Clinical trial NCT02954991
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Mirati Therapeutics Inc.
Start date: 2016-11-07; Completion date: 2021-11-04
Enrollment: 161 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the clinical activity of nivolumab in combination with 3 separate investigational agents, glesatinib, sitravatinib, or mocetinostat.

Detailed description:
Glesatinib is an orally administered multi-targeted tyrosine kinase inhibitor (TKI) that primarily targets the Axl and Mesenchymal-Epithelial Transition (MET) receptors. Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Mocetinostat is an orally administered histone deacetylase (HDAC) inhibitor. Nivolumab is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including anti-tumor immune response. Combining an immunotherapeutic PD-L1 checkpoint inhibitor with an agent that has both immune modulatory and antitumor properties could enhance the antitumor efficacy observed with either agent alone.

The study will begin with a lead-in dose escalation evaluation of two dose levels of each investigational agent in combination with nivolumab. Following completion of the lead-in dose escalation, enrollment into the Phase 2 study will proceed.

Arms: arm 1: Glesatinib oral tablet administered twice daily in combination with Nivolumab administered as 240 mg IV every 2 weeks or 480 mg IV every 4 week arm 2: Sitravatinib oral capsule administered daily in combination with nivolumab administered as 240 mg IV every 2 weeks or 480 mg IV every 4 week arm 3: Mocetinostat oral capsule administered three times weekly in combination with nivolumab administered as 240 mg IV every 2 weeks or 480 mg IV every 4 week
Interventions: intervention 1: Glesatinib intervention 2: Sitravatinib intervention 3: Mocetinostat intervention 4: Nivolumab
Intervention descriptions: intervention 1: Glesatinib is a small molecule multi-targeted receptor tyrosine kinase inhibitor intervention 2: Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases. intervention 3: Mocetinostat is an HDAC inhibitor. intervention 4: nivolumab is a programmed death receptor-1 (PD-1) blocking antibody

Protocol documents:
ICF_002.pdf: 
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RESEARCH PATIENT INFORMATION AND CONSENT FORM  
TITLE: 
A Parallel Phase 2 Study of Glesatinib, Sitravatinib or 
Mocetinostat in Combination With Nivolumab in Advanced 
or Metastatic Non-Small Cell Lung Cancer 
 
This consent form contains important information to help you decide whether 
to participate in this research study. 
The study staff will explain this study to you.  Ask questions about anything that is not clear at 
any time.  You may take home an unsigned copy of this consent form to think about it and 
discuss it with family or friends. 
➢ Being in this study is voluntary – your choice. 
➢ If you join this study, you can still stop at any time. 
➢ No one can promise that a study will help you. 
➢ Do not join this study unless all of your questions are answered. 
After reading and discussing the information in this consent form you should 
know: 
• Why this research study is being done; 
• What will happen during the study; 
• Any possible benefits to you; 
• The possible risks to you; 
• Other options you could choose instead of being in this study; 
• How your personal health information will be treated during the study and after the study is 
over; 
• Whether being in this study could involve any cost to you; and 
• What to do if you have problems or questions about this study. 
Please read this consent form carefully. 


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TITLE: 
A Parallel Phase 2 Study of Glesatinib, Sitravatinib or 
Mocetinostat in Combination With Nivolumab in 
Advanced or Metastatic Non-Small Cell Lung Cancer 
 
PROTOCOL NO.:  
MRTX-500 
 
SPONSOR:  
 
Mirati Therapeutics, Inc. 
 
INVESTIGATOR:  
Enter PI name 
 
SITE(S): 
 
 
Enter addresses of all locations to be used 
 
 
 
 
 
 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Contact Name 
 
 
 
 
Telephone Number (24 hours) 
 
Patient’s 
Name: 
 
Medical Record 
Number: 
 


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INVITATION TO PARTICIPATE IN A RESEARCH STUDY 
You are being asked to take part in a clinical research study at [enter site name].  This consent 
form explains why this research study is being performed and what your role will be if you 
choose to participate.  This form also describes the possible risks related with taking part in this 
study. 
You are being asked to take part in this study because you have a diagnosis of advanced or 
metastatic lung cancer, for which the proposed study treatment is a reasonable next treatment or 
because there are no standard therapies beyond those you have already received.  
Before agreeing to participate in this research study, it is important that you read and understand 
the following explanations of the study and the proposed study procedures.  Clinical studies 
include only patients who choose to take part.  Please take your time to make your decision.  Ask 
the study doctor or the study staff to explain any words in this document that you don’t 
understand.  Make sure that all your questions have been answered to your satisfaction.  If you 
decide to participate in this study, you will be asked to sign this consent form to confirm that you 
have been informed of the nature of the study and what it involves. 
A description of this clinical study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This website will not include information that can identify you.  At most, 
the website will include a summary of the results.  You can search this website at any time. 
PURPOSE OF THE RESEARCH STUDY 
WHY IS THIS STUDY BEING DONE? 
This is a study of 3 different investigational (experimental) drugs given in combination with the 
immunotherapy nivolumab (also known as OPDIVO®).  Immunotherapy is treatment that uses 
your body’s own immune system to help fight cancer. The 3 investigational drugs are being 
developed by Mirati Therapeutics, Inc., which is the company that will provide these drugs.  
“Investigational” means that the drugs are being tested but have not been proven to help patients 
with the disease you have and are not approved by the U.S. Food and Drug Administration 
(FDA).  Nivolumab is an FDA approved agent and is made by Bristol Myers Squib.  The study is 
being funded and organized by Mirati Therapeutics, Inc. 
This study will evaluate if patients with non-small cell lung cancer will benefit from treatment by 
adding any of the investigational drugs to nivolumab.  The study will enroll patients into 3 
groups, each testing a different investigational drug in combination with nivolumab.  Your study 
site has been assigned to enroll patients into the group that will receive nivolumab in 
combination with the investigational agent sitravatinib.  This consent form will describe what to 
expect with sitravatinib and nivolumab.   
Other objectives of the study include assessing how quickly the investigational drugs are 
absorbed into the blood stream and how fast they are removed.  Several laboratory tests will be 


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performed using samples of tumor tissue or blood to understand how and why the drugs may 
work together in the treatment of lung cancer.   
BACKGROUND – SITRAVATINIB AND NIVOLUMAB 
Sitravatinib is an experimental drug that belongs to a class of drugs known as tyrosine kinase 
inhibitors.  Sitravatinib is being developed as a possible treatment for different types of cancer. 
Sitravatinib is designed to block specific proteins that are thought to cause tumors to grow and to 
prevent growth of new blood vessels that help cancer tumors to grow and spread.  In addition, 
research indicates that sitravatinib may help stimulate a patient’s immune system, improving its 
ability to recognize and attack cancer cells.   
Nivolumab is an FDA approved, prescription drug that belongs to a class of drugs known as 
checkpoint inhibitors; specifically, nivolumab is an inhibitor of the Programmed Cell Death 
(or PD-1).  Cancers can have extra signal molecules (PD-L1 molecules) on their surface that 
make the immune system accept them as normal, helping the cancer cells avoid attack by the 
immune system.  Nivolumab can block these signal molecules, allowing the immune system to 
recognize and attack cancer cells. 
This study will evaluate whether the combination of immune system stimulation caused by 
sitravatinib and improved recognition of tumor cells caused by nivolumab results in more 
anti-tumor activity (tumor shrinkage) than would be expected with either agent used alone. 
DESCRIPTION OF THE RESEARCH STUDY 
The study for sitravatinib plus nivolumab will include groups of patients with non-small cell lung 
cancer, including patients who have previously received prior treatment with a checkpoint 
inhibitor (as many as 125 patients) and patients who have not previously received treatment with 
a checkpoint inhibitor (as many as 61 patients). Including all investigational treatment groups 
and sub-studies, as many as 25 study sites in the United States and 280 patients are expected to 
participate in this study.   
WHAT HAPPENS BEFORE ANY TREATMENT? 
Screening Tests 
Before you can enroll in the study, screening tests will be done to help the study doctor decide if 
you are eligible to take part in this study.   
The following tests and procedures will be performed during screening: 
• Your complete medical history will be recorded, including any cancer treatments you may 
have previously received. 
• You will be asked how well you are able to perform the normal activities of daily living. 


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• You will be asked about any other medications you are taking, including over the counter 
medications and natural supplements. 
• You will have a full physical exam, including measurement of your vital signs (blood 
pressure, pulse rate, and temperature), weight and height. 
• Blood (about 3 teaspoons) and urine will be collected for routine tests and a test to ensure 
your blood is clotting normally. This may be repeated at other times during the study if your 
study doctor feels it is necessary. 
• Blood (about 2 teaspoons) will be collected to measure markers of the immune system 
(biomarkers) that may change during treatment.   
• Women who are able to have children will have a blood (about 1 teaspoon) or urine 
pregnancy test. This may be repeated at other times during the study if your study doctor 
feels it is necessary. 
• You will have an electrocardiogram (ECG), which is a test that shows how the heart is 
working by measuring its electrical activity.   
• You will have an echocardiogram (ECHO, an ultrasound of the heart) to evaluate the 
pumping function of your heart. 
• You will have a computed tomography (CT) scan, a whole body bone scan and a magnetic 
resonance imaging (MRI) brain scan to evaluate any tumor(s) before treatment.  Depending 
on the status and location of the tumor(s), other scan methods may be used instead.  This will 
be determined by your study doctor.   
Collection of Tumor Samples to Test for Immune System Markers 
For patients who have not received prior checkpoint inhibitor treatment, testing of your tumor 
collected after your most recent treatment is necessary for study entry.  This testing is not 
optional.  Whether your tumor has no/low or high PD-L1 signal molecule expression must be 
known to enter the correct study group.  If the same test has been performed recently for a 
different purpose, the results may be adequate to meet the needs of the study and permission to 
use the information is requested.  You may have tumor tissue already available from a recent 
biopsy or procedure performed since your last treatment.  If you have not had a recent biopsy, 
you will need to have a new biopsy to obtain a sample.  Your study doctor will describe what to 
expect in your case.  
For patients who have received prior checkpoint inhibitor treatment, the researchers conducting 
this study would like to send samples of your tumor to central laboratories to be tested for PD-L1 
signal molecule expression and other immune system markers before you start study treatment 
and again during treatment.  These experimental markers may help researchers understand 
whether and how sitravatinib and nivolumab work together to treat cancer, and which future 
patients with cancer may benefit the most from treatment with sitravatinib and nivolumab in 
combination.  This testing is not required for study entry but is very valuable in learning how and 
why the combination therapy may be effective in treating cancer.  If the same test has been 
performed recently for a different purpose, the result may be enough to meet some of the needs 


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of the study and permission to use the information is requested.  You may have tumor tissue 
already available from a recent biopsy or procedure performed since your last treatment.  If you 
have not had a recent biopsy or surgery, you may be asked to have a new biopsy to obtain a 
sample.  You study doctor will describe what to expect in your case.  
Collection of Blood for Tumor Gene Testing 
In addition to the immune system tests described above, the researchers conducting this study 
would like to send samples of your blood to central laboratories to test for changes in the genetic 
molecules from the tumor.  Genes are forms of DNA that are passed along as cells multiply; the 
genes tell the cells how to grow and function.  The genes from tumors are not those that are 
passed from parent to child and determine things like hair and eye color.  Gene molecules (DNA) 
from the tumor can be found not only in tumor tissue but also in the blood.  These molecules 
were originally in tumor cells but have been released and are now circulating in the blood.  
Circulating tumor DNA (ctDNA) cannot start the growth of new tumors but can be used to test 
for gene changes.  The tests for ctDNA and genes in the tumor tissue will help researchers know 
whether your tumor has gene changes (increased number of copies or mutations) that may be 
targeted by the investigation study treatment in addition to possibly helping nivolumab be 
effective. 
Your blood samples for ctDNA testing and tumor tissue sample will be kept for a maximum of 
10 years, after which they will be destroyed; however, you may request at any time that your 
samples be destroyed earlier, if you wish to do so.  Your samples will only be identified by a 
unique study number.  However, even if you were not eligible to participate in the study, limited 
information about your case may be collected to help interpret any findings (e.g. your age, 
gender, type of cancer, and information on your prior treatments).  This will allow the 
researchers to study future questions about the cancer disease and study drug. 
WHAT HAPPENS DURING TREATMENT? 
Study Drug Regimen 
Sitravatinib capsules will be taken by mouth once every day.  Nivolumab infusions will be 
administered by intravenous infusion (infusion of the liquid medication directly into your vein) 
either once every 2 weeks or once every 4 weeks.  Your study doctor will discuss which dosing 
is best for you.  If you experience side effects, or your doctor or study team notices abnormal 
findings in your lab or EKG results, your dosing regimen of both sitravatinib and nivolumab may 
be interrupted.  Treatment is divided into cycles; each cycle is 28 days in length. 
Study Drug Administration 
Sitravatinb will be provided as capsules.  The dose of sitravatinib that you will receive will be 
based on the experience of people treated in the study before you.  Your study doctor will tell 
you the dose of sitravatinib to expect.  You will take sitravatinib once daily.  You may receive 
different strengths of sitravatinib capsules to make the right dose.  The study doctor or nurse will 
tell you exactly how many capsules of each strength to take.  If you experience intolerable side 


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effects, your dose of sitravatinib may be lowered.  Both you and your doctor will know which 
dose of sitravatinib you will receive.   
• Sitravatinib capsules should be taken on an empty stomach at least 2 hours after the previous 
meal and 1 hour before the next meal.  
• You will swallow the sitravatinib capsules with at least 200 mL (less than 1 cup) of water.   
• Sitravatinib capsules should be swallowed whole and not be chewed.   
• If you miss a dose or vomit after taking a dose, you should not make up the dose and do not 
double up the next dose.   
• You will be given a diary card by the study staff for each sitravatinib treatment cycle.  You 
should record each time you take sitravatinib capsules, and any missed doses on the diary 
card.  Take the diary card with you to every clinic visit.  At the end of each treatment cycle, 
the study staff will collect the diary card to keep in the study records.   
Nivolumab will be administered by intravenous infusions (infusion of the liquid medication 
directly into your vein).  Either the standard flat dose of 240 mg will be administered in the clinic 
every 2 weeks or the standard flat dose of 480 mg will be administered in the clinic every 4 
weeks.  The infusions will last about 30 minutes.  Your study doctor will discuss which dosing is 
best for you. 
WHICH TESTS AND PROCEDURES WILL BE PERFORMED DURING TREATMENT? 
Every time you are seen in the clinic, your vital signs will be measured and you will be asked if 
you are experiencing any symptoms of your disease, other illnesses or side effects of treatment, 
and to provide the list of the medications you are taking. 
The list of tests and procedures described below may be done a little earlier or later than the day 
indicated.  The tests may also be done more frequently than indicated if your doctor feels it is 
necessary.  If the screening tests are performed close to the first day of dosing, some of the tests 
listed below for Day 1 may not need to be repeated. 
CYCLE 1 
The following tests and procedures will be performed during Cycle 1. 
Day 1:  
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms of your disease, other illnesses, or 
after start of treatment, side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests.   
• Blood (about 2 teaspoons) will be drawn prior to sitravatinib dosing to measure biomarkers. 


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• You will have two sets of three ECGs performed before the pre-dose blood draws and one set 
4 hours after sitravatinib dosing. 
• Blood (about 1 teaspoon each time) will be drawn for sitravatinib pharmacokinetic (PK) 
testing within 30 minutes prior to dosing and again at about 30 minutes, 4 hours and 6 hours 
after dosing.  PK testing is the measurement of the amount of sitravatinib in your blood.  
• You will start your oral treatment with sitravatinib.  
• You will receive your first infusion of nivolumab on study while at the clinic. 
Day 15: 
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be drawn for routine tests.   
• You will have one set of three ECGs performed before the pre-dose blood draws.  
• Blood (about 2 teaspoons) will be drawn prior to sitravatinib dosing to measure biomarkers. 
• Blood (about 1 teaspoon) will be drawn prior to sitravatinib dosing for PK testing.   
• You will continue your treatment regimen with sitravatinib and nivolumab. 
CYCLE 2 
The following tests and procedures will be performed during Cycle 2. 
Day 1: 
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests.   
• You will have one set of three ECGs performed prior to sitravatinib dosing. 
• Blood (about 1 teaspoon) will be drawn prior to sitravatinib dosing for PK testing.   
• If you agree, you will have a tumor biopsy taken to measure immune system markers that 
may change during study treatment.   
• You will continue your treatment regimen with sitravatinib and nivolumab. 
Day 15:  
• A physical exam including measurement of your vital signs and weight will be performed. 


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• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests.   
• You will have one set of three ECGs performed before sitravatinib dosing. 
• Blood (about 1 teaspoon) will be drawn prior to sitravatinib dosing for PK testing.   
• You will continue your treatment regimen with sitravatinib and nivolumab. 
CYCLE 3  
The following tests and procedures will be performed during Cycle 3.  
Day 1: 
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests.   
• Blood (about 1 teaspoon) will be drawn prior to sitravatinib dosing for PK testing. 
• You will have an echocardiogram performed 
• You will have one set of three ECGs performed before sitravatinib dosing.  
• You will continue your treatment regimen with sitravatinib and nivolumab. 
Day 15:  
If you are receiving your nivolumab administration every 4 weeks (Q4W) or have discontinued 
nivolumab (with continuation of sitravatinib) you will not need to come into the clinic for this 
visit. 
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests.   
• You will continue your treatment regimen with sitravatinib and nivolumab. 
CYCLE 4 AND LATER TREATMENT CYCLES 
The following tests and procedures will be performed during Cycle 4 and each future treatment 
cycle. 


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Day 1:  
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be drawn for routine tests.   
• During Cycle 5 only, blood (about 1 teaspoon) will be drawn prior to sitravatinib dosing for 
PK testing.   
• During Cycle 5 only, you will have one set of three ECGs performed before sitravatinib 
dosing. 
• You will continue your treatment regimen with sitravatinib and nivolumab. 
Day 15:  
If you are receiving your nivolumab administration every 4 weeks (Q4W) or have discontinued 
nivolumab (with continuation of sitravatinib) you will not need to come into the clinic for Day 
15 visits beyond Cycle 2 Day 15. 
• A physical exam including measurement of your vital signs and weight will be performed. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• You will continue your treatment regimen with sitravatinib and nivolumab. 
Assessment of your disease:  
In addition, every 8 weeks you will have CT or MRI scans to measure the size of the tumor(s).  
Depending on where your tumors are located, a whole body bone scan may be performed or 
scans in addition to a CT scan may be used.   
If your tumor responds well to treatment, at the time that you have CT or MRI scans performed 
to confirm the response (4-8 weeks after it is first observed) you will have a blood draw (about 
4 teaspoons) to see whether the tumor response has changed the amount or kind of circulating 
tumor DNA. 
At any time between Screening and the last day of treatment you may need to return to the clinic 
for additional evaluations if your doctor feels this is necessary to follow any side effects of 
treatment or symptoms of your disease more closely.  If you experience a severe side effect of 
treatment, an unscheduled blood sample for PK assessment may be drawn. 
COVID-19 Pandemic:  
To keep you, the study doctor and their staff safe during the COVID-19 Pandemic, some of your 
visits may be conducted remotely by telephone/video conference or at your residence by a 


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qualified home health care professional, if such a service is available. The study doctor will 
discuss these options with you in detail if they are applicable. Let your study doctor know if you 
have any questions about visit requirements or options. 
LENGTH OF STUDY 
HOW LONG WILL I REMAIN ON THE STUDY? 
You may remain on this study for as long as your disease doesn’t get worse such that the doctor 
feels you should stop study treatment, and as long as you tolerate the drugs (the side effects are 
not severe), and you wish to continue.   
Treatment with sitravatinib and nivolumab will be stopped if: 
• your disease worsens such that the doctor feels treatment should be stopped; 
• side effects are very severe; 
• your doctor feels that this is no longer the best treatment for you; 
• you choose to no longer participate; 
• you do not comply with the study procedures (for example, if you do not take study 
medication, or do not return as instructed for clinic visits); or 
• you become pregnant. 
In addition, the study may be stopped early and at any time based on the decision of the sponsor 
(Mirati Therapeutics, Inc.), if deemed appropriate. 
By signing this consent form, you are indicating your intention to cooperate with the study 
requirements.  However, you may decide to stop treatment or stop your participation in this study 
at any time.  Your care and your future care will not be affected by your decision to stop 
participating in this study.  You should tell the study doctor if you are thinking about stopping or 
decide to stop participation in this study.   
If you discontinue study treatment, your study doctor will explain other treatments available to 
you. 
WHAT WILL HAPPEN AT THE END OF TREATMENT AND AFTER THAT? 
At the time you stop treatment, the following tests and procedures will be performed unless they 
were performed recently: 
• You will have a full physical exam, including measurement of your vital signs and weight. 
• You will be asked if you are experiencing any symptoms or side effects. 
• You will be asked to give a list of all medications you are taking. 
• Blood (about 3 teaspoons) will be collected for routine tests. 


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• Blood (about 2 teaspoons) will be drawn to measure biomarkers. 
• You will have an ECG performed. 
• You will have an echocardiogram performed. 
• You will have a blood draw (about 4 teaspoons) to see whether the tumor response has 
changed the amount or kind of circulating tumor DNA. 
• If you agree, you will have a tumor biopsy taken to measure immune system markers that 
may change during study treatment.   
In addition, the study staff will contact you at least 28 days after your last study treatment dose to 
see if you are having any continuing side effects.  If you are experiencing serious side effects at 
that time, you will be asked to allow follow-up until the side effects resolve or return to normal.   
You will also be contacted by the study staff by phone every 2 months after study participation 
to ask how you are doing and what new treatments you are receiving for your lung cancer.   
If you end study treatment for reasons other than worsening of your disease, you will continue to 
have disease assessments performed until you start new treatment for your lung cancer or your 
disease worsens. 
POTENTIAL RISKS, SIDE EFFECTS, AND DISCOMFORTS 
While on this study, you are at risk for potential side effects (symptoms that may be related to 
your study treatment).  These side effects will vary in people and are unpredictable.  You should 
discuss these with the study doctor. 
Sitravatinib 
Among the side effects described in the most recent formal summary of experience (cut-off date 
26 June 2021) with sitravatinib in 220 patients treated with sitravatinib alone, approximately 865 
patients treated with sitravatinib in combination with either nivolumab or tislelizumab (a drug 
similar to nivolumab), 10 patients treated with sitravatinib in combination with nivolumab and 
ipilimumab (an immunotherapy), and 13 patients treated with sitravatinib in combination with 
pembrolizumab (a drug similar to nivolumab) and enfortumab vedotin (an antibody drug 
conjugate chemotherapy) the following were the most common side effects, either related to 
sitravatinib when given alone or when given in combination with one of the other drugs 
mentioned above: 
Drug related side effects reported in ≥10% of the patients: 
• Diarrhea 
• Fatigue (tiredness) 
• Nausea 
• Increased blood pressure 


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• Vomiting 
• Decreased appetite 
• Changes in the skin of the hands and feet; redness, swelling, pain and/or formation of blisters 
(Hand and Foot Syndrome) 
• Abnormal liver tests (may indicate possible liver damage) 
• Weight loss 
• Hoarse voice 
• Inflamed and sore mouth  
• Reduced thyroid function 
• Protein in urine (which may indicate problems with the kidneys) 
Drug-related side effects reported in ≥5% and <10% of the patients include:  
• Increase in pancreatic enzymes (this could indicate damage to the pancreas due to injury, 
infection, or inflammation) 
• Abdominal pain 
• Dry mouth 
• Skin rash 
• Dizziness 
• Decrease in red blood cells (anemia which may cause tiredness) 
• Constipation 
• Change in taste 
• Decrease in platelets (cells that help form blood clots to stop bleeding) 
• Increase in thyroid stimulating hormone (may indicate reduced thyroid function) 
• Increase in alkaline phosphatase (may indicate liver damage or bone disorder) 
• Low albumin (may indicate liver disease, kidney disease, malnutrition, infection, 
inflammation, or thyroid disease) 
Less common (<5%) but significant drug-related side effects observed include: 
• Decrease in the pumping of the heart  
• Blood clots, including those involving the lung 
• Very high blood pressure 
• Inflammation of the pancreas 
• Decrease in white blood cells (risk of infection) with development of fever 


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• Inflammation of the colon or skin (seen with sitravatinib given alone); and inflammation of 
the lungs, colon, skin, thyroid, or heart muscle (seen with sitravatinib given with nivolumab) 
• Ischemic or hemorrhagic (bleeding) stroke 
• Life-threatening bleeding 
• Decreased sodium levels in the blood (which can manifest as loss of energy, nausea, 
vomiting, confusion and muscle spasms) 
• Decreased potassium levels in the blood (which can manifest as severe muscle weakness) 
• Increased potassium levels in the blood (which can manifest as muscle weakness, numbness, 
tingling, nausea, abdominal pain, diarrhea, chest pain, heart palpitations or arrhythmia) 
• Acute kidney injury (which can cause fatigue, loss of appetite, confusion, nausea and 
vomiting) 
• Electrocardiogram QT prolongation, effects on the electrical system of the heart, which 
might cause arrhythmias 
• Life-threatening infection 
Other less frequent (<1%) but significant adverse events that have been observed, include: 
• Heart failure or stopping of the heart 
• Heart attack 
• Hepatic encephalopathy (decline in brain function due to severe liver damage) 
• Life-threatening stomach ulcer perforation (hole) 
• Life-threatening bowel ulcer 
• A syndrome that can include headache, confusion, visual disturbances, and/or seizures, 
sometimes with stroke-like symptoms, typically occurring with hypertension (and known as 
posterior reversible encephalopathy syndrome [PRES] or reversible posterior 
leukoencephalopathy syndrome). These symptoms tend to resolve after a period of time, 
although visual changes sometimes remain 
Based on what is commonly seen in patients receiving other cancer therapies from the same class 
of drug, additional side effects may occur on this study, including difficulty with wound healing. 
Nivolumab (OPDIVO®) 
The following information is provided in the most recent FDA approved Prescribing Information 
for OPDIVO. Your study doctor will inform you of any new OPDIVO risks. 
What is the most important information I should know about OPDIVO? 
OPDIVO is a medicine that may treat your melanoma, lung cancer, kidney cancer, blood cancer 
or head and neck cancer by working with your immune system.  OPDIVO can cause your 


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immune system to attack normal organs and tissues in many areas of your body and can affect 
the way they work.  These problems can sometimes become serious or life-threatening and can 
lead to death.  These problems may happen anytime during treatment or even after your 
treatment has ended. Call or see your study doctor right away if you develop any symptoms 
of the following problems or these symptoms get worse: 
Lung problems (pneumonitis).  Symptoms of pneumonitis may include:  
• new or worsening cough  
• chest pain  
• shortness of breath 
 
Intestinal problems (colitis) that can lead to tears or holes in your intestine.  Signs and 
symptoms of colitis may include: 
• diarrhea (loose stools) or more bowel movements than usual 
• blood in your stools or dark, tarry, sticky stools 
• severe stomach-area (abdomen) pain or tenderness 
Liver problems (hepatitis).  Signs and symptoms of hepatitis may include: 
• yellowing of your skin or the whites of 
your eyes  
• dark urine (tea colored) 
• severe nausea or vomiting  
• bleeding or bruising more easily than 
normal 
• pain on the right side of your stomach area 
(abdomen)  
• feeling less hungry than usual 
• drowsiness 
• decreased energy 
 
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas).  
Signs and symptoms that your hormone glands are not working properly may include: 
• headaches that will not go away or 
unusual headaches  
• hair loss 
• extreme tiredness  
• feeling cold 
• weight gain or weight loss  
• constipation 
• dizziness or fainting  
• voice gets deeper 
• changes in mood or behavior, such as 
decreased sex drive, irritability, or 
forgetfulness 
• excessive thirst or lots of urine 
 


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Kidney problems, including nephritis and kidney failure.  Signs of kidney problems may 
include: 
• decrease in the amount of urine  
• swelling in your ankles 
• blood in your urine  
• loss of appetite 
 
Skin Problems.  Signs of these problems may include: 
• rash  
• skin blistering 
• itching  
• ulcers in mouth or other mucous 
membranes 
Problems in other organs.  Signs of these problems may include: 
• changes in eyesight  
• severe muscle weakness 
• severe or persistent muscle or joint pains 
• chest pain 
 
Getting medical treatment right away may keep these problems from becoming more 
serious. 
Your study doctor will check you for these problems during treatment with OPDIVO. Your 
study doctor may treat you with corticosteroid or hormone replacement medicines. Your study 
doctor may also need to delay or completely stop treatment with OPDIVO, if you have severe 
side effects. 
What should I tell my study doctor before receiving OPDIVO? 
Before you receive OPDIVO, tell your study doctor if you: 
• have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus 
• have had an organ transplant 
• have lung or breathing problems 
• have liver problems 
• have any other medical conditions 
• are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby. 
o Females who are able to become pregnant should use an effective method of birth control 
during and for at least 5 months after the last dose of OPDIVO. Talk to your study doctor 
about birth control methods that you can use during this time. 
o Tell your study doctor right away if you become pregnant during treatment with 
OPDIVO. 


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• are breastfeeding or plan to breastfeed. It is not known if OPDIVO passes into your breast 
milk.  Do not breastfeed during treatment with OPDIVO. 
Tell your study doctor about all the medicines you take, including prescription and over-
the-counter medicines, vitamins, and herbal supplements. 
Know the medicines you take. Keep a list of them to show your study doctor and pharmacist 
when you get a new medicine. 
What are the possible side effects of OPDIVO? 
OPDIVO can cause serious side effects, including: 
See “What is the most important information I should know about OPDIVO?” 
Severe infusion reactions.  Tell your doctor or nurse right away if you get these symptoms 
during an infusion of OPDIVO: 
• chills or shaking  
• dizziness 
• itching or rash  
• fever 
• flushing  
• feeling like passing out 
• shortness of breath or wheezing 
• back or neck pain 
Complications of stem cell transplant that uses donor stem cells (allogeneic). These 
complications can be severe and can lead to death. Your study doctor will monitor you for signs 
of complications if you have an allogeneic stem cell transplant. 
The most common side effects of OPDIVO when used alone include: 
• feeling tired 
• pain in muscles, bones, and joints 
• diarrhea 
• weakness 
• shortness of breath 
• decreased appetite 
• upper respiratory tract infection 
• headache 
• vomiting 
• rash 
• itchy skin 
• nausea 
• cough 
• constipation 
• back pain 
• fever 
• stomach area (abdominal) pain 
• urinary tract infection 
These are not all the possible side effects of OPDIVO. For more information, ask your study 
doctor. 
Unexpected and possibly severe, life-threatening or fatal side effects could occur.  This is the 
first time that sitravatinib will be given in combination with nivolumab, therefore, there may be 
side effects that have not been reported for either study drug when given alone.  The study has 


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been designed to monitor closely for side effects, but unexpected side effects are possible.  The 
long-term effects of sitravatinib and nivolumab are unknown.   
If significant new side effects or information about your disease and sitravatinib and nivolumab 
are discovered during this study, you will be told.   
This research study may involve unpredictable risks to the participants. 
Other Risks 
As with any new drug exposure, there is a risk of allergic reactions that can be fatal.  These 
reactions usually start shortly after taking the drug.  Symptoms may be skin itching and redness, 
difficulty breathing and/or low blood pressure and may be severe in some cases.   
Tell your study doctor about any side effects you are experiencing and seek medical attention 
when necessary. 
Other unknown side effects are possible. 
Blood Draws 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn.  Frequent blood 
collection may cause anemia (low red blood cell count).   
CT Scans and Bone Scans 
You may feel some discomfort or anxiety when lying inside the CT scanner.  A dye is injected 
and may cause you to get a metallic taste in your mouth, to feel warm and, rarely, experience 
nausea or vomiting.  You will be exposed to a low amount of radiation used for the CT scan.  If 
you are especially concerned with radiation exposure, you should discuss this with the study 
doctor. 
MRI Scans 
MRI examinations release radio waves, which are very noisy.  Although radio and magnetic 
waves used in MRI examinations are not associated with any known side effects, long term 
effects still remain undetermined.  You may experience brief claustrophobia (discomfort, fatigue 
or fear as a result of being in a small, enclosed space) during the MRI procedure.  If this happens, 
you may be given medication to increase your comfort level or you may request to end 
participation in the MRI procedure.  There are no known effects from exposure to the magnetic 
fields. 
ECG 
The risks during ECGs can include skin irritation and a rash due to wearing and the removal of 
the electrodes.  The electrodes only detect electrical impulses produced by the heart.  No 


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electricity passes through the body from the machine, and there is no danger of getting an 
electrical shock. 
Tumor Biopsies 
The risks of tumor biopsy include possible pain, discomfort, bleeding, swelling, scarring, 
bruising and infection, which can be life-threatening or fatal in rare cases.  To reduce these risks, 
the site of the biopsy will be numbed and sterile techniques will be used.  An allergic reaction to 
the anesthetic may occur.  A scar may form at the biopsy site.  There may be additional side 
effects, including severe side effects, depending on the location of your biopsy.  Your doctor will 
discuss with you the safest method and location to perform this biopsy. 
Pregnancy-Related Risks 
Nivolumab (OPDIVO) can harm an unborn baby.  It is not known if treatment with sitravatinib 
will also harm an unborn or breastfeeding baby.  Women enrolled in the study (or your female 
partner if you are male) should not become pregnant or breastfeed a baby during the study and 
for 6 months after treatment completion.  If you are a pregnant woman, you will not be enrolled 
in this study.   
If women enrolled in the study (or your female partner if you are a male enrolled in the study) 
become pregnant during the study, you must tell your study doctor right away.  The Sponsor may 
ask for access to both the mother and the infant’s medical records for a minimum of 3 months 
after delivery.  Should that need arise, written consent will be requested to provide such 
information. 
If you are a woman of childbearing potential or if you are a man with a partner of childbearing 
potential, you and/or your partner must use an effective form of birth control approved by the 
study doctor during the clinical study and until 6 months after the last dose of study drug, or be 
in a situation, in the opinion of the doctor, not requiring birth control (such as being post 
menopausal for more than 1 year or effective surgical sterilization). 
Examples of effective surgical sterilization include bilateral tubal ligation sterilization at least 
6 months before the screening visit, hysteroscopic sterilization (e.g., ESSURE or ADIANA 
procedure) with confirmation test (hysterosalpingogram) at least 6 months before the screening 
visit, or a vasectomy at least 6 months before the screening visit. 
Therapies to be Avoided During Participation in Study 
The following treatments to be avoided during the study: 
• Other anti-cancer treatment including chemotherapy and radiotherapy. 
• Other investigational (experimental) therapy.   
• Herbal medications and preparations. 
• Medications that are processed by liver enzymes, your doctor will council you on these. 


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• Medications known to have risk of changing the electrical activity in the heart. 
• Medications that suppress or reduce the strength of the body’s own immune system.  Some of 
these types of medications may be allowed to treat your symptoms or other medical 
conditions.  Your doctor will council you on these. 
• Vaccines against certain viruses like measles, mumps, and chickenpox.  Some types of 
vaccinations, such as the flu vaccine, are permitted.  Your doctor will council you on these. 
Other medications should only be used with caution because sitravatinib in combination with 
nivolumab may alter the way these drugs work.  Your doctor will review all medications you are 
taking. 
NEW INFORMATION 
During the study, you will be informed of any relevant new information on the study drugs 
sitravatinib and nivolumab.   
ALTERNATE PROCEDURES OR TREATMENTS 
You may choose not to take part in this study and discuss other treatment options and their 
related benefits and risks with your study doctor.  Alternatives include participation in a different 
clinical trial to receive an experimental drug or treatment with available cancer treatments 
different than those you have already received.  Your study doctor will give you more 
information about the best alternative for you. 
COSTS 
The study sponsor will provide sitravatinib free of charge for your use in this study.  You or your 
insurance provider or health plan will be responsible for all costs related to your medical care not 
covered as part of this study. 
Any tests or procedures that are being done solely for the purpose of this research study will be 
performed free of charge to you. 
You might have unexpected expenses from being in this research study.  These charges may be 
submitted to your health insurance.  However, your health insurance may not pay these charges 
because you are in a research study.  Ask the study doctor to discuss the costs that will or will 
not be covered by the sponsor. 
PAYMENT FOR PARTICIPATION 
You will not receive payment for participation in this study.   


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COMPENSATION FOR INJURY 
If, during the course of the study, you experience any injury as a direct result of taking part in 
this study, proper care will be provided to you and your insurance provider or health plan will be 
billed for the cost of treatment.  Your insurance or health plan provider may or may not pay for 
treatment of injuries as a result of your participation in this study.  If you have concerns about 
your insurance coverage, you may want to contact your insurance or health plan provider. 
There is no plan to provide any financial compensation for such injury except for what may be 
provided through remedies available to you under the law.  No money is available from the 
institution where you are being treated or from the sponsor of this study as compensation for 
research-related injury.  You will be asked to cooperate in obtaining any proceeds from 
insurance or other party coverage that may be available to you for such medical care. 
You do not waive any of your legal rights by signing this form. 
VOLUNTARY PARTICIPATION/WITHDRAWAL 
Make sure that your study doctor has answered your questions.  You can ask your study doctor 
questions at any time in the future. 
Taking part in this study is voluntary.  You can refuse to take part right now or can stop taking 
part at any time.  Deciding not to take part or deciding to leave the study later will not result in 
any penalty or any loss of benefits to which you are entitled. 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent for any of the following reasons: 
• if it is in your best interest; 
• you do not consent to continue in the study after being told of changes in the research that 
may affect you; 
• you do not continue to meet the study requirements; or 
• for any other reason. 
You will be given a copy of this signed and dated consent form. 
In no way does signing this consent form waive your legal rights nor does it relieve the study 
doctor(s), sponsor(s) or involved institutions from their legal and professional responsibilities. 
SOURCE OF FUNDING FOR THE STUDY 
Funding for this research study will be provided by Mirati Therapeutics, Inc. 


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POTENTIAL BENEFITS 
You may have an improvement in your disease from the study treatment; however this cannot be 
guaranteed.  Your condition may stay the same or get worse. We hope the information learned 
from the study will benefit other people with your condition in the future. 
AUTHORIZATION FOR USE AND DISCLOSURE OF PROTECTED 
HEALTH INFORMATION 
During the course of this study, your study doctor and the study staff at [insert site name] will be 
collecting information about you that they may share with certain individuals.  Medical/study 
records that identify you, and the consent form signed by you, may be inspected by: 
• The study sponsor and any authorized representative including study monitors and auditors 
who verify the accuracy of the study information, individuals with medical backgrounds who 
determine the effect that the study drugs have on the disease and who monitor the safety of 
the study drugs, and/or individuals who put all the study information together in report form; 
• The United States of America Food and Drug Administration (FDA); 
• Governmental agencies in other countries where the study drug is being used or considered 
for approval; and 
• [insert IRB name] 
This information may include your medical history, treatment schedule, and the results of any of 
your tests, therapies, or procedures.  The purpose of collecting this information is to learn about 
how the study drugs affect your disease and any side effects you may experience as a result of 
your treatment. 
Because of the need to release information to the parties mentioned above, absolute 
confidentiality cannot be guaranteed.  The results of this study may be presented at meetings or 
in publications.  However, your identity will not be disclosed in those presentations.  All 
reasonable steps will be taken to ensure confidentiality. 
You have the right to see and reproduce your medical/study records related to the research study 
for as long as this information is held by the study doctor.  However, in some studies, in order to 
ensure the scientific value of the study, patients are not able to view or reproduce their 
medical/study records until the research has been completed with all participants in the study.  If 
possible for this study, your study doctor will be able to discuss your clinical test results with 
you. 
There is no expiration date for the use of this information as stated in this authorization.  You 
may withdraw your authorization to share your personal health information at any time in 
writing.  Contact the study staff for specific instructions on how to do this.  If you withdraw your 
authorization, you will be removed from the study, and the study doctor and study staff will no 
longer use or disclose your personal health information in connection with this study, unless they 
need to use or disclose some of your research-related personal health information to preserve the 


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scientific value of the study.  [insert study site name] and/or the study sponsor may continue to 
use any study data that were collected before you canceled your authorization. 
If you refuse to provide your authorization to disclose your protected health information, you 
will not be able to participate in this research study. 
Your personal health information will be protected according to state and federal law.  All 
reasonable steps will be taken to ensure confidentiality. 
CONTACT INFORMATION FOR QUESTIONS OR PROBLEMS 
If you have questions about taking part in this study, if at any time you feel you have suffered a 
research-related injury or a reaction to the study drug, or if you have questions, concerns, or 
complaints about the research, you can ask your study doctor, [insert name, phone numbers, 
hours available – should be a 24 hr number]. 
If you have questions about your rights as a research patient or if you have questions, concerns or 
complaints about the research, you may contact: 
[insert IRB name, address, contact numbers] 
[insert IRB name] is a group of people who perform independent review of research. 
[insert IRB name] will not be able to answer some study-specific questions, such as questions 
about appointment times.  However, you may contact [insert IRB name] if the research staff 
cannot be reached or if you wish to talk to someone other than the research staff. 
 
 


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CONSENT/AUTHORIZATION FOR TUMOR SAMPLE AND BLOOD 
COLLECTION AND TESTING 
1. You are being asked to give permission to use samples of your tumor to test for PD-L1 signal 
molecule expression and immune system markers.  Testing of PD-L1 expression is required 
for patients who have not previously been treated with a checkpoint inhibitor.  This is 
optional for patients who have been previously treated with a checkpoint inhibitor. 
I elect to ____ or not to ____ have tumor samples tested. 
 
Patient's Initials ______ 
2. You are being asked to have one or more biopsies of your tumor during the study if your 
doctor thinks that a biopsy can be performed with only reasonable risks.  Having these 
biopsies is optional and will not determine whether you can participate in the study.  If you 
indicate now that you are willing to have these biopsies, you have the right to later change 
your mind and not have the biopsies taken.   
I elect to ____ or not to ____ have one or more biopsies of my tumor taken while 
participating in the study.  Patient's Initials ______ 
3. You are being asked to give permission to use samples of your blood to test for tumor genes.  
The testing will be done during screening and at several time points during study treatment.   
I elect to ____ or not to ____ have blood samples used for to test for tumor genes. 
Patient's Initials ______ 
4. You are being asked to give permission to collect previous test results about tumor PD-L1 
expression or tumor genes in the blood or tumor tissue. 
 
I elect to ____ or not to ____ allow collection of results from previous tests performed. 
 
 
Patient's Initials ______   
 
 


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CONSENT/AUTHORIZATION 
I have read the information in the consent form (or it has been read to me).  I have had the 
chance to ask questions about this study and reflect and consult with others as needed.  I agree to 
participate in this study.  By signing this consent form, I am not giving up any of my legal rights.  
I have been given a copy of this consent form. 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
 
PRINTED NAME OF PATIENT 
 
 
 
SIGNATURE OF PATIENT 
 
DATE 
 
-------------------------- Use this legal representative section only if applicable --------------------- 
I confirm that the information in the consent form and any other written information was 
accurately explained to the extent compatible with the patient’s understanding.  The patient 
freely consented to be in the research study. 
 
 
PRINTED NAME OF LEGAL REPRESENTATIVE 
 
 
 
SIGNATURE OF LEGAL REPRESENTATIVE 
 
DATE 
 
______________________________________________________________________ 
Authority of Patient’s Legally Authorized Representative or Relationship to Patient 
 


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-------------------------- Use this witness section only if applicable -------------------------- 
If this consent form is read to the patient because the patient is unable to read the form, an 
impartial witness not affiliated with the research or study team must be present for the consent 
and sign the following statement: 
I confirm that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the patient.  The patient freely consented 
to be in the research study. 
 
 
SIGNATURE OF IMPARTIAL WITNESS 
 
DATE 
 
Note:  This signature block cannot be used for translations into another language.  A translated 
consent form is necessary for enrolling patients who do not speak English. 


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ATTESTATION STATEMENT 
I confirm that the research study was thoroughly explained to the patient.  I reviewed the consent 
form with the patient and answered the patient’s questions.  The patient appeared to have 
understood the information and was able to answer the following questions correctly: 
1. What is the purpose of this study? 
2. If you decide to be in the study, what will you be asked to do? 
3. What is the possible benefit of participating in this study? 
4. What are the possible risks of participating in this study? 
5. If you decide not to participate in this study, what options do you have? 
6. Will participating in this study cost you anything?  If so, what will you have to pay for? 
7. Do you have to be in this study? 
8. If you decide to be in the study, can you leave the study when you want to? 
 
 
Printed Name of Person Conducting the  
Informed Consent Discussion 
 
Date 
 
 
Signature of Person Conducting the Informed 
Consent Discussion 
 
Date 
 


Signature Page for V15 VV-CLIN-000933
Signature Page for V15 VV-CLIN-000933
Approval
Lisa Latven
Director, Clinical Operations
Clinical Science
Approved
24-Oct-2021 21:36:32 GMT+0000
Approval
Ronald Shazer
Executive Medical Director
Clinical Development
Approved
25-Oct-2021 19:26:54 GMT+0000

Prot_000.pdf: 
Protocol Number: MRTX-500 
 
Official Title: A Parallel Phase 2 Study of Glesatinib, 
Sitravatinib or Mocetinostat in Combination With Nivolumab 
in Advanced or Metastatic Non-Small Cell Lung Cancer 
 
NCT Number: NCT02954991 
 
Document Date: 11-February-2020 




 
MRTX-500 v6.0 – Phase 2 in NSCLC 
Confidential 
Glesatinib, Sitravatinib, or Mocetinostat with Nivolumab 
Page 2 of 147 
 
 
 
Mirati Therapeutics, Inc. 
 
 
 
 
 
 
 
 
DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
05 May 2016 
NA 
Amendment #1, 
Version 2.0 
31 May 2016 
At the request of US Food and Drug Administration during 
IND review: 
 
Revised definition of Dose Limiting Toxicity to include 
any grade 4 non-hematologic toxicity and any toxicity 
requiring treatment suspension for more than 2 weeks.  
 
Added inclusion criterion that patients with tumors 
positive for EGFR mutation or ALK fusion must have 
received treatment with an applicable tyrosine kinase 
inhibitor. 
Amendment #2, 
Version 3.0 
06 June 2017 
Study Summary: 
 
Added study arm allowing for enrollment of 
patients who have experienced disease progression 
after prior first line chemotherapy (checkpoint 
inhibitor therapy [CIT] naïve).  Patients will be 
stratified by PD-L1 expression.  
 
Revised statistical considerations to Predictive 
Probability Design allowing for flexibility in the 
number of evaluable patients for making study 
decisions. 
Schedule of Assessments (Table 1): 
 
Added clarification for CIT Naïve cohorts for PD-
L1 testing prior to enrollment. 
 
Clarified footnote 12 to require collection of RR 
interval to calculate QTcF. 
 
Removed requirement for ECHO at Cycle 2 for 
patients in the mocetinostat and sitravatinib arms. 
 
Clarified footnote 13 for the timing of on-study 
disease evaluations to be calculated based on the 
calendar from the first day of dosing. 
Section 1 Introduction: 
 
Updated clinical data section for consistency with 
the most current version of the Investigator’s 
Brochure for glesatinib, sitravatinib and 
mocetinostat and the nivolumab package insert. 
Section 1.9 Study Rationale:  
 
Added rationale for including patients who are 
checkpoint inhibitor therapy naïve.  
Section 3 Study Design: 
 
Added study arm allowing for enrollment of 
patients who have experienced disease progression 
after prior first line chemotherapy (checkpoint 


 
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Document 
Version Date 
Summary of Changes 
inhibitor therapy [CIT] naïve).  Patients will be 
stratified by PD-L1 expression.  
 
Revised statistical considerations to Predictive 
Probability Design allowing for flexibility in the 
number of evaluable patients for making study 
decisions. 
 
Added definition of evaluable population. 
 
Nivolumab will be administered as per the approved 
labeling of 240 mg every 2 weeks (per Protocol 
Administrative letter dated 26Sep16). 
Section 4.1 Inclusion criteria: 
 
Inclusion criteria #2: updated to include patients 
who have not received prior treatment with a 
checkpoint inhibitor in the CIT naïve arm.  
 
Removed criteria #2b and included these patients in 
exclusion criteria #2. 
 
Added inclusion criteria #3 regarding PD-L1 assay 
for CIT naïve patients.  
Section 4.2 Exclusion criteria:  
 
Revised exclusion #1 to note that patients are 
eligible if brain metastases are adequately treated 
and patients are neurologically stable (except for 
residual signs or symptoms related to the CNS 
treatment) for at least 2 weeks prior to enrollment 
without the use of corticosteroids, or on a stable or 
decreasing dose of ≤ 10 mg daily prednisone (or 
equivalent). 
 
Added exclusion #1a: Patients with carcinomatous 
meningitis. 
 
Added exclusion #2: Patients who test positive for 
EGFR, ROS1, ALK mutations or ALK fusions or 
any other mutations for which there are tyrosine 
kinase inhibitors available or under development. 
 
Revised exclusion #7 to include patients with a 
history of chronic hepatitis C that is no longer 
present. 
Section 5 Study Treatments: 
 
Added reference to the Pharmacy Manual for details 
on dose strengths, bottle size and number of units 
per bottle supplied.  
Section 5.4 Concomitant medications and Appendix 3: 
 
Added sitravatinib arm patients to those who should 
avoid medications that may prolong QT interval. 
Section 7.3.5 Sample collection for PD-L1 expression: 


 
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Document 
Version Date 
Summary of Changes 
 
Added language regarding tissue sample collection 
for PD-L1 expression through the central laboratory 
for the CIT naïve cohort.  
Section 9.1.2 Statistics: 
 
Revised statistical considerations to Predictive 
Probability Design allowing for flexibility in the 
number of evaluable patients for making study 
decisions. 
 
Added statistics regarding CIT naïve patients.   
Section 9.3.2 Statistics: 
 
Added definition of Phase 2 clinical activity 
evaluable population.  
Addressed clerical errors and made minor clarifications. 
Amendment #3, 
Version 4.0 
15 June 2018 
 
Added update on status of glesatinib, sitravatinib and 
mocetinostat cohorts. 
 
Updated anticipated number of patients in study. 
 
Added update on preliminary results of sitravatinib plus 
nivolumab segment of study in Section 1.5.3.2.2. 
 
Added two sitravatinib PK sub-studies: 
o 
Appendix 5 – PK of three sitravatinib capsule 
formulations 
o 
Appendix 6 – PK of sitravatinib administered with 
food  
 
Adjusted sitravatinib CIT-experienced cohort expansion 
plan following discussion with the US FDA: combined 
CIT-experienced cohorts (prior clinical benefit and no 
prior clinical benefit) for the purpose of enrollment 
expansion, with the limit of 125 patients in the 
combined population. 
 
Eliminated potential consideration of expansion of 
enrollment into sitravatinib CIT-naïve cohorts beyond 
Stage 2. 
 
Clarified schedule for triplicate ECGs. 
 
Clarified exclusion criterion concerning patients with 
tumors having driver mutations. 
 
Updated details concerning sitravatinib free-base 
capsule content and storage. 
 
Added guidance for sitravatinib or nivolumab dose 
management: 
o 
Sitravatinib recommended Phase 2 starting dose: 
120 mg QD. 


 
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Document 
Version Date 
Summary of Changes 
o 
Following sitravatinib dose reduction and control of 
adverse event, re-challenge at a higher sitravatinib 
dose is permitted at the discretion of the 
Investigator. 
o 
In the event of sitravatinib-related AE, dose 
reduction with continuous treatment is preferred 
over repeated dose interruption. 
o 
If sitravatinib or nivolumab treatment is interrupted, 
administration of the other study drug may continue 
at the discretion of the Investigator.  
 
Updated nivolumab information and guidance to 
OPDIVO US Prescribing Information dated April 2018.  
Provided web site with current manufacturer updates for 
consultation during conduct of the study. 
o 
Updated recommended dose of nivolumab to either 
240 mg Q2W or 480 mg Q4W, infused over 
approximately 30 minutes, per Product Information 
changes and at the discretion of the Investigator. 
o 
Updated reprint of nivolumab AE management 
guidelines per OPDIVO US Product Information 
dated April 2018. 
 
Added that disease assessments will be performed until 
objective disease progression is documented or 
subsequent anti-cancer therapy is begun.   
 
Addressed clerical errors and made minor clarifications. 
Amendment #4, 
Version 5.0 
16 August 
2018 
Following FDA review of Amendment #3, Amendment # 4 
is implemented to provide additional details in the update on 
clinical experience in the sitravatinib segment of the study 
and to clarify the purpose of enrollment beyond Stage 2.  
The two amendments together describe changes to the 
protocol for Study MRTX-500.  A document showing a 
composite of the changes is available from the Sponsor.  
 
Updated preliminary safety and clinical activity results 
of ongoing studies of sitravatinib monotherapy and the 
sitravatinib plus nivolumab segment of the current study 
in Section 1.5.3.2. 
 
Clarified that the purpose of enrollment beyond Stage 2 
is to further evaluate safety and efficacy in the treatment 
setting (previous description of the purpose was to 
narrow the 95% CI around the ORR point estimate). 
 
Clarified timing of early triplicate ECGs for patients 
participating in the PK sub-studies that includes a lead-
in period. 




 
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Document 
Version Date 
Summary of Changes 
 
Provide more clarity with unacceptable toxicity on prior 
checkpoint inhibitor treatment (CIT-experienced 
patients only) within Exclusion Criterion #4 
 
Provide clarification with active or prior 
immunocompromising conditions within Exclusion 
Criterion #6 
 
Updates provided to sitravatinib formulation, packaging 
and storage within section 5.1.2.1 
 
Table 9: Sitravatinib Dose Reductions were updated 
based on sitravatinib dose formulations utilized in the 
study 
 
Table 15: Investigational Study Treatment Dose 
Modifications – Non-Hematological Drug-Related 
Toxicities was updated to provide clarity 
 
Global change: volume of water during sitravatinib 
administration was updated to keep it consistent across 
all sitravatinib dosings 
 
Global editorial changes and fix formatting errors 
 
 
 


 
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STUDY SUMMARY 
Title:  
A Parallel Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in 
Combination With Nivolumab in Advanced or Metastatic Non-Small 
Cell Lung Cancer 
Rationale:  
Combining an immunotherapeutic PD-1/PD-L1 checkpoint inhibitor 
with an agent that has both immune modulatory and antitumor 
properties could enhance the antitumor efficacy observed with either 
agent alone.   
The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well 
established based on robust clinical efficacy achieved with 
well-tolerated inhibitors directed toward oncogenic tyrosine kinases.  
In addition, selected TKIs have been shown to modulate the 
immunogenic status of tumors, improve tumor perfusion by reducing 
intratumoral pressure and modulate subsets of immune cells, 
increasing the frequency and function of effector immune elements, 
while decreasing the number and function of immune suppressor cells.  
Taken together, these effects on the tumor microenvironment (TME) 
may lead to improved efficacy when TKIs are combined with 
checkpoint inhibitors.  The TAM (Tyro3, Axl and MERTK) receptor 
tyrosine kinases (RTKs) are expressed by select innate immune cell 
subpopulations including macrophages and dendritic cells.  The TAM 
receptors cooperate to create and maintain an immunosuppressive 
TME.  MERTK suppresses the M1 macrophage pro-inflammatory 
cytokine response involving IL-12, IL-6 and TNF and enhances M2 
macrophage anti-inflammatory cytokine production involving IL-10, 
IL-4, TGFβ and hepatocyte growth factor (HGF).  Given that anti-
tumor host defense is usually mediated by cytotoxic T lymphocytes 
whose activation and stimulation is supported by Th1 type cytokines, 
the inhibition of Axl and MERTK are predicted to enhance an anti-
tumor immune response.  Furthermore, both Axl and MERTK are 
expressed by natural killer (NK) cells and negatively regulate NK cell 
activity in the TME as part of a feedback regulatory mechanism 
resulting in decreased NK cell anti-tumor activity and enhanced tumor 
progression and metastasis.  Given the immunosuppressive function of 
TAM RTKs in the TME, inhibition of Axl and MERTK may 
complement PD-1/PD-L1 checkpoint inhibition to unleash the host 
anti-cancer immune response. 
The MET (Mesenchymal-Epithelial Transition) RTK is implicated in 
modification of tumor immune responses based on its role in 
mediating an immunosuppressive TME as well as its role in regulating 
antigen presenting cell (APC) function.  MET is expressed by 


 
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immature CD14-positive monocytes and can induce an 
immunosuppressive phenotype when its ligand, hepatocyte growth 
factor (HGF), is secreted by tumor stroma and mesenchymal stem 
cells (MSCs).  Depletion of CD14-positive monocytes or 
neutralization of HGF secretion by MSCs reverses the suppression of 
T effector proliferation and triggers a shift back toward a Th1 
activated T cell phenotype.  MSCs are also implicated in expansion of 
immunosuppressive myeloid-derived suppressor cells (MDSCs), 
which are also dependent on the secretion of HGF.  APCs (i.e., 
dendritic cells) also express MET and the activation of MET by HGF 
results in suppression of APC function including both antigen 
presenting capacity and antigen-dependent T cell responses.  
Therefore, inhibition of MET may enhance the antitumor response by 
restoring APC function and reducing or eliminating MDSCs within 
the TME.   
Glesatinib is an orally administered multi-targeted TKI that primarily 
targets the Axl and MET receptors.  Additional RTK targets 
potentially include the MERTK, DDR2, and PDGFR and  
receptors.  The TKI profile of glesatinib suggests the potential for 
synergistic anti-tumor effect when administered in combination with a 
checkpoint inhibitor.   
Inhibition of the VEGF receptor family and KIT may further enhance 
antitumor immunoreactivity by depletion of immunosuppressive 
cellular subset from the TME including regulatory T cells and 
MDSCs.  T regulatory cells express VEGFR2 and the inhibition of 
VEGFR2 utilizing a specific VEGFR2 antibody antagonist or VEGFA 
neutralizing antibody (but not a VEGFR1 antagonist) inhibited Treg 
proliferation in vitro and in tumor-bearing mice and patient peripheral 
blood.  MDSCs notably express both KIT and VEGFR1 and the 
inhibition of these RTKs using pharmacologic or genetic approaches 
resulted in the inhibition of MDSC viability in vitro and depletion of 
this cell population in mouse tumor models. 
Sitravatinib is an orally-available, potent small molecule inhibitor of a 
closely related spectrum of RTKs including MET, Axl, MERTK, 
VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, 
and selected Eph family members.  In addition to the 
immunostimulatory effects of Axl and MET inhibition, sitravatinib 
may further condition the TME in favor of antitumor activity by its 
immunomodulatory effects mediated through VEGFR and KIT 
inhibition.   


 
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Histone deacetylases (HDACs) have been implicated in the epigenetic 
regulation of innate and adaptive immunity.  Increasing evidence 
supports the proposal that spectrum-selective inhibitors of class I 
HDACs can reverse immune evasion and elicit antitumor host 
response through immunostimulatory mechanisms.  The 
immunomodulatory properties of class I HDAC inhibitors are reported 
to be mediated through multiple mechanisms including: 1) induction 
of programmed cell death ligand 1 (PD-L1) expression on the tumor 
cell surface, 2) induction of tumor associated antigens (TAAs) and 
MHC Class I and Class II molecules on tumor cells, 3) induction of 
immunogenic cell death via activation and cross-presentation of tumor 
antigens by antigen presenting cells (APCs), 4) enhanced function of 
T effector cells, and 5) decreased function of immunosuppressive cell 
subsets including Tregs and MDSCs.  In addition, HDAC inhibitors 
are associated with anticancer effects through inhibiting cell cycle 
progression and inducing apoptosis in tumor cells.   
Mocetinostat is an orally administered spectrum-selective Class I/IV 
HDAC inhibitor specifically targeting HDACs 1, 2, 3 and 11.  Given 
these pleiotropic immune activating effects of class I HDAC 
inhibitors, combination therapy of mocetinostat with checkpoint 
inhibition may result in increased efficacy compared to 
immunotherapy alone.   
Nivolumab is a human immunoglobulin G4 (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. 
This study will evaluate the clinical activity of nivolumab in 
combination with 3 separate investigational agents, glesatinib, 
sitravatinib or mocetinostat.  The study will begin with a lead-in dose 
escalation evaluation in small cohorts of patients administered one of 
the investigational study treatments in combination with nivolumab.  
Following identification of the dose level to be used in the Phase 2 
evaluation for each investigational study treatment, full enrollment 
will proceed.   
Target 
Population: 
Patients with advanced or metastatic non-squamous NSCLC, who 
have experienced disease progression on or after prior treatment with 
a checkpoint inhibitor therapy (CIT) (CIT- experienced) or patients 
who have experienced disease progression after prior first line 
platinum-based doublet chemotherapy (CIT- naive).  


 
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Number in 
Trial:  
As many as 280 patients.   
Primary 
Objective:  
To evaluate the clinical activity of nivolumab in 3 combination 
regimens with the investigational agents glesatinib, sitravatinib, or 
mocetinostat, in patients with non-squamous NSCLC. 
Secondary 
Objectives: 
 To evaluate the safety and tolerability of the combination 
regimens in the selected population. 
 To evaluate secondary efficacy endpoints of the combination 
regimens in the selected population. 
 To evaluate the pharmacokinetics (PK) of the investigational 
agents administered in combination with nivolumab. 
 To evaluate the PK of three sitravatinib capsule formulations. 
 To evaluate the PK of sitravatinib administered with food. 
Exploratory 
Objectives: 
 
 
 
 
 
 
 
 
 
 
Primary 
Endpoints: 
Objective Response Rate (ORR) as defined by Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Secondary 
Endpoints: 
 Safety characterized by type, incidence, severity, timing, 
seriousness and relationship to study treatment of adverse events 
and laboratory abnormalities. 
 Secondary efficacy endpoints: 
o Duration of Response (DR); 
o Clinical Benefit Rate (CBR); 
o Progression-Free Survival (PFS); 


 
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o 1-Year Survival Rate; and 
o Overall Survival (OS). 
 Blood plasma concentrations of the investigational agents. 
Exploratory 
Endpoints: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Segment 
Update 
June 2018 
Glesatinib:  Enrollment into glesatinib cohorts was discontinued in 
November 2017 as the result of Sponsor portfolio reprioritization.  
The decision was not based on patient safety in Study MRTX-500.  
Five patients were treated with nivolumab plus glesatinib in this study.  
Sitravatinib:  Enrollment is ongoing in all sitravatinib cohorts.  A brief 
summary of preliminary results available to date is presented in 
Section 1.5.3.2.2.  
Mocetinostat:  Enrollment into mocetinostat cohorts is not planned at 
this time.  Results from a parallel Phase 1/2 clinical trial of 
mocetinostat in combination with durvalumab, a PD-L1 inhibitor, are 
pending.  Plans for further investigation of mocetinostat in 
combination with checkpoint inhibitor therapies are pending.  
Study Design: 
Study MRTX-500 is an open-label, parallel Phase 2 evaluation of 
nivolumab in combination with 3 investigational agents, glesatinib, 
sitravatinib or mocetinostat, in patients with locally advanced, 
unresectable or metastatic non-squamous NSCLC.  Patients who have 
experienced progression of disease on or after treatment with a 
checkpoint inhibitor (CIT-experienced) as well as those who have 
experienced disease progression after treatment with platinum-based 
doublet chemotherapy (CIT- naïve) will be enrolled.  The primary 


 
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objective is to evaluate the clinical activity of the combination study 
treatments using ORR in accordance with RECIST 1.1.  Secondary 
objectives include evaluation of safety, secondary efficacy endpoints, 
and PK for the investigational agents.  The Schedule of Assessments 
to be performed in the study is presented in Table 1.  Pharmacokinetic 
and blood biomarker sample collection and triplicate ECG assessment 
time points are presented in Table 2, Table 3, and Table 4.  Specifics 
of two sitravatinib sub-studies are presented in appendices, including 
the PK evaluation of three sitravatinib capsule formulations 
(Appendix 5) and the PK of sitravatinib administered with food 
(Appendix 6). 
The treatment arms included in this study are the following: 
1. Glesatinib plus nivolumab. 
2. Sitravatinib plus nivolumab. 
3. Mocetinostat plus nivolumab. 
To control bias in assignment of individual patients to treatment arms 
and to mitigate the risk of medication errors with the 3 investigational 
study treatments administered in specific regimens, study sites will be 
aligned with one specified treatment combination.  Site alignment 
may change as patient cohorts are filled or patient recruitment factors 
shift at sites. 
The study will begin with a lead-in dose escalation evaluation of two 
dose levels of each investigational agent in combination with 
nivolumab in small cohorts of CIT-experienced patients.  The dose 
escalation plan is described below under Study Treatments and in 
more detail in Section 3.1.   
Following completion of the lead-in dose escalation evaluation, 
enrollment into the Phase 2 will proceed.   
For CIT-experienced patients, each investigational study treatment 
arm (i.e., glesatinib, sitravatinib and mocetinostat) will be stratified by 
prior outcome of treatment with a checkpoint inhibitor: 
a. Clinical benefit (i.e., RECIST defined partial, complete response 
or stable disease for at least 12 weeks [-2 week window permitted 
for radiograph scheduling]) followed by radiographic progression 
of disease. 


 
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b. No prior clinical benefit (i.e., radiographic progression of disease 
≤ 12 weeks after initiation of treatment [+2 week window 
permitted for radiograph scheduling]).   
For patients without prior checkpoint inhibitor therapy (CIT-naïve), 
each investigational study treatment arm (i.e., glesatinib, sitravatinib, 
and mocetinostat) will be stratified according to PD-L1 status: 
a. Having tumor with no/low PD-L1 expression. 
b. Having tumor with high PD-L1 expression. 
Tumor PD-L1 expression will be determined by the PD-L1 (28-8) 
companion diagnostics (CDx) assay completed through the central 
laboratory.  No/low PD-L1 expression is defined as positivity < 5% of 
tumor cells; high PD-L1 expression is defined as positivity ≥ 5% of 
tumor cells.  Tumor samples used to establish PD-L1 expression for 
eligibility must have been collected after the most recent systemic 
therapy. 
The main Phase 2 study will include 12 parallel evaluations of clinical 
activity of nivolumab combination regimens (depicted in the figure 
below).  A Predictive Probability Design will be applied to each 
treatment arm, as described under Statistical Considerations.  Patients 
enrolled in the lead-in dose escalation evaluation and receiving the 
dose of investigational study treatment selected for the Phase 2 study 
will be included in the analysis of the Phase 2 endpoints.   
 




 
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Disease response and progression as documented by the Investigator in 
the Case Report Form (CRF) will be the basis for patient management 
and study expansion decision making.  Unconfirmed objective 
responses recorded in the CRF may be used as the initial basis for 
expansion of study enrollment; however, follow-up evaluations on 
patients with unconfirmed responses must continue to support the 
decision to continue to the full number of patients to be included in the 
next stage.  Disease assessments will be performed until objective 
disease progression is documented or subsequent anti-cancer therapy is 
begun.  Central radiology review for disease response and progression 
may be added to the study during Stage 2.  If this occurs, central 
review of all radiologic assessments performed in the study will be 
expected (including retrospective review of patients enrolled in Stage 
1), and central radiology review for disease response will be the basis 
for the primary statistical analyses to estimate the objective response 
rate and its confidence interval, as well as the duration of response and 
PFS. 
Study 
Treatments: 
Throughout the study, nivolumab will be administered in accordance 
with approved labeling.  Nivolumab is to be administered by 
intravenous infusion, using either regimen included in the approved 
label: 240 mg every 2 weeks (Q2W) or 480 mg every 4 weeks (Q4W).  
Guidance for adverse event management and associated nivolumab 
treatment modifications are provided in product labeling and replicated 
in Section 5.2. 
The investigational agents will be administered in the following 
regimens: 
1. 
Glesatinib tablets administered orally, twice daily (BID).   
2. 
Sitravatinib capsules administered orally, once daily (QD).   
3. 
Mocetinostat capsules administered orally, three times weekly 
(TIW, e.g., Monday, Wednesday and Friday). 
The study will begin with a lead-in dose escalation evaluation of two 
dose levels of each investigational agent in combination with 
nivolumab in small cohorts of CIT-experienced patients.  In addition, a 
dose de-escalation step may be undertaken as appropriate.   
 
 


 
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Investigational Study Drug Starting Dose Levels for Cohorts 
of Patients in the Lead-In Dose Evaluation 
Drug 
Regimen 
Dose Escalation Steps 
1 
2 
-1 
Glesatinib 
Tablets 
Twice Daily 
500 mg 
750 mg 
350 mg 
Sitravatinib 
Capsules  
Once Daily 
120 mg 
150 mg 
80 mg 
Mocetinostat 
Capsules 
Three Times 
Weekly 
70 mg 
90 mg 
50 mg 
Guidelines for adverse event management and associated treatment 
modifications of each agent are provided in Section 5.1. 
The dose escalation phase of the study will employ the modified 
toxicity probability interval (mTPI) method for dose escalation and 
reduction decision making.   
Statistical 
Considerations: 
This Phase 2 study will use a Predictive Probability Design (Lee-2008) 
in each treatment arm and strata.  In creating the statistical designs, the 
Type 1 error (α) is constrained to <0.05 and Power (1-β) is constrained 
to ≥0.90.   
Statistical Design Applied to CIT-Experienced and CIT-Naïve with 
No/Low PD-L1 Expression 
The ORR using nivolumab in the population with advanced non-
squamous NSCLC having prior disease progression on a checkpoint 
inhibitor or patients with non-squamous NSCLC without prior 
checkpoint inhibitor therapy with no/low PD-L1 expression is assumed 
to be 5% (p0); thus, this rate is considered uninteresting.  The target 
ORR using the investigational agents in combination with nivolumab in 
this study is 30% (p1).  Stage 1 of enrollment will include a minimum 
of 9 evaluable patients in each treatment strata. With exactly 9 
evaluable patients at Stage 1, if at least 1 patient has an Objective 
Response, 8 additional evaluable patients will be enrolled in the 
treatment stratum, for a total sample size of 17 evaluable patients.  If at 
least 3 Objective Responses are observed in a treatment stratum, further 
investigation may be warranted.  If the true ORR is 5% (null 
hypothesis), the probability of early termination during the study is 
0.63; the Type 1 error is equal to 0.0466 and the power is equal to 
0.9045.   


 
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Statistical Design Applied to CIT-Naïve with High PD-L1 
Expression 
The ORR using nivolumab in the population with non-squamous 
NSCLC having high PD-L1 expression is assumed to be 27% (p0); thus, 
this rate is considered uninteresting.  The target ORR using the 
investigational agents in combination with nivolumab is 50% (p1).   
Stage 1 of enrollment will include approximately 17 evaluable patients. 
With exactly 17 evaluable patients at Stage 1, if at least 5 patients have 
Objective Responses, 27 additional evaluable patients will be enrolled, 
for a total sample size of 44 evaluable patients.  If at least 18 Objective 
Responses are observed, further investigation may be warranted.  If the 
true ORR is 27% (null hypothesis), the probability of early termination 
during the study is 0.50; the Type 1 error is equal to 0.0303 and the 
power is equal to 0.9018.   
The exact stopping rules for all cohorts will be calculated based on the 
Predictive Probability Design, once the exact number of patients 
evaluable at Stage 1 is known. The aim is to get a minimum of 9 
evaluable patients at Stage 1 for CIT-experienced and CIT-naïve with 
no/low PD-L1 expression cohorts and a minimum of 17 evaluable 
patients at Stage 1 for CIT-naïve with high PD-L1 expression cohort. 
Expansion Beyond Stage 2 
The original protocol provided that if results in any strata were of high 
interest for efficacy, enrollment might be expanded to as many as 100 
patients total in each cohort to narrow the 95% Confidence Interval (CI) 
around the ORR point estimate.  Protocol Amendment 3 (Version 4.0) 
eliminates enrollment expansion beyond Stage 2 except in the 
sitravatinib segment of the study enrolling patients with CIT-
experience.   
For the sitravatinib segment of the study enrolling patients with CIT-
experience, expansion of enrollment beyond Stage 2 will be managed as 
one cohort that includes all patients, regardless of prior clinical benefit 
during treatment with CIT.  Based on preliminary clinical activity 
results (described in Section 1.5.3.2.2), enrollment into the combined 
cohort will expand to as many as 125 patients total, to further evaluate 
safety and efficacy in this setting.   
Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of 
enrollment is not anticipated. 


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Table 1: 
Schedule of Assessments  
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 adverse events. 
Assessments 
Screen/ 
Baseline 
Cycle 1 
Cycle 2 and 3 
≥ Cycle 4 
End of Treatment15 
Within 28 
days 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
 (± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before 
study 
specific 
assessments 
 
 
 
 
 
 
 
 
Tumor Tissue Collection 
for PD-L1 Expression and 
Tumor Gene Alterations2 
X 
 
 
 
 
 
 
 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
 
X 
 
Abbreviated Physical 
Exam3 
 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test5 
X 
As clinically indicated 
 
Hematology6,7 
X 
X 
X 
X 
X 
X 
 
X 
 


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Table 1: 
Schedule of Assessments (Continued) 
Assessments 
Screen/ 
Baseline 
Cycle 1 
Cycle 2 and 3 
≥ Cycle 4 
End of Treatment15 
Within 28 
days 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15   
 (± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Coagulation6,7 
X 
As clinically indicated 
 
Urinalysis6,7 
X 
As clinically indicated 
 
Serum Chemistry6,7 
X 
X 
X 
X 
X 
X 
 
X 
 
Thyroid Function Test6,7 
X 
X 
 
X 
 
X 
 
X 
 
Blood for 
Pharmacokinetics8 
 
See Table 2, Table 3, and Table 4 and sub-study appendix Table 22, Table 23, Table 24, and Table 25 
 
Biopsy of Tumor for 
Biomarker Studies 
(Optional)9 
 
Pre-dose X 
 
Cycle 2  
Only 
X 
 
 
 
X 
 
Blood Samples – Flow 
Cytometry10 
X 
See Table 2, Table 3, and Table 4 
X 
 
Blood Samples – Protein 
and Cytokine Biomarkers10 
 
See Table 2, Table 3, and Table 4 
X 
 
ctDNA blood sample11 
X 
 
 
Time of confirmation of disease response PR or CR 
X 
 
Single 12-Lead ECG12 
X 
As clinically indicated except – 
Mocetinostat arm: Day 1 of each treatment cycle 
X 
 
Triplicate 12-Lead ECG12 
 
See Table 2, Table 3, and Table 4 
 
 


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Table 1: 
Schedule of Assessments (Continued) 
Assessments 
Screen/ 
Baseline 
Cycle 1 
Cycle 2 and 3 
≥ Cycle 4 
End of Treatment15 
Within 28 
days 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
 (± 2 days) 
Day 1 
(± 2 days) 
Day 15 
 (± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Echocardiogram 
(Mocetinostat and 
Sitravatinib Treatment 
Arms Only) 
X 
 
X 
Mocetinostat 
arm only 
X 
Cycle 3 only 
 
X 
Mocetinostat 
arm only 
 
X 
 
Disease Evaluation13 
X 
 
Every 8 weeks (± 10 days) for ~1 year  
and then every 16 weeks 
 
Investigational Agent 
Dispensing and/or 
Reconciliation 
 
X 
 
X 
 
X 
 
 
 
Nivolumab 
Administration 
 
X 
X if Q2W 
X 
X if Q2W 
X 
X if Q2W 
 
 
Adverse Events14 and 
Concomitant Medications 
SAEs only 
Throughout 
 
Long Term Follow-up16 
 
 
 
 
 
 
 
 
X 
1 
Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to 
initiation of any study specific assessments.   
2 
Tumor Testing for PD-L1 Expression and Tumor Gene Alterations: Encouraged for all patients.  Archival tumor tissue allowed.  For patients enrolled in 
CIT Naïve cohorts, the sample must have been collected following the completion of the most recent systemic treatment regimen and the central 
laboratory testing is to begin prior to study entry.  Biopsy may precede informed consent if performed as Standard of Care (SOC) or to assess eligibility 
for a different clinical trial.   
3 
Physical Examinations: A complete physical examination required at Screening and End of Treatment only.  Height will be recorded at screening only.  
All other evaluations will be symptom-directed, abbreviated evaluations.   
4 
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated.   


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5 
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.   
6 
Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.   
7 
Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 19) will be performed by 
local laboratories.   
8 
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2, Table 3 and Table 4 
and sub-study appendix Table 22, Table 23, Table 24, and Table 25.  In addition, 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 the investigational agent.   
9 
Tumor Biopsy for Biomarker Studies:  Consent for serial sampling of tumor tissue (preferably the same lesion) is requested but is not mandatory for 
study entry.  If tumor biopsy has been performed during screening, then that biopsy may be used for the baseline assessment.  Markers of interest in 
tumor tissue include PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) including proliferating (Ki67+) CD8+ cells, natural killer cells 
(NK-cells), T regulatory cells (Tregs), macrophages and myeloid derived suppressor cells (MDSCs).  Gene expression analyses may also be performed.   
10 
Blood Samples for Biomarker Studies:  Blood samples for flow cytometry and protein/cytokine assays will be collected as outlined in Table 2, Table 3 
and Table 4.  Markers of interest in circulation include circulating PD-L1, Tregs, MDSCs, NK-cells, flow cytometry for T- and B-cell including CD4, 
CD8 and Ki67, monocytes and selected cytokines including CD8A, GZMB, IFNγ, CXCL9, CXCL10, CXCL11, and TBX21.  Patients participating in 
the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 are exempt from sample collection for biomarker 
studies, including flow cytometry and protein/cytokine assays.   
11 
Blood samples for ctDNA analysis:  Blood will be collected in two 10ml Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and 
stability at ambient temperatures.   
12 
12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 2, Table 3 and Table 4.  Only for the mocetinostat containing 
treatment arm, ECGs are to be performed on Day 1 of each cycle, either as a triplicate ECG accompanying PK or as a single ECG.  In addition, ECGs 
are to be performed as clinically indicated.  Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and QTc intervals.  RR 
interval should be recorded during each ECG assessment in order to calculate QTcF.   
13 
Disease Evaluations: To be performed at screening (28 day window allowed) and every 8 weeks from Cycle 1 Day 1 (± 10 days window for all other 
assessments except screening) until Week 49 (~1 year) and then every 16 weeks.  All on-study disease evaluations should be based on a calendar 
beginning from the first day of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, abdomen and pelvis, as well as 
brain Magnetic Resonance Imaging (MRI) with and without gadolinium or Computed Tomography Scan (CT) with contrast, a whole body bone scan 
and evaluation of any superficial lesions.  Subsequent disease assessments should include all sites of disease identified at baseline or suspected to have 
developed; bone scans may be performed half as often (every 16 weeks) as other radiology evaluations and should be performed during assessment for 
confirmation of disease response.  More detailed guidance on exceptional circumstances is provided in the protocol.   
14 
Adverse Events: SAEs will be reported from the time of informed consent until at least 28 days after the last administration of investigational agent or 
nivolumab.  Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution 
or stabilization of acute AEs and/or ongoing SAEs.   


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15 
End of Treatment: All patients will be followed for AEs for at least 28 days after the last dose of Study Treatment.  Assessments that have been 
completed in the previous 4 weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule).   
16 
Long Term Follow-up: Survival status and subsequent therapies will be collected during long term follow-up every 2 months (±14 days) from the End 
of Treatment visit until death or lost to follow-up. Follow-up may be performed by telephone contact.   
 


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Table 2: 
Glesatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments   
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1  
Day 15  
(± 2 days) 
Cycle 2, 3, 5  
Day 1  
(± 2 days) 
Cycle 2  
Day 15   
(± 2 days) 
Collection Time and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 
hour) 
30 min  
(± 10 
min) 
3 hour 
(2-4 hour) 
6 hour 
(5-8 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 
hour) 
PK Sample 1 
 
X 
X 
X 
X 
X 
X 
X 
Flow Cytometry 2 
X 
X 
 
 
 
X 
 
 
Protein and Cytokine Biomarkers 2 
 
X 
 
 
 
X 
 
 
Triplicate ECG 3 
 
X 
 
X 
 
X 
X 
X 
1 
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Glesatinib dosing and sampling should precede nivolumab infusion. 
2 
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the 
same day as the pre-dose Cycle 1 Day 1 sample.   
3 
ECGs should be taken in triplicate, each reading at least 2 minutes apart.  On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 minutes 
prior to dosing (e.g., at 15 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.   
 
 


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Table 3: 
Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments  
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1  
Day 15  
(± 2 days) 
Cycle 2, 3, 5  
Day 1  
(± 2 days) 
Cycle 2 
Day 15  
(± 2 days) 
Collection Time and 
Allowable Window 
Within 28 
days 
Pre-dose 
30 min  
(± 10 min) 
4 hour 
(3-5 hour) 
6 hour 
(5.5-8 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PK Sample 1, 4 
 
X 
X 
X 
X 
X 
X 
X 
Flow Cytometry 2, 5 
X 
X 
 
 
 
X 
 
 
Protein and Cytokine 
Biomarkers 2, 5 
 
X 
 
 
X 
 
 
Triplicate ECG 3, 6 
 
X 
(-1 
hour) 
X 
(-0.5 
hour) 
 
X 
 
X 
X 
X 
1 
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede nivolumab infusion.   
2 
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing.  The screen/baseline sample should not be collected on the 
same day as the pre-dose Cycle 1 Day 1 sample. 
3 
ECGs should be taken in triplicate, each reading approximately 2 minutes apart.  On Cycle 1 Day 1 only, two sets of triplicate ECGs should be done 
within 1 hour prior to dosing (e.g., at 30 minute intervals prior to dosing) to firmly establish the baseline for the patient.  One set of triplicate ECGs is 
required at all other time points. In general, ECGs should be performed prior to the respective PK blood collection.  Examples of the schedule are 
presented below: 
o 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
o 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK).  
4 
Sample schedules for sitravatinib formulation and food effect evaluations are presented in Appendix 5 and Appendix 6, Table 22, Table 23, Table 24, and 
Table 25.  
5 
Patients participating in the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 are exempt from sample 
collection for biomarker studies, including flow cytometry and protein/cytokine assays. 
6 
Patients participating in the sitravatinib formulation and food effect sub-studies described in Appendix 5 and Appendix 6 will undergo evaluation by 
triplicate ECG on Lead-In Day 1 instead of Cycle 1 Day 1.   
 
 


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Table 4: 
Mocetinostat Schedule of PK, Biomarker Samples and Triplicate ECG Assessments 
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1 Day 15 (± 2 days) 
Cycle 2, 3, 5 
Day 1 (± 2 days) 
Collection Time 
and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 
hour) 
1 hour  
(0.5-1.5 
hour) 
3 hour 
(2-4 hour) 
7 hour 
(6-8 
hour) 
Pre-dose 
(-0.5-0 
hour) 
1 hour  
(0.5-1.5 
hour) 
Pre-dose 
(-0.5-0 
hour) 
1 hour  
(0.5-1.5 
hour) 
PK Sample 1 
 
X 
X 
X 
X 
X 
X 
X 
X 
Flow Cytometry 2 
X 
X 
 
 
 
X 
 
 
 
Protein and 
Cytokine 
Biomarkers 2 
 
X 
 
 
 
X 
 
 
 
Triplicate ECG 3 
 
X 
X 
 
 
X 
 
X 
X 
1 
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  On days mocetinostat and nivolumab are both administered and 
scheduled for PK assessment, mocetinostat dosing and sampling should precede nivolumab infusion.   
2 
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the 
same day as the pre-dose Cycle 1 Day 1 sample.   
3 
ECGs should be taken in triplicate, with readings at least 2 minutes apart. On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 
minutes prior to dosing (e.g., at 15 minute intervals) to firmly establish the baseline.  In general, ECGs should be performed prior (within -30 to -5 
minutes) to the respective PK blood collection. 
 


 
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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
DOCUMENT HISTORY ..................................................................................................2 
STUDY SUMMARY ..........................................................................................................8 
TABLE OF TABLES .......................................................................................................31 
TABLE OF FIGURES .....................................................................................................32 
LIST OF ABBREVIATIONS .........................................................................................33 
1 
INTRODUCTION AND RATIONALE .................................................................36 
1.1 
Disease and Therapeutic Strategy ...............................................................36 
1.1.1 
Non-Small Cell Lung Cancer .....................................................36 
1.2 
Overall Rational for Proposed Combination Regimens ............................37 
1.3 
Checkpoint Pathway .....................................................................................38 
1.4 
Glesatinib Background .................................................................................38 
1.4.1 
Glesatinib Drug Substance .........................................................39 
1.4.2 
Non-Clinical Data .......................................................................39 
1.4.3 
Clinical Experience .....................................................................40 
1.5 
Sitravatinib Background ..............................................................................41 
1.5.1 
Sitravatinib Drug Substance ......................................................42 
1.5.2 
Non-Clinical Data .......................................................................42 
1.5.3 
Sitravatinib Clinical Experience ...............................................43 
1.6 
Mocetinostat Background ............................................................................47 
1.6.1 
Mocetinostat Drug Substance ....................................................47 
1.6.2 
Mocetinostat Non-Clinical Data ................................................48 
1.6.3 
Mocetinostat Clinical Data .........................................................51 
1.7 
Nivolumab .....................................................................................................52 
1.7.1 
Nivolumab Drug Substance .......................................................52 
1.7.2 
Nivolumab Non-Clinical Data ...................................................52 
1.7.3 
Nivolumab Clinical Data ............................................................53 
1.8 
Expectations for Combination of Study Investigational Agents 
and Nivolumab ..............................................................................................58 
1.8.1 
Potential for Drug-Drug Interactions .......................................58 
1.8.2 
Evaluation of Potential for Increased Toxicities with 
Combination Use of Nivolumab and Study 
Investigational Agents ................................................................58 
1.9 
Study Rationale .............................................................................................59 
2 
STUDY OBJECTIVES ............................................................................................62 
2.1 
Objectives ......................................................................................................62 
2.1.1 
Primary Objective ......................................................................62 
2.1.2 
Secondary Objectives .................................................................62 
2.1.3 
Exploratory Objectives ..............................................................63 
2.2 
Endpoints .......................................................................................................63 
2.2.1 
Primary Endpoints .....................................................................63 
2.2.2 
Secondary Endpoints ..................................................................63 


 
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2.2.3 
Exploratory Endpoints ...............................................................63 
3 
STUDY DESIGN ......................................................................................................64 
3.1 
Lead-In Dose Escalation Evaluation ...........................................................65 
3.1.1 
Definition of Dose Limiting Toxicity .........................................65 
3.1.2 
Enrollment and Dose Escalation Plan .......................................66 
3.1.3 
Definition of Maximum Tolerated Dose ...................................67 
3.1.4 
Selection of Phase 2 Dose for Investigational Study 
Drugs ............................................................................................67 
3.2 
Phase 2 Study ................................................................................................67 
4 
PATIENT SELECTION AND ENROLLMENT ...................................................73 
4.1 
Inclusion Criteria ..........................................................................................73 
4.2 
Exclusion Criteria .........................................................................................74 
4.3 
Life Style Guidelines .....................................................................................77 
4.4 
Enrollment into Study ..................................................................................77 
5 
STUDY TREATMENTs ..........................................................................................78 
5.1 
Investigational Agents ..................................................................................78 
5.1.1 
Glesatinib .....................................................................................78 
5.1.2 
Sitravatinib ..................................................................................80 
5.1.3 
Mocetinostat ................................................................................85 
5.1.4 
Instructions Common to Investigational Study 
Treatments ...................................................................................89 
5.2 
Nivolumab Study Drug.................................................................................93 
5.2.1 
Formulation and Packaging .......................................................93 
5.2.2 
Preparation and Dispensing .......................................................93 
5.2.3 
Administration ............................................................................94 
5.2.4 
Infusion Modification and Discontinuation..............................94 
5.2.5 
Nivolumab Adverse Event Management Guidelines ...............96 
5.3 
Medication Error ..........................................................................................98 
5.4 
Concomitant Therapies ................................................................................98 
5.4.1 
Concomitant Medication(s) ........................................................98 
5.4.2 
Concomitant Surgery or Radiation Therapy .........................100 
5.4.3 
Other Anticancer or Experimental Therapy .........................100 
6 
STUDY ASSESSMENTS .......................................................................................100 
6.1 
Screening .....................................................................................................100 
6.2 
Study Period ................................................................................................101 
6.3 
End of Treatment Assessment ...................................................................101 
6.4 
Long-Term Follow-up and End of Study Assessment .............................101 
6.5 
Patient Discontinuation/Withdrawal ........................................................101 
7 
PROCEDURES .......................................................................................................102 
7.1 
Efficacy ........................................................................................................102 
7.2 
Safety Assessments ......................................................................................104 
7.2.1 
Adverse Events ..........................................................................104 
7.2.2 
Physical Examination and Vital Signs ....................................104 
7.2.3 
Laboratory Safety Assessments ...............................................104 
7.2.4 
Electrocardiogram (ECG) ........................................................105 


 
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7.2.5 
Echocardiogram (ECHO) ........................................................105 
7.3 
Laboratory Studies .....................................................................................106 
7.3.1 
Pharmacokinetic Evaluation....................................................106 
7.3.2 
Pharmacodynamic Evaluation in Tumor Tissue ...................106 
7.3.3 
Pharmacodynamic Evaluation in Blood .................................106 
7.3.4 
Circulating Tumor DNA ..........................................................107 
7.3.5 
Sample Collection for PD-L1 Expression and Tumor 
Gene Alterations .......................................................................107 
7.4 
Post-treatment Follow-up ..........................................................................107 
8 
ADVERSE EVENT REPORTING .......................................................................108 
8.1 
Sponsor Medical Monitor Personnel ........................................................108 
8.2 
Adverse Events ............................................................................................108 
8.2.1 
Laboratory Abnormalities .......................................................109 
8.2.2 
Severity Assessment ..................................................................109 
8.2.3 
Causality ....................................................................................109 
8.3 
Serious Adverse Events ..............................................................................110 
8.3.1 
Definition of a Serious Adverse Events ...................................110 
8.3.2 
Exposure During Pregnancy ....................................................111 
8.4 
Reporting of SAEs and AEs .......................................................................112 
8.4.1 
Reporting Period .......................................................................112 
8.4.2 
Reporting Requirements ..........................................................112 
9 
STATISTICS ...........................................................................................................113 
9.1 
Hypothesis and Sample Size ......................................................................113 
9.1.1 
Lead-In Dose Escalation Evaluation .......................................113 
9.1.2 
Phase 2 .......................................................................................114 
9.2 
Data Handling .............................................................................................115 
9.3 
Analysis Populations ...................................................................................116 
9.3.1 
Modified Intent-to-Treat Population ......................................116 
9.3.2 
Clinical Activity Evaluable Population ...................................116 
9.3.3 
Safety Population ......................................................................116 
9.3.4 
Molecular Marker Evaluable Population ...............................116 
9.3.5 
Pharmacokinetic Evaluable Population .................................116 
9.3.6 
Pharmacodynamic Evaluable Population ..............................116 
9.4 
Efficacy Endpoint Definitions and Analyses ............................................117 
9.4.1 
Objective Response Rate ..........................................................117 
9.4.2 
Clinical Benefit Rate .................................................................117 
9.4.3 
Duration of Response ...............................................................117 
9.4.4 
Progression Free Survival ........................................................117 
9.4.5 
Overall Survival ........................................................................118 
9.5 
Safety Data Presentations and Summaries ...............................................118 
9.5.1 
Adverse Events ..........................................................................118 
9.5.2 
Prior and Concomitant Medications .......................................118 
9.5.3 
Clinical and Laboratory Assessments .....................................118 
9.5.4 
Patient Demographics, Baseline Characteristics and 
Disposition .................................................................................119 


 
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9.5.5 
Analysis of Study Treatment Dosing.......................................119 
9.6 
Other Study Endpoints...............................................................................119 
9.6.1 
Pharmacokinetic Analysis ........................................................119 
9.6.2 
Pharmacodynamic and Exploratory Analyses .......................120 
9.7 
Interim Analysis ..........................................................................................120 
9.8 
Data Monitoring Committee ......................................................................120 
10 ETHICS AND RESPONSIBILITIES ...................................................................120 
10.1 
Ethical Conduct of the Study .....................................................................120 
10.2 
Obligations of Investigators .......................................................................120 
10.3 
Institutional Review Board/Ethics Committee/Research Ethics 
Board (IRB/EC) ..........................................................................................121 
10.4 
Informed Consent Form .............................................................................121 
10.5 
Confidentiality.............................................................................................121 
10.6 
Reporting of Serious Breaches of the Protocol or ICH GCP ..................122 
11 RECORDS MANAGEMENT................................................................................122 
11.1 
Source Documentation ...............................................................................122 
11.2 
Study Files and Records Retention ...........................................................122 
12 QUALITY CONTROL AND QUALITY ASSURANCE ....................................123 
12.1 
Monitoring Procedures ..............................................................................123 
12.2 
Auditing and Inspection Procedures .........................................................123 
13 CHANGES IN STUDY CONDUCT .....................................................................123 
13.1 
Protocol Amendments ................................................................................123 
13.2 
Protocol Deviations .....................................................................................124 
14 END OF TRIAL ......................................................................................................124 
14.1 
End of Trial in a European Union Member State ...................................124 
14.2 
End of Trial in all other Participating Countries ....................................124 
14.3 
Premature Termination .............................................................................124 
15 STUDY REPORT AND PUBLICATION POLICY ............................................125 
16 REFERENCES .......................................................................................................125 
APPENDIX 1. ECOG PERFORMANCE STATUS ...................................................129 
APPENDIX 2. DOSE-FINDING SPREADSHEET OF THE MODIFIED 
TOXICITY PROBABILITY INTERVAL (MTPI) METHOD .......130 
APPENDIX 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING STUDY TREATMENT...........131 
APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 
1.1 GUIDELINES .................................................................................133 
APPENDIX 5. SITRAVATINIB SUB-STUDY TO EVALUATE THE 
PHARMACOKINETICS OF THREE FORMULATIONS .............138 
APPENDIX 6. SITRAVATINIB SUB-STUDY TO EVALUATE 
PHARMACOKINETICS WHEN ADMINISTERED WITH 
FOOD ....................................................................................................144 
 


 
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TABLE OF TABLES 
Table 1: 
Schedule of Assessments ..........................................................................19 
Table 2: 
Glesatinib Schedule of PK, Biomarker Samples and Triplicate 
ECG Assessments .....................................................................................24 
Table 3: 
Sitravatinib Schedule of PK, Biomarker Samples and Triplicate 
ECG Assessments .....................................................................................25 
Table 4: 
Mocetinostat Schedule of PK, Biomarker Samples and Triplicate 
ECG Assessments .....................................................................................26 
Table 5: 
Summary of Adverse Events for Study 516-001 as of 26 June 2018 
- Most Frequent (≥10%) Treatment-Related, Treatment Emergent 
Adverse Events and ≥ Grade 3 Events in At Least Two Patients ........44 
Table 6: 
Summary of Adverse Events for Study MRTX-500 as of 
26 June 2018 - Most Frequent (≥10%) Treatment-Related 
(Sitravatinib and/or Nivolumab), Treatment Emergent Adverse 
Events and ≥ Grade 3 Events in At 
Least Two Patients ...................................................................................46 
Table 7: 
Investigational Study Drug Starting Dose Levels for Cohorts of 
Patients in the Lead-In Dose Evaluation ...............................................65 
Table 8: 
Glesatinib Sequential Dose Reductions for Individual Patients ..........79 
Table 9: 
Sitravatinib Free Base Formulation Sequential Dose Reductions 
for Individual Patients .............................................................................82 
Table 10: 
Sitravatinib Dose Modification for Increased Blood Pressure ............83 
Table 11: 
Mocetinostat Sequential Dose Reductions for Individual Patients .....86 
Table 12: 
Definitions of Pericardial Events ............................................................87 
Table 13: 
Pericardial Effusion and Patient Management Guidelines ..................88 
Table 14: 
Investigational Study Treatment Modification for Increased 
Hepatic Transaminase1 ............................................................................91 
Table 15: 
Investigational Study Treatment Dose Modifications –  
Non-Hematological Drug-Related Toxicities1, 2 .....................................92 
Table 16: 
Recommended Dose Modifications for OPDIVO – Reprinted from 
OPDIVO US Prescribing Information ...................................................95 
Table 17: 
Management of Nivolumab Immune-Related Adverse Events 
– Reprinted from OPDIVO US Prescribing Information ....................96 
Table 18: 
Treatment Interruption for Major Surgery ........................................100 
Table 19: 
Laboratory Safety Parameters .............................................................105 
Table 20: 
Estimates of 95% CI Using Clopper-Pearson After Enrollment of 
125 Patients .............................................................................................115 
Table 21: 
Pharmacokinetic Parameters in Dog Following Oral Administration 
of Three Sitravatinib Capsule Formulations .......................................139 
Table 22: 
PK Sample Collection and Triplicate ECG Schedule During 
Lead-In Period .......................................................................................142 
Table 23: 
PK Sample Collection and Triplicate ECG Schedule Cycle 1 
Day 15 (± 2 Days) ...................................................................................143 


 
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Table 24: 
PK Sample Collection and Triplicate ECG Schedule During 
Lead-In Period .......................................................................................146 
Table 25: 
PK Sample Collection and Triplicate ECG Schedule Cycle 1 
Day 15 (± 2 Days) ...................................................................................146 
 
TABLE OF FIGURES 
Figure 1: 
Mocetinostat Modulates Expression of PD-L1 and Antigen 
Presentation Regulatory Genes in NCSLC Cell Lines .........................49 
Figure 2: 
Mocetinostat Modulates Key Immune Cell Populations In Vivo ........50 
Figure 3: 
Study Diagram .........................................................................................71 


 
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LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CFR 
Code of Federal Regulations 
CDx 
Companion Diagnostics 
CI 
Confidence Interval 
CIT 
Checkpoint Inhibitor Therapy 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography Scan 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
DLT 
Dose Limiting Toxicity 
DR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EIU 
Exposure In-Utero 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HDAC 
Histone Deacetylases 
HDPE 
High-Density Polyethylene 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 


 
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LIST OF ABBREVIATIONS (CONTINUED) 
IND 
Investigational New Drug 
INR 
International Normalized Ration 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
MAb 
Monoclonal Antibody 
MDSC 
Myeloid-derived Suppressor Cell 
MDSCs 
Myeloid-Derived Suppressor Cells   
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHC 
Major Histocompatibility Complex 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTPI 
Modified Toxicity Probability Interval  
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NK 
Natural Killer 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Objective Progression of Disease 
PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PKAP 
Pharmacokinetic Analysis Plan 
PPD 
Predictive Probability Design 
PR 
Partial Response 


 
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LIST OF ABBREVIATIONS (CONTINUED) 
PTT 
Partial Thromboplastin Time 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TAA 
Tumor Associated Antigens 
TIW 
Three Times Weekly 
Treg 
T Regulatory Cells 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 


 
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1 INTRODUCTION AND RATIONALE 
1.1 
Disease and Therapeutic Strategy 
1.1.1 
 Non-Small Cell Lung Cancer 
Lung cancer remains the leading cause of cancer-related death in the United States (US).  
Approximately 221,200 new cases of lung cancer are expected to be diagnosed in the US 
in 2015, and approximately 158,040 deaths will be attributed to lung cancer 
(Cancer Facts and Figures-2015).  Non-small cell lung cancer (NSCLC) accounts for 
approximately 83% of lung cancer cases (Cancer Facts and Figures-2015), of which 
approximately half are classified as adenocarcinoma of the lung; squamous cell 
carcinoma accounts for approximately one-third of NSCLC cases and large cell 
carcinoma is less frequently diagnosed. 
In 1995, the use of cisplatin-based chemotherapy was reported to lead to modest 
improvement in survival in patients with advanced NSCLC as compared to best 
supportive care, with a 27% reduction in death as reported in a meta-analysis of 11 trials 
(NSCLC Collaborative Group-1995).  Subsequently, other chemotherapeutic agents have 
been reported to be active in NSCLC, leading to a comparison of 4 platinum-based 
doublets in the first-line treatment setting, all of which demonstrated similar activity 
(Schiller-2002).  The importance of histology in the selection of first-line treatment for 
NSCLC was later described in the development of bevacizumab and pemetrexed.  In a 
Phase 3 clinical trial, treatment with bevacizumab, a monoclonal antibody directed 
against vascular endothelial growth factor (VEGF), demonstrated an improvement in 
survival when added to doublet chemotherapy, specifically in patients with 
non-squamous NSCLC (Sandler-2006).  Similarly, treatment with pemetrexed, an 
antifolate chemotherapeutic agent, resulted in an improvement in survival when used as 
part of a chemotherapy doublet in patients with non-squamous NSCLC, but with a 
probable decrease in survival among patients with squamous cell NSCLC 
(Scagliotti-2008).  Based on the results of these and other trials, platinum-based 
chemotherapy doublets, with or without bevacizumab in selected patients, remain a 
standard of care for most patients with advanced NSCLC in the first-line treatment 
setting.   
Effective options are limited however for patients with advanced NSCLC whose disease 
progresses after first-line treatment.  Over the past few years there has been increasing 
interest in treating cancer with immunotherapy, in particular manipulating the anticancer 
host immune response with human monoclonal antibodies (MAbs). 
Nivolumab, a fully human IgG4, PD-1 receptor antagonist, was evaluated in a Phase 3 
clinical trial of patients with squamous cell carcinoma of the lung with disease 
progression during or after first-line chemotherapy.  This study demonstrated a 
significant improvement in survival compared with docetaxel, with a hazard ratio (HR) of 
0.59 (95% CI: 0.44, 0.79, p<0.001) (Brahmer-2015).  A similar Phase 3 trial of patients 


 
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with non-squamous NSCLC that had progressed during or after platinum-based doublet 
chemotherapy demonstrated an improvement in survival with nivolumab over docetaxel 
(HR 0.73, 96% [sic] CI 0.59, 0.89, p=0.002) (Borghaei-2015).  OPDIVO® (nivolumab) 
was approved by the FDA for the treatment of patients with metastatic NSCLC with 
progression on or after platinum-based chemotherapy.  Nivolumab was approved in the 
US in March 2015 for squamous NSCLC and October 2015 for non-squamous NSCLC. 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  In a large international Phase 1 clinical trial, 
pembrolizumab was given to 495 patients with advanced NSCLC to evaluate safety, 
side-effect profile, and antitumor activity (Garon-2015).  Patients (some of whom had 
received previous therapy and some of whom had not) were treated with various doses 
and regimens of pembrolizumab.  Pembrolizumab had an acceptable side-effect profile 
and showed anti-tumor activity.  Among all patients, the objective response rate was 
19.4%, and the median duration of response was 12.5 months.  The median duration of 
progression-free survival was 3.7 months, and the median duration of overall survival 
was 12.0 months.  Keytruda® (pembrolizumab) was approved by the FDA in October 
2015 for the treatment of patients with metastatic squamous or non-squamous NSCLC 
with progression on or after platinum-based chemotherapy.  Despite these advances, most 
patients with advanced NSCLC have incurable disease, and additional, effective 
treatment options are needed.   More recently, a trial of pembrolizumab, demonstrated an 
advantage of pembrolizumab over standard chemotherapy in patients with untreated, 
advanced NSCLC characterized by ≥ 50% tumor PD-L1 expression.  Improvement was 
reported across multiple efficacy endpoints including survival along with a favorable 
safety profile (Reck-2016), leading to the approval of pembrolizumab in the first-line 
treatment setting in this patient population in the US. 
1.2 
Overall Rational for Proposed Combination Regimens 
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated 
clinical activity across a range of cancer types, including non-small cell lung cancer 
(Brahmer-2015, Borghaei-2015, Garon-2015).  While this therapy leads to durable 
clinical responses in a subset of patients, strategies to improve its clinical efficacy and 
overcome innate or acquired resistance to checkpoint inhibitor monotherapy are needed.  
Combination therapy with agents that target the molecular and cellular mechanisms of 
resistance to checkpoint inhibitor therapy is a rational approach to improving outcomes in 
patients. 
Resistance mechanisms have been described based on fundamental knowledge of the 
immune system as well as emerging clinical data.  Expression of PD-L1 appears to 
correlate with response in multiple clinical studies (Herbst-2014, Tumeh-2014).  In the 
tumor microenvironment, PD-L1 can be upregulated in tumor cells via oncogenic 
signaling or in response to immune stimulatory factors such as interferon gamma (IFN-γ).  
Therefore, the absence of PD-L1 expression may reflect a tumor cell population and 
microenvironment with a suppressed immune response.  A potentially related state 


 
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termed immunological ignorance was recently described and is characterized by a near 
complete absence of immune markers in the tumor.  Tumors harboring a non-functional 
immune response or an excluded immune cell infiltrate represent additional cellular 
patterns found associated with resistance to checkpoint inhibition (Herbst-2014).   
Several immune cell types normally function to suppress immune responses, are often 
found in abundance in cancer and may underlie these recently described resistance 
mechanisms to checkpoint blockade (Vanneman-2012).  Regulatory T cells (Tregs), 
myeloid-derived suppressor cells (MDSCs) and M2-polarized macrophages, in particular, 
are immunosuppressive in nature as they counteract pro-inflammatory immune responses 
and lead to tolerance.  Inhibition of the accumulation and/or function of these cell types 
therefore represents a rational combination strategy to reprogram the immunosuppressive 
tumor microenvironment and increase the effectiveness of PD-1/PD-L1 therapy.  As 
described in further detail below, both glesatinib and sitravatinib target key receptor 
tyrosine kinases present on these immune cell types.  Moreover, in addition to inhibiting 
some of the same immunosuppressive cell types noted above, mocetinostat enhances 
tumor antigen presentation, increases immunologic cell death and recruits 
pro-inflammatory cell types through modulation of gene expression in the tumor cell 
compartment.  In summary, these therapies selectively inhibit key molecular and cellular 
pathways strongly implicated in checkpoint inhibitor resistance and therefore represent 
rational strategies to enhance or restore anti-tumor immunity when combined with 
nivolumab. 
1.3 
Checkpoint Pathway 
The PD-1 receptor along with the ligands PD-L1 and PD-L2 constitutes an immune 
checkpoint pathway that inhibits T-cell activation when engaged (Mellman-2011, 
Topalian-2015).  PD-1 is expressed on T-cells whereas PD-L1 and PD-L2 are expressed 
on some cancer cells and immune cell types.  PD-L1 is the predominant ligand expressed 
in solid tumors and is upregulated by IFNg.  PD-L1 normally functions to limit collateral 
damage in normal tissues where an immune response has been triggered.  When PD-L1 is 
upregulated in tumors, this functions to block the immune response and avoid elimination 
by the host.  PD-L1 expression in tumor, including in lung cancer, has been associated 
with poor survival motivating the development of PD-1 pathway inhibitors (Mu-2011). 
1.4 
Glesatinib Background 
Glesatinib (MGCD265) is an orally administered multi-targeted receptor tyrosine kinase 
(RTK) inhibitor that primarily targets the Axl and MET receptors.  Additional RTK 
targets potentially include MERTK, DDR2, and PDGFR and  receptors.  This subset 
of tyrosine kinases is involved in a number of processes implicated in human cancer 
including regulation of tumor growth and cell survival pathways, tumor invasion and 
metastatic progression, as well as tumor angiogenesis. 


 
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Background information in addition to that presented below is available in the 
MGCD265 Investigator’s Brochure. 
1.4.1 
Glesatinib Drug Substance 
The chemical structure of glesatinib (MGCD265) is as follows: 
MGCD265 Free Base 
 
 
Chemical Formula: 
C31H27F2N5O3S2 
Molecular Weight: 
619.71 g/mol 
 
1.4.2 
Non-Clinical Data 
Glesatinib demonstrated potent, concentration-dependent inhibition of the kinase activity 
of MET, Axl, MERTK, PDGFR family and DDR2 in biochemical assays and inhibited 
phosphorylation in cell-based assays.  Glesatinib also inhibited MET-dependent cell 
viability and migration and endothelial tube formation and angiogenesis in cell-based 
experiments.  In a variety of human tumor xenograft models, glesatinib demonstrated 
anti-tumor efficacy including robust tumor regression in models exhibiting genetic 
alterations of the MET RTK including MET mutations and gene amplification. 
The potential for glesatinib cardiovascular effects was tested in vitro and in vivo.  The 
IC50 for potassium (hERG/Kv11.1) and sodium channel (hNav1.5) inhibition were not 
calculated but were estimated to be >30 M, a level that far exceeds exposures observed 
clinically.  In a dog cardiovascular study, oral treatment with glesatinib did not affect 
hemodynamic functions (heart rate; systolic, mean and diastolic arterial pressure) or 
electrocardiogram parameters at dose levels up to 40 mg/kg.   
In in vitro membrane permeability studies, Glesatinib was highly permeable and did not 
show significant efflux (efflux ratio 0.7) suggesting that glesatinib is not a substrate of 
Pgp or BCRP (efflux transporters). 
N
S
O
F
H
N
N
NH
O
H
N
S
O
F


 
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Protein binding studies of glesatinib in mouse, rat, and human plasma demonstrated 
greater than 99.9% protein binding by an ultrafiltration assay; binding to dog plasma 
proteins was 99.8%.  In addition, a serum shift experiment in a cell-based assay estimated 
glesatinib to be 98% bound to human plasma.   
Glesatinib is relatively stable when incubated in human liver microsomes, suggesting that 
it is not extensively metabolized by the cytochrome P-450 system.  Reaction phenotyping 
shows that metabolism of glesatinib that does occur appears to be mediated by several 
CYP enzymes without a specific enzyme predominance.  Additionally, in vitro studies in 
human liver microsomes and in primary cultures of fresh human hepatocytes indicate that 
glesatinib is neither a potent inhibitor nor a potent inducer of CYP enzymes at the 
clinically observed concentration levels.   
1.4.3 
Clinical Experience 
1.4.3.1 
Glesatinib Pharmacokinetics 
Following single dose administration of 750 mg BID SDD glesatinib tablets, MGCD265 
was rapidly absorbed, with median Cmax occurring 6 hours after dosing.  The mean 
elimination half-life was 30.9 hours.  Drug accumulation was observed after multiple 
dose administration, whereby Cmax and AUC0-12 were 4.0- and 4.5-fold higher, 
respectively, than single dose administration.  The mean peak to trough ratio at steady 
state was 1.12.  At steady state, mean Cmax,ss, Cave,ss and AUC0-12,ss  values were 432 
ng/mL, 396 ng/mL and 4751 ng•h/mL, respectively. 
1.4.3.2 
Glesatinib Clinical Safety 
Single agent glesatinib has been evaluated using various oral formulations and regimens 
in Phase 1, 1/2, and 2 clinical trials in over 370 patients with advanced malignancies.   
As of 17 January 2017, in Study No. 265-101, a total of 165 patients have been treated 
with single agent glesatinib daily dosing.  Dose escalation started at 24 mg/m2 
administered once daily and progressed through multiple formulation changes.  The 
maximum tolerated dose (MTD) with the non-aqueous suspension formulation was 
defined as 1050 mg BID, with diarrhea and fatigue being the most common dose-limiting 
adverse events.  The SDD tablet formation was introduced with the expectation that the 
incidence and severity of diarrhea would be reduced as compared with the non-aqueous 
formulation that includes Miglyol® as an excipient.  The dose escalation evaluation of the 
SDD formulation identified that the recommended dose when glesatinib is administered 
as a single agent is 750 mg BID; 1000 mg BID using the SDD formulation exceeded the 
maximum tolerated dose.  The incidence, severity and speed of onset of diarrhea were 
less among patients receiving the SDD formulation as compared to the non-aqueous 
suspension formulation.   
Across the clinical trial program, the most commonly observed treatment-emergent 
adverse events (TEAEs) reported as related to glesatinib when administered alone were 


 
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diarrhea (62%), nausea (39%), fatigue (31%), vomiting (26%), aspartate 
aminotransferase (AST) increase (25%), and alanine aminotransferase (ALT) increase 
(20%).  Grade 3 TEAEs that were reported as related to treatment in more than one 
patient included diarrhea (8%), fatigue (5%), AST increase, ALT increase, lipase 
increase, nausea, and vomiting (2% each), and abdominal pain, anemia, blood alkaline 
phosphatase increase, blood phosphorus decrease, dehydration, hypertension, 
hypokalemia (1% each).  Adverse events of grade 4 that were reported related to 
treatment included lipase increase in 3 patients (1%) and amylase increase and 
lymphocyte count decrease (< 1%).  Events listed in the Investigator’s Brochure as 
glesatinib Adverse Drug Reactions (ADRs) include diarrhea, nausea, vomiting, fatigue, 
asthenia, AST and ALT increase and dehydration. 
Based on reported clinical experience with glesatinib and similar agents, and non-clinical 
data with glesatinib, guidance to the Investigator is provided for selected adverse events 
in Section 5.1.1.4. 
1.5 
Sitravatinib Background 
Sitravatinib (MGCD516) is an orally-available, potent small molecule inhibitor of a 
closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, 
MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and 
selected Eph family members.  Receptor tyrosine kinases (RTKs) are key regulators of 
signaling pathways leading to cell growth, survival, and migration (Blume Jensen-2001).  
These kinases are found dysregulated in many cancers through overexpression, genetic 
alteration or co-expression with high affinity ligands (Blume Jensen-2001).  Multiple 
sitravatinib RTK targets are genetically altered in a variety of cancer indications and act 
as oncogenic drivers promoting cancer development and progression.   
Background information in addition to that presented below is available in the 
Sitravatinib (MGCD516) Investigator’s Brochure. 


 
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1.5.1 
Sitravatinib Drug Substance 
The chemical structure 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 
 
1.5.2 
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 RTKs 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 RTK targets including MET, RET, FLT3 and others.   
In vitro results from the hERG 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, sitravatinib is classified as a 
highly permeable compound, and not a substrate of P-gp and BCRP.   


 
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Using an ultra-centrifugation technique sitravatinib was 98.6% bound to human plasma 
proteins.   
Sitravatinib was evaluated for cytochrome P-450-mediated metabolism using human liver 
microsomes and recombinant human enzymes.  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.  In vitro studies in human primary cultures of cryopreserved 
human hepatocytes and human liver microsomes indicate that sitravatinib is unlikely to 
inhibit or induce the tested enzymes at the systemic concentrations associated with 
150 mg daily administration. 
1.5.3 
Sitravatinib Clinical Experience 
1.5.3.1 
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 150 mg.  Mean elimination half-life 
varies between 35 and 53 hours after oral administration.  Drug accumulation is observed 
after multiple dose administration and averaged 2.7-fold for Cmax and 3.1-fold for 
AUC0-24.  Mean peak to through ratio at steady state is 1.8.  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 116 ng/mL, 95.1 ng/mL and, 2281 mg.h/mL, respectively. 
1.5.3.2 
Sitravatinib Clinical Trial Experience 
1.5.3.2.1 
Sitravatinib Monotherapy 
Study 516-001 is a multi-center Phase 1/1b clinical trial of sitravatinib as monotherapy in 
patients with advanced solid tumor diseases.  The Phase 1 dose-escalation segment of the 
study evaluated sitravatinib dose levels between 10 mg and 200 mg administered QD.  
Dose-limiting toxicity (DLT) was reported in four patients who developed palmar-plantar 
erythrodysesthesia, neuropathy, mucositis, or fatigue.  The maximum tolerated dose was 
identified as 150 mg QD and, based on long-term tolerability, the recommended Phase 2 
dose is 120 mg QD.  The sitravatinib exposure achieved using 120 mg QD is expected to 
be adequate to inhibit the target TAM and VEGF receptors necessary to achieve 
antitumor activity in combination with nivolumab.    
The Phase 1b segment is ongoing, evaluating the clinical activity of sitravatinib in 
patients having tumors with selected histological diagnoses and/or tumor gene alterations 
targeted by sitravatinib.   
As of 26 June 2018, preliminary safety data are available for 153 patients treated in Study 
516-001.  Treatment-related adverse events reported in ≥ 10% of patients and Grade 3 or 
higher AEs reported in at least two patients are listed in Table 5.   


 
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Table 5: 
Summary of Adverse Events for Study 516-001 as of 26 June 
2018 - Most Frequent (≥10%) Treatment-Related, Treatment 
Emergent Adverse Events and ≥ Grade 3 Events in At Least 
Two Patients  
Adverse Event (Preferred Term) 
N=153 
All Grades 
n (%) 
Grade ≥3 
n (%) 
Diarrhea 
74 (48) 
16 (11) 
Fatigue 
65 (43) 
9 (6) 
Hypertension 
56 (37) 
29 (19) 
Nausea 
45 (29) 
5 (3) 
Vomiting  
40 (26) 
4 (3) 
Decreased appetite 
38 (25)  
1 (1) 
Palmar-plantar erythrodysaesthesia  
28 (18) 
6 (4) 
Aspartate aminotransferase increase 
26 (17) 
1 (1) 
Alanine aminotransferase increase 
25 (16) 
1 (1) 
Hypothyroidism 
22 (14) 
0 
Weight decrease 
21 (14) 
2 (1) 
Dysphonia 
18 (12) 
0 
Stomatitis 
18 (12) 
0 
Abdominal pain 
16 (11) 
0 
Rash 
15 (10) 
0 
Lipase increased 
13 (9) 
6 (4) 
Mucosal inflammation 
13 (9) 
3 (2) 
Anaemia 
13 (9) 
2 (1) 
Rash maculo-papular 
10 (7) 
3 (2) 
Hypophosphataeamia 
9 (6) 
5 (3) 
Amylase increased 
9 (6) 
2 (1) 
Ejection fraction decreased 
7 (5) 
3 (2) 
Pulmonary embolism 
6 (4) 
6 (4) 
Embolism 
4 (3) 
2 (1) 
Left ventricular dysfunction 
3 (2) 
3 (2) 
Pancreatitis 
3 (2) 
2 (1) 


 
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Grade 4 AE events reported as related to treatment in 1 patient each (0.7%) included 
dehydration, febrile neutropenia and lipase increased.  Grade 5 treatment-related adverse 
event of cardiac arrest was reported in one patient.  Treatment-related SAEs were 
reported in 24 patients (16%) and included diarrhea, nausea and vomiting (3% each); 
fatigue (2%); pancreatitis, pulmonary embolism, and hypertension (1.3% each); cardiac 
arrest, ejection fraction decreased, embolism, febrile neutropenia, headache, hypotension, 
left ventricular dysfunction, lipase increased, odynophagia, oropharyngeal pain, palmar-
plantar erythrodysesthesia and tachycardia (0.7% each).  Fifty patient deaths were 
reported in this study, with the primary cause of death being the disease under study 
(n=31), unknown (n=12), other (n=7), including sepsis (n=3), and hypoxic respiratory 
failure, respiratory failure, gastrointestinal bleed, or cardiac arrest (n=1 each).   
Efficacy results are awaited from the Phase 1b segment of Study 516-001. 
1.5.3.2.2 
Sitravatinib in Combination with Nivolumab, Current Study 
Update as of June 2018 
The current study began with a lead-in safety evaluation of sitravatinib in combination 
with nivolumab administered by intravenous infusion, 240 mg Q2W.  The starting dose 
for sitravatinib was 120 mg administered orally, once daily, in 28-day cycles.  No 
protocol defined DLTs were reported in the first 6 evaluable patients treated at the 
sitravatinib starting dose 120 mg daily in combination with nivolumab administered by 
intravenous infusion, 240 mg Q2W.  Based on the experience of patients enrolled into the 
516-001 study and the patients enrolled in the MRTX-500 study, 120 mg daily was 
selected as the Phase 2 dose of sitravatinib in combination with nivolumab.   
As of 26 June 2018, preliminary safety data are available for 70 patients treated in the 
sitravatinib segment of Study MRTX-500.  The data summarized below include the 
experience of patients enrolled in all sitravatinib patient strata in MRTX-500 (i.e., both 
CIT-experienced and CIT-naïve).  Treatment-related AEs reported in ≥ 10% of patients 
and Grade 3 or higher AEs reported in at least two patients are listed in Table 6.   
 
 


 
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Table 6: 
Summary of Adverse Events for Study MRTX-500 as of 26 June 
2018 - Most Frequent (≥10%) Treatment-Related (Sitravatinib 
and/or Nivolumab), Treatment Emergent Adverse Events and ≥ 
Grade 3 Events in At Least Two Patients  
Adverse Event (Preferred Term) 
N=70 
All Grades 
n (%) 
Grade ≥3 
n (%) 
Diarrhea 
31 (44) 
8 (11) 
Nausea 
28 (40) 
0 
Fatigue 
27 (39) 
2 (3) 
Decreased appetite 
18 (26) 
0 
Vomiting 
18 (26) 
1 (1) 
Dysphonia 
17 (24) 
0 
Weight decrease 
16 (23) 
1 (1) 
Hypertension 
16 (23) 
9 (13) 
Alanine aminotransferase increase 
12 (17) 
0 
Aspartate aminotransferase increase 
10 (14) 
0 
Stomatitis 
10 (14) 
1 (1) 
Palmar-plantar erythrodysaesthesia 
10 (14) 
1 (1) 
Hypothyroidism 
10 (14) 
0 
Mucosal Inflammation 
8 (11) 
3 (4) 
Lipase increase 
4 (6) 
2 (3) 
Hyponatremia 
5 (7) 
2 (3) 
Grade 4 events related to treatment were seen in 1 patient each (1.4%) included:  
hypertensive crisis, gastric ulcer perforation, and hypomagnesaemia.  Grade 5 treatment-
related cardiac arrest was reported in one patient.  The Investigator stated that the death 
was due to the patient's disease process; however, the treating physician felt that 
sitravatinib could not be ruled out because of the known cardiac effects. The Sponsor 
assessed the Cardiac Arrest as unlikely related to sitravatinib and not related to 
nivolumab because of the Investigator statement and the event occurred 4 days after 
initiating treatment with sitravatinib (steady state PK is reached in a mean time of 11 to 
15 days).  Treatment-related SAEs were reported in 13 patients (19%); diarrhea (3%), 
and fatigue, vomiting, hypertension, cardiac arrest, hypertensive crisis, syncope, 
confusional state, myocarditis, gastric ulcer perforation, hypoxia, deep vein thrombosis, 
pulmonary embolism, anaemia, dehydration, hyponatraemia, and pancreatitis in one 
patient each (1.4% each).  Immune-related AEs (irAEs) of special interest reported were 
pneumonitis and myocarditis in one patient each and attributed to treatment with 
sitravatinib and nivolumab.  The case of pneumonitis was reported as Grade 3 on Cycle 1 


 
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Day 15 and resulted in permanent discontinuation of study treatment; the event did not 
meet the criteria for SAE reporting.  The case of myocarditis was reported as Grade 3 on 
Cycle 1 Day 15, resolved following study treatment interruption, but recurred upon 
rechallenge.  The patient permanently discontinued study treatment and the event was 
reported as an SAE.  The patient subsequently developed clinically significant pericardial 
effusion requiring treatment.  Three deaths were reported in this study, disease under 
study, staphylococcal sepsis, and cardiac arrest (n=1 each).    
Nonclinical 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.   
Based on reported clinical experience with sitravatinib and similar agents, and nonclinical 
data with sitravatinib, guidance to the Investigator is provided for selected AEs in Section 
5.1.2.4. 
Please refer to the latest Sitravatinib (MGCD516) Investigator’s Brochure for more 
information. 
1.6 
Mocetinostat Background 
Mocetinostat (MGCD0103) is an oral, second generation benzamide inhibitor of HDAC 
1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo (Fournel-2008, 
Zhou-2008).   
Background information in addition to that presented below is available in the 
MGCD0103 Investigator’s Brochure. 
1.6.1 
Mocetinostat Drug Substance 
The chemical structure of mocetinostat (MGCD0103) is as follows: 
MGCD0103 Free Base 
 
 
Chemical Formula:  
C23H20N6O 
Molecular Weight:  
396.45 g/mol 


 
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1.6.2 
Mocetinostat Non-Clinical Data 
Mocetinostat is a selective, potent, and dose-dependent inhibitor of human Class I 
(isoforms 1, 2, and 3) and Class IV (isoform 11) HDACs.  There was weak or no activity 
against Class II HDACs or HDAC 8.  Mocetinostat is a potent competitive inhibitor of 
HDAC 1, with a Ki of 64 nM.  Binding was reversible, with high affinity and slow 
kinetics.  Mocetinostat induced acetylation of core histones H4 and H3 in human bladder 
carcinoma (T24) cells, with an EC50 of 0.4 μM and 0.2 μM, respectively.  Acetylation of 
histones was also observed in A549 human non-small cell lung carcinoma cells and 
A2780-S human ovarian carcinoma cells.  Core histone acetylation was dose-dependent 
and was correlated with HDAC inhibition. 
In the in vitro hERG assay, the IC50 for mocetinostat was > 50µM on the potassium 
current, which far exceeds exposures observed clinically.  Results of a cardiovascular 
safety pharmacology study in Beagle dogs showed no test article-related changes in heart 
rate, arterial pressure (systolic, mean, or diastolic), or in ECG parameters at dose levels 
up to 100 mg/m2 (5 mg/kg). 
In a bidirectional permeability study with Caco-2 cell lines, mocetinostat is classified as 
highly permeable; the efflux ratio was < 2, hence it is not a P-gp or BCRP substrate. 
The fractional binding of mocetinostat to human plasma was measured via equilibrium 
dialysis.  At concentrations of 0.5, 1 and 10 μM, mocetinostat showed binding of 95.1%, 
97.5%, and 95.2%, respectively. 
Mocetinostat is metabolized by cytochrome P-450 enzymes that include CYP 2E1 and 
3A, and possibly also CYP 2C8 and 2C19.  Caution should be used when mocetinostat is 
administered with concomitant medications that are inhibitors or inducers of CYP 2E1, or 
strong inhibitors or inducers of CYP 3A4.  Mocetinostat does not appear to be a strong 
inducer of CYP enzymes but may be an inhibitor of CYP 2C9.  Caution should be used 
when mocetinostat is administered with concomitant medications that are substrates for 
CYP 2C9.  In vitro studies indicate that mocetinostat has a low potential for P-gp 
inhibition at the levels observed in patients. 
Nonclinical Studies Supporting Mocetinostat and Checkpoint Inhibitor 
Combination  
Nonclinical studies evaluated the mechanism of action of mocetinostat, its immune 
stimulatory properties, and the effect of combination treatment with immune checkpoint 
inhibitors.  Initial studies were performed to assess the effect of mocetinostat on PD-L1, 
on major histocompatibility complex (MHC) class I and II molecules, and on immune 
co-stimulatory molecule gene and protein expression, across a panel of NSCLC cell lines 
in vitro.  Mocetinostat demonstrated a concentration-dependent increase in PD-L1 gene 
expression ranging from 2- to 15-fold in all four NSCLC cell lines evaluated (H23, 
H1437, H1703, H1792) (Figure 1).  In addition, mocetinostat increased PD-L1 
cell-surface protein expression in 5 NSCLC cell lines, demonstrated by flow-cytometric 


 
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analysis utilizing a specific PD-L1 antibody.  The increased expression of PD-L1 on 
tumor cells by mocetinostat may signal a shift in dependence of tumor cells on evading 
tumor-immune response via a PD-1-dependent mechanism.  In addition, mocetinostat 
demonstrated a concentration-dependent increase in gene expression of several members 
of the human leukocyte antigen (HLA) gene complex, in all four NSCLC lines evaluated 
(Figure 1).  HLA genes comprise the human MHC Class I and II molecules that regulate 
the presentation of tumor-associated antigens (TAAs) at the cell surface to enable 
recognition by cytotoxic T cells (CD8+).  The induction of gene expression of 
MHC-class-I-related molecules, MIC-A and MIC-B, were also observed in all four 
NSCLC cell lines evaluated.  The effector cytolytic responses of T cells and NK cells 
against tumor cells are mediated by NKG2D receptor-dependent engagement of MIC-A 
and MIC-B on target tumor cells, indicating that immune stimulatory properties of 
mocetinostat involve both innate and adaptive immune responses.  Finally, mocetinostat 
induced the expression of the immune co-stimulatory molecule CD86, which is required 
for T-cell activation and antigen-dependent immune response against tumor cells 
expressing and presenting TAAs. 
Figure 1: 
Mocetinostat Modulates Expression of PD-L1 and Antigen 
Presentation Regulatory Genes in NCSLC Cell Lines   
 


 
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Gene modulation in NSCLC post mocetinostat treatment.  Cells were seeded in 10 cm dishes and incubated 
with various doses of mocetinostat or DMSO for 48 hours.  RNA was extracted with Qiagen RNEasy plus 
kit.  Relative gene expression, by quantitative polymerase chain reaction (PCR), was normalized to DMSO 
treatment.   
To determine effect on CD4- and CD8-positive effector T cells and immunosuppressive 
cellular subsets including T regulatory cells (Tregs) and myeloid-derived suppressor cells 
(MDSCs), mice bearing syngeneic subcutaneous CT26 colon tumors were treated with 
100 mg/kg mocetinostat by daily oral gavage.  In these studies, mocetinostat 
demonstrated an increase in splenic CD4-positive T effector cells and mature cytolytic 
CD8-positive T cells in tumors compared to vehicle controls by day six of administration 
(Figure 2).  In addition, mocetinostat treatment decreased tumor FoxP3-positive 
immunosuppressive Tregs and CD11b/Gr1-positive MDSCs in tumors compared to 
vehicle controls by day nine of administration.   
Figure 2: 
Mocetinostat Modulates Key Immune Cell Populations In Vivo 
 
Mocetinostat modulates immune cell populations.  Fresh tumor and spleen samples in cold PBS were 
delivered within 45 minutes.  Stained samples were loaded into Attune Autosampler for FACS analysis.  
Flow cytometry markers included percentages of: T-Cells (CD4+ and CD8+), Regulatory T-Cells (Tregs) 
Proliferation marker CD8+ cells that are Ki67+, MDSC (CD11b/Gr1+).  Error bars represent standard 
deviation. 
To determine the effects of mocetinostat and PD-L1 antibody combination therapy on 
tumor growth, CT26 tumor-bearing mice were treated with either agent alone or in 
combination over selected administration schedules.  On Day 23, a statistically 
significant decrease in relative tumor volume was observed in the mocetinostat plus 
PD-L1 antibody combination group with a three day mocetinostat lead-in period 
compared with either single agent alone. 


 
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1.6.3 
Mocetinostat Clinical Data 
1.6.3.1 
Mocetinostat Pharmacokinetics  
The pharmacokinetics of mocetinostat has been evaluated in clinical trials, after single 
and repeated dose administration.  In general, mocetinostat was rapidly absorbed 
following administration with 200 mL of a low pH beverage, with maximum 
concentration (Cmax) occurring 0.5 to 1.5 hours after dosing.  The elimination half-life 
ranged from approximately 7 to 12 hours.  As determined from the Cmax and AUC values, 
exposure to mocetinostat following oral dosing appears to increase with doses up to 
110 mg.  No significant drug accumulation is expected with administration of mocetinostat 
three times weekly.   
1.6.3.2 
Mocetinostat Clinical Safety 
As of November 2016, mocetinostat has been administered orally as a single agent or in 
combination with chemotherapy to more than 489 clinical trial patients with various 
forms of hematological or solid tumor diseases.  Regimens investigated included daily 
and three times weekly administration.  The recommended Phase 2 treatment regimen for 
single agent mocetinostat is 90 mg as a fixed dose three times weekly (e.g., Monday, 
Wednesday and Friday) 
Among 306 patients participating in clinical trials of mocetinostat single agent, 
treatment-related AEs were reported in 90.5% of patients.  The most frequent AEs 
considered related to study drug (occurring in ≥5% of patients in a preferred term 
category) were reported for nausea (61.4%), fatigue (57.5%), diarrhea (46.7%), vomiting 
(37.3%), anorexia (26.8%), decreased weight (19.3%), anemia (15.4%), 
thrombocytopenia (13.1%), dyspepsia (11.8%) and abdominal pain (11.4%).  The most 
frequent Grade 3/4 AEs considered related to study drug were the following fatigue 
(19.0%), thrombocytopenia (8.8%), neutropenia (6.5%), nausea (5.2%), anemia (5.6%), 
asthenia (4.6%), and anorexia (4.2%).  Events listed in the Investigator’s Brochure as 
mocetinostat ADRs include nausea, vomiting, diarrhea, anorexia, fatigue and asthenia.   
Bladder toxicity resulting in dysuria and rarely hemorrhagic cystitis has been described in 
a few patients receiving mocetinostat.  Symptoms may include dysuria, pollakiuria, 
hematuria, urgency, and bladder spasm and have been reported most commonly after 
multiple cycles of treatment. 
Pericardial AEs have been reported in clinical trials of mocetinostat.  The types of 
pericardial events included pericarditis, pericardial effusion, and cardiac tamponade.  Of 
the pericardial adverse events, pericardial effusion was the most common.  Findings of 
the analysis include a higher rate of pericardial SAEs among patients with Hodgkin 
lymphoma (9.5%) as compared to patients with leukemia or NHL (4.5% and 3.8%, 
respectively).  Most of the pericardial AEs occurred during the first cycle of treatment.  
The majority of pericardial findings, including SAEs, resolved completely without 
sequelae, and no pericardial event was considered fatal.  Screening assessments for 


 
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pericardial events were not included in the mocetinostat program during most of the prior 
clinical trial experience.  The current study includes screening assessments and exclusion 
criteria to ensure that baseline status is known. 
Grade 3 AEs of QTc prolongation (> 500 msec) were reported in 4 of 435 patients in 
clinical trials with mocetinostat; 3 of those 4 events were also reported as part of SAEs.  
Three of the 4 patients already had a prolonged QTc at baseline.  Three of the events of 
QTc prolongation occurred in a setting of GI disturbances associated with dehydration 
and/or hypotension.  In 2 cases, there was definite hypokalemia, with concomitant low 
magnesium in one patient, and in both cases, the QTc values decreased quickly to 
baseline levels after IV administration of potassium and magnesium.  Concomitant 
treatment with drugs identified as having the potential to cause QTc prolongation may 
have been a factor in 2 patients. 
Based on reported clinical experience with mocetinostat, guidance to the Investigator is 
provided for selected adverse events in Section 5.1.3.4. 
1.7 
Nivolumab 
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 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 immunoglobulin G4 
(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 
USPI OPDIVO [nivolumab]. 
1.7.1 
Nivolumab Drug Substance 
Generic Name: 
Nivolumab 
Other Name:  
OPDIVO 
Molecular Weight:  
146 kDa 
1.7.2 
Nivolumab Non-Clinical Data 
Please refer to the latest US prescribing information USPI OPDIVO [nivolumab].   


 
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1.7.3 
Nivolumab Clinical Data 
Please refer to the latest US prescribing information USPI OPDIVO [nivolumab].   
1.7.3.1 
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. 
Based on a population PK analysis, the clearance of nivolumab increased with increasing 
body weight supporting a weight-based dose.  The population PK analysis suggested that 
the following factors had no clinically important effect on the clearance of nivolumab: 
age (29 to 87 years), gender, race, baseline 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 (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 [TB] less 
than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB 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 (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic 
impairment (TB greater than 3 times ULN and any AST). 
1.7.3.2 
Nivolumab Anti-Drug Antibodies 
Of 2085 patients who were treated with OPDIVO as a single agent at 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. 


 
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1.7.3.3 
Immune-Mediated Adverse Events 
1.7.3.3.1 
Immune-Mediