missing Dates
The following rules will be applied to impute missing start and stop dates in appropriate data types (e.g., 
AEs or concomitant medications). Imputations of missing dates will only apply to summary tables (and not 
listings).
Start Date
If the start date is completely missing (i.e., the day, month, and year are all unknown) the start date will be 
set to the date of first dose of study medication.
Missing Day Only
x
If the month and year of the incomplete date are the same as the month and year of the first 
dose date, then the day of the first dose date will be assigned to the missing day. 
x
If either the year is before the year of the first dose date or if both years are the same, but the 
month is before the month of the first dose date, then the last day of the month will be assigned 
to the missing day. 
x
If either the year is after the year of the first dose date or if both years are the same, but the 
month is after the month of the first dose date, then the first day of the month will be assigned 
to the missing day.
Missing Month Only
x The day will be treated as missing and both month and day will be replaced according to the 
below procedure. 
Missing Day and Month
x If the year of the incomplete date is the same as the year of the first dose date, then the day and 
month of the first dose date will be assigned to the missing fields.
x If the year of the incomplete date is before the year of the first dose date, then January 1 will be 
assigned to the missing fields.
x If the year of the incomplete date is after the year of the first dose date, then January 01 will be 
assigned to the missing fields.
If the stop date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date.
Stop Date
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Missing Day Only
x If the month and year of the incomplete date are the same as the month and year of the last visit 
date, then the day of the last visit date will be assigned to the missing day.
x If either the year is before the year of the last visit date or if both years are the same, but the 
month is before the month of the last visit date, then the last day of the month will be assigned 
to the missing day.
x If either the year is after the year of the last visit date or if both years are the same, but the 
month is after the month of the last visit date, then the first day of the month will be assigned 
to the missing day.
Missing Month Only
x The day will be treated as missing and both month and day will be replaced according to the 
below procedure.
Missing Day and Month
x If the year of the incomplete date is the same as the year of the last visit date, then the day and 
month of the last visit date will be assigned to the missing fields.
x If the year of the incomplete date is before the year of the last visit date, then January 01 will be 
assigned to the missing fields.
x If the year of the incomplete date is after the year of the last visit date, then January 01 will be 
assigned to the missing fields.
9.2.
Protocol Deviations
Potential planned or unplanned protocol deviations noted during clinical monitoring will be documented by
category 
(i.e., 
inclusion 
criteria, 
exclusion 
criteria, 
study 
drug
administration,
study 
procedures/assessments, study visit schedule, informed consent, and other). All deviations will be 
reviewed, categorized, designated important or not important, and finalized prior to database lock.
Important protocol deviations will be defined as those potentially impacting safety or efficacy 
assessments. Additional details of what will be considered important can be found in the Protocol 
Deviation Guidance document.
10.
Interim Analyses
No interim statistical analysis is planned during this study. 
11.
Statistical Methods
All data collected during this study will be displayed in data listings, unless otherwise specified. Data 
listings will be sorted by patient identifier for safety and efficacy listings. Screen failures will be excluded 
from all tables and listings, except for SAE listings (which includes all patients that provides informed
consent). In addition, listings will include all relevant derived variables.
Descriptive statistics (mean, median, standard deviations [STD], minimum and maximum values) for 
continuous variables will be presented. Mean and median will be presented to 1 decimal more than
original data. STD will be presented to 2 decimals more than original data. Minimum and maximum will 
match the decimal points in the original data. For categorical variables, summary measures will include
the frequency and percentage (with 1 decimal place) of patients in each category.
Unless otherwise noted, missing data will not be imputed or carried forward.
All data summaries and tabulations will be prepared with SAS Version 9.4 or higher.
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11.1. Patient Disposition
The number and percentage of patients enrolled and treated in the study will be presented. The number 
and percentage of patients and each population to which they belong will be presented as well as the 
number and percentage of patients who withdrew from the study and a breakdown of the corresponding 
reasons for withdrawal and the number and percentage of patients who discontinued nivolumab or 
sitravatinib with the corresponding reasons. Summaries will be reported for all screened patients.
Disposition will be summarized descriptively for all screened patients.
11.2. Important Protocol Deviations
Important protocol deviations for patients in the Enrolled Population will be reported by category. 
Important protocol deviations will be listed.
11.3. Treatments
11.3.1.
Prior and Concomitant Medications
Concomitant medications will be coded using World Health Organization (WHO) Drug Enhanced (version: 
March 2018).
Prior medications will be tabulated separately for the Safety population and Enrolled population by 
Anatomical Therapeutic Chemical Classification level 2, level 4, and preferred drug name using counts 
and percentages. Concomitant medications will be summarized separately for the Safety population and 
Enrolled population and by sitravatinib starting dose and by segment. Concomitant medications in 
segment 1 are defined as the medications started between the first dose and the last dose of sitravatinib
in segment 1. Concomitant medications in segment 2 are defined as the medications started between the 
first dose of nivolumab and the last dose of sitravatinib or nivolumab in segment 2.
Prior and concomitant medications will be included in a patient data listing.
11.4. Demographic and Baseline Characteristics
Demographic and baseline data will be summarized descriptively for the Safety population. For 
continuous variables, descriptive statistics will include the mean, STD (or standard error), median, range, 
and interquartile range. For categorical variables, descriptive statistics will include the number and 
percent.
Demographic variables to be summarized include gender, reproductive status for female, race, ethnicity, 
age (years), baseline weight (kg), baseline height (cm), baseline Eastern Cooperative Oncology Group 
(ECOG) status, and smoking history. Age is calculated from date of informed consent and date of birth.
Primary disease history will be tabulated for the Safety population and will include the summary statistics 
(count and percentage) for primary tumor stage (TX, T0, T1, T1a, T1b, T2, T2a, T2b, T3, T3a, T3b, T3c, 
T4), regional lymph node stage (NX, N0, N1), and distant metastasis stage (M0, M1).
Prior primary disease treatment (systemic therapies; radiotherapy, and surgery) will be tabulated for the 
Safety population and include the summary statistics (count and percentage).
Medical history will be tabulated by system organ class (SOC) and preferred term (PT) using counts and
percentages for the Safety population.
Demographic, primary disease history, and prior primary disease treatment data will be listed by patient.
11.5. Medical History
Medical history will be tabulated by system organ class (SOC) and preferred (PT) using counts and
percentages for the Safety population. Medical history will be listed by patient.
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11.6. Efficacy Analyses
11.6.1.
Primary Variable
Descriptive statistics (frequency and percentage) for point in time objective response (either CR or PR) 
prior to surgery and pCR based on the response assessments by the Investigator and the exact 95% 
Clopper-Pearson confidence interval of the response rate will be presented. Summaries will be presented 
in the Clinical Activity Evaluable Population and Safety Population. An exact test for single proportion 
(two-sided α=5%) will be performed to test H0: percentage of patients with ccRCC achieving a point in 
time objective response (either CR or PR) prior to surgery ≤5% against H1: percentage of patients with 
ccRCC achieving a point in time objective response prior to surgery >5%. Descriptive statistics (frequency 
and percentage) for point in time objective response will be presented; In addition, exact binomial 95% 
CIs for the percentage will be displayed.
11.6.2.
Secondary Variables
11.6.2.1.
Time to Surgery:
Time-to-surgery will be summarized descriptively using the Kaplan-Meier estimate. The median, 
25th percentile, and 75th percentile of time-to-surgery and their two sided 95% CIs (Brookmeyer and 
Crowley, 1982) will be calculated where appropriate. In addition, minimum and maximum will also be 
displayed. Kaplan-Meier plots will be provided for time-to-surgery. Delays in Surgery will be presented 
using descriptive statistics.
Censoring Rules
No censoring rules will apply to this variable.
11.6.2.2.
DFS:
DFS will be summarized descriptively using the Kaplan-Meier estimate. The median, 25th percentile, and 
75th percentile of time-to-surgery, and DFS and their two sided 95% CIs (Brookmeyer and Crowley, 1982)
will be calculated where appropriate. Kaplan-Meier plots will be provided for DFS.
Censoring Rules
The following censoring rules will be applied to DFS:
x
Event time will be censored on the date of surgery, or date of last follow-up assessment 
documenting absence of recurrence or Death, whichever occurs later for patients within the 
follow-up period and disease-free at the time of an analysis.
For staggered surgeries, date of surgery should reflect the latest of the surgery dates in the clinical 
database.
All secondary analyses will be conducted in the Clinical Activity Evaluable population.
11.7. Safety Analyses
All safety analyses will be summarized in the Safety population.
11.7.1.
Extent of Study Drug Exposure
Descriptive statistics will be provided separately for each study drug, for the duration of exposure (days),
number of doses received, cumulative dose received (mg) and absolute and relative dose intensities as 
well as compliance.
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Number and percentage of patients with at least 1 dose reduced and reasons for reduction (only for
sitravatinib), at least 1 injection (for nivolumab) or dose (for sitravatinib) interrupted and reasons for 
injection/dose interruption will be presented. For sitravatinib dose interruption, include a minimum of 3 
days of consecutive interruption as the threshold for what counts as treatment interrupted.
Information regarding patients’ dosing regimens will be listed separately for each study drug.
11.7.2.
Adverse Events
All adverse event summary tables will be based on the Safety Population and presented by segment and 
in total. An overall summary of TEAEs by segment will be presented. TEAEs in segment 1 are defined as
TEAEs started between the first dose and the last dose of sitravatinib in segment 1. TEAEs in segment 2
are defined as TEAEs started between the first dose of nivolumab and the last dose of sitravatinib or 
nivolumab in segment 2.
A breakdown of the number and percentage of patients reporting each adverse event categorized by 
SOC and PT will be presented. Note that counting will be by patient not event and patients are only 
counted once within each SOC or PT. The following summaries will be presented:
x
Treatment-emergent adverse events
x
Treatment-related treatment-emergent adverse events
x
Sitravatinib-related treatment-emergent adverse events
x
Nivolumab-related treatment-emergent adverse events
x
CTCAE Severity Grade 3 or greater treatment-emergent adverse events
x
CTCAE Severity Grade 3 or greater treatment-related treatment emergent adverse events
x
CTCAE Severity Grade 3 or greater Sitravatinib-related treatment-emergent adverse events
x
CTCAE Severity Grade 3 or greater Nivolumab-related treatment-emergent adverse events
x
Treatment-emergent adverse events leading to dose reduction or interruption of either study drug
x
Treatment-related treatment-emergent adverse events leading to dose reduction or interruption of 
either study drug
x
Treatment-emergent adverse events leading to drug discontinuation of either study drug
x
Treatment-related treatment-emergent adverse events leading to drug discontinuation of either 
study drug.
TEAEs will be presented by PT in descending order of frequency. 
AESIs and irAEs will be summarized separately by SOC and PT. Separate listings will be provided for 
AESIs and irAEs.
The following summaries will be presented by SOC, PT, and maximum CTCAE grade:
x
Treatment-emergent adverse events
x
Treatment-related treatment-emergent adverse events
x
Sitravatinib-related treatment-emergent adverse events
x
Nivolumab-related treatment-emergent adverse events.
The following summaries will be presented by PT and maximum CTCAE grouped grade:
x
Treatment-emergent adverse events
x
Treatment-related treatment-emergent adverse events
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x
Sitravatinib-related treatment-emergent adverse events
x
Nivolumab-related treatment-emergent adverse events.
All AEs (including non-treatment-emergent events) recorded on the CRF will be listed using the Enrolled 
Population.
11.7.3.
Deaths and Serious Adverse Events
TEAEs that lead to death and SAEs will be summarized by SOC and PT. The following summaries will be 
presented:
x
Serious treatment-emergent adverse events
x
Serious treatment-related treatment-emergent adverse events
x
Serious Sitravatinib-related treatment-emergent adverse events
x
Serious Nivolumab-related treatment-emergent adverse events
x
Treatment-emergent adverse events leading to death
x
Treatment-related treatment-emergent adverse events leading to death
x
Sitravatinib-related treatment-emergent adverse events leading to death
x
Nivolumab-related treatment-emergent adverse events leading to death
A listing of AEs leading to death will be presented. A listing of patients who experience a SAE (including 
those occurring during screening) will also be presented.
11.7.4.
Laboratory Data
All laboratory data will be summarized in International System (SI) units. The conversion factors from 
conventional to SI units will be documented in the Local Lab Conventions document for this study. In 
general, laboratory data will be presented by visit. Values at unscheduled visits will be included in the 
summary of maximum for all study visits and minimum for all study visits, which will present the largest 
and smallest values observed for each patient post-baseline for each test.
Selected parameters will be presented in shift tables of baseline against worst grade test result. The shift 
from baseline to worst post baseline (including unscheduled visit) NCI CTCAE Version 5.0 grade will be 
presented for albumin (albumin increased), AST (AST increased), ALT (ALT increased), bilirubin (bilirubin 
increased), creatinine (creatinine increased), hemoglobin (anemia), neutrophils (neutrophil count 
decreased), platelets (platelet count decreased), sodium (hyponatremia and hypernatremia), potassium
(hypokalemia 
and 
hyperkalemia), 
calcium 
(hypocalcemia 
and 
hypercalcemia), 
phosphate 
(hypophosphatemia), and uric acid (hyperuricemia).
For sodium, potassium, and calcium, separate grading criteria exist depending whether the analyte is 
high or low. For the purpose of shift tables, all low values will be included in the Grade 0 group in the shift 
tables for high values, and vice versa (all high values should be included in the Grade 0 group in the shift 
tables for low values.
Patients with at least 1 on-study (i.e. from signing of the informed consent until End of Study evaluation)
measurement for each laboratory parameter will be included, regardless of whether or not a baseline
assessment is present.
Clinical laboratory results will be listed by subject. Laboratory values that meet Grade 3 or 4 criteria 
according to NCI CTCAE Version 5.0 will also be listed separately.
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11.7.4.1.
Hematology 
Hematology parameters include hemoglobin, platelet count, WBC count, lymphocytes, and neutrophils. 
The coagulation parameters include partial thromboplastin time (PTT), and international normalized ratio 
(INR).
Descriptive statistics will be provided for each test result and for change from baseline by visit and by 
sitravatinib starting dose (120mg and 80mg). Multiple measurements taken during the visit for a patient 
will be represented by the most severe value for each hematology test. The most severe value will be 
determined first by the value closest to the upper or lower limit of the normal limits (dependent on which 
direction is considered severe) if the value is within the normal limits. If the value is outside the normal 
limits, the value furthest from the upper or lower limit will be selected (dependent on which direction is 
considered severe). In the event that this algorithm does not allow for determining the most severe (e.g. a
tie, etc.) the first chronological value will be selected. Low values are considered the most severe for all 
hematology parameters. Shift tables (for hemoglobin (anemia), neutrophils (neutrophil count decreased), 
platelets (platelet count decreased)), summarizing the shift from baseline grade to each post-baseline 
visit, maximum post-baseline CTCAE grade including unscheduled visits, and last assessment on study 
will be presented. Patients who develop a Grade 3 toxicity will be listed.
11.7.4.2.
Chemistry 
Serum chemistry parameters include ALT, AST, alkaline phosphatase, total bilirubin, lipase, amylase, 
creatinine, uric acid, BUN, albumin, sodium, potassium, chloride, magnesium, phosphate, calcium and 
bicarbonate.
Descriptive statistics will be provided for each test result and for change from baseline by visit and by 
sitravatinib starting dose (120mg and 80mg). Multiple measurements taken during the visit for a patient 
will be represented by the most severe value as noted in Section 11.7.4.1. For all chemistry analytes, the 
most severe value is the highest value, with the exception of albumin, chloride, and bicarbonate. The 
most severe could be in either direction for glucose, potassium, sodium, and calcium. For these analytes, 
if within the normal limits, then the value closest to the normal limit (either direction) will be selected. If 
outside the normal limits, then the value most distant from the normal limit (either direction) will be used. 
Shift tables (for AST (AST increased), ALT (ALT increased), creatinine (creatinine increased), sodium 
(hyponatremia 
and 
hypernatremia), 
potassium 
(hypokalemia 
and 
hyperkalemia),
phosphate 
(hypophosphatemia), and uric acid (hyperuricemia), summarizing the shift from baseline grade to each 
post-baseline visit, maximum post-baseline CTCAE grade including unscheduled visits, and last 
assessment on study will be presented. Patients who develop a ≥ Grade 3 toxicity will be listed.
11.7.4.3.
Urinalysis
Urinalysis results for the parameters blood and protein will be listed.
11.7.4.4.
Thyroid
Results will be listed for TSH.
11.7.4.5.
CTCAE Coding of Laboratory Data
Where laboratory values are categorized into NCI CTCAE v5.0 grades, the categories are defined
according to the criteria available on the following website: http://evs.nci.nih.gov/ftp1/CTCAE/About.html
Note that grades are applied based only on the numeric SI value of the parameter assessed; clinical
signs and symptoms are not considered. Where categories are only distinguished by clinical signs or 
symptoms, the lowest of the possible grades will be assigned.
NCI CTCAE grades will be applied for the following lab parameters: 
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x
Hematology: hemoglobin, WBC, lymphocyte, neutrophils, and platelets.
x
Chemistry: ALT, albumin, Alkaline phosphatase, AST, total bilirubin, calcium, creatinine, 
phosphate, magnesium, potassium, sodium, uric acid.
Laboratory measurements that are within their institutional limits of normal and are not graded as 1-4, per 
the CTCAE, will be summarized as “Grade 0,” which is defined as normal.
11.7.4.6.
Hy’s Law
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN concurrent with an 
increase in total bilirubin to ≥ 2 × ULN but without increase in alkaline phosphatase (i.e., alkaline 
phosphatase < 2 × ULN) meets the criteria for Hy’s Law and raises the concern for drug-induced liver 
injury when no other cause of the abnormal laboratory results is identified.
A figure displaying patients who are at risk for a drug induced liver injury according to Hy’s law will be 
presented. A listing of patients at risk will also be presented.
11.7.5.
Vital Signs
Clinically significant findings noted during screening will be reflected on the medical history CRF, while 
those noted during study treatment will be collected on the AE CRFs. The following vital signs will be 
summarized: pulse rate (beats/min), systolic blood pressure (SBP; mmHg), diastolic blood pressure 
(DBP; mmHg), body temperature (C), Height (cm) and weight (kg). Height will be recorded at screening 
only. 
All vital signs and change from baseline through the last study visit will be summarized. This will include a 
summary of the maximum and minimum values observed while the patient was on treatment and change 
from baseline to that observed value.
All vital signs including all baseline and post-baseline ECOG will be listed.
11.7.6.
Physical Examinations, ECGs, and Other Observations Related 
to Safety
11.7.6.1.
Physical Examination
Complete physical examinations will be conducted during screening and EOS/Withdrawal visits only.
Abbreviated physical examinations will be performed on Day 1, Day 15, Day 29, and Day 43 (if patient 
has Day 43 visit). Any new abnormal physical exam findings will be collected as AEs. Physical 
Examination data will be listed for the Safety population.
11.7.6.2.
Electrocardiogram
A summary of ECG parameters including heart rate (beats/min), QT interval (msec), QTcF (msec),
rhythm, and RR interval (msec) and change from baseline will be presented for each planned visit as well 
as the minimum, maximum, and last observation on treatment. In addition, a summary will be generated 
for patients with QTcF increased to value >450 and ≤480 msec, , >480 and ≤500 msec, and value >500 
msec, and patients with change-from-baseline QTcF increased by ≤30, 30 to ≤60 msec, and by >60 
msec. A shift from baseline to worst CTCAE grade summary will also be presented.
A listing of the ECG results along with the overall interpretation will be presented. For assessments where 
triplicate ECGs are taken, the individual values will be displayed.
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11.7.6.3.
Echocardiogram 
LVEF data from the echocardiogram will be summarized for the Screening, Day 29 and Preop Rebaseline
results only in the safety population. Additionally, patients who have at least one post-baseline decrease 
in value will be summarized using the following categories: decrease from baseline of 10-<20% decrease
from baseline and value ≥40%, 10-<20% decrease from baseline and value <40%, ≥20% drop from 
baseline and value ≥40%, and ≥20% drop from baseline and value <40%.
LVEF will be graded per CTCAE v5.0. The grades are as follows:
x
Grade 1: n/a
x
Grade 2: Resting ejection fraction (EF) 50–40%; 10-19% drop from baseline
x
Grade 3: Resting EF 39-20%; ≥20% drop from baseline
x
Grade 4: Resting EF <20%
x
Grade 5: n/a
Shift in LVEF results from baseline to worst post-baseline by CTCAE Grade will be presented.
Echocardiogram results will be listed for the screened population.
11.7.6.4.
Pregnancy Test
Pregnancy testing data will be listed for the Safety population. 
11.7.6.5.
Long Term Follow-up
Long term follow-up/survival data will be listed for the safety population. Additionally, all follow-up disease 
recurrence will be listed.
11.7.6.6.
Death Report
Death report data will be summarized and listed for the Enrolled Population.
12.
Validation
PRA seeks to ensure the quality of the results provided for the study in the form of TFLs, and the derived 
datasets used in their creation, through the following processes:
The entire set of TFLs will be checked for completeness and consistency prior to its delivery to the client 
by the lead statistical programmer, the lead statistician, and a senior level statistician, or above, who is 
not a member of the project team.
The PRA validation process will be repeated any time TFLs are redelivered using different data. 
Execution of this validation process will be documented through the study Table of Programs that will be 
provided to Mirati at study conclusion.
13.
References
Brookmeyer, R and Crowley, J. A confidence interval for mean survival time. Biometrics, 1982, 38, 29-41.
Ji Y, Liu P, Li Y, et al. A modified toxicity probability interval method for dose-finding trials. Clin Trials. 
2010 Dec;7(6):653-63.
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Appendix 1 Glossary of Abbreviations
Glossary of Abbreviations:
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
C
Celsius
ccRCC
Clear Cell Renal Cell Carcinoma
CI
Confidence Interval
CO2
Carbon Dioxide
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography Scan
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
Circulating Tumor Deoxyribonucleic Acid
DBP
Diastolic Blood Pressure
DFS
Disease-Free Survival
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOS
End of Study
INR
Internal Normalized Ratio
irAE
Immune-related Adverse Event
IV
Intravenous
MDSC
Myeloid-Derived Suppressor Cell
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
mTPI
Modified Toxicity Probability Interval
NCI
National Cancer Institute
NGS
Next Generation Sequencing
NK
Natural Killer
NSCLC
Non-small Cell Lung Cancer
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pCR
Pathological Complete Response
PD
Progressive Disease
PD-L1
Programmed Cell Death Ligand 1
PK
Pharmacokinetic
PR
Partial Response
PT
Preferred Term
PTT
Partial Thromboplastin Time
QD
Once Daily
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SI
International System
SMQs
Standardised MedDRA Queries
SOC
System Organ Class
STD
Standard Deviation
TEAE
Treatment-emergent Adverse Event
TFL
Tables, Figures, and Listings 
TSH
Thyroid-stimulating Hormone
WBC
White Blood Cell
WHO
World Health Organization
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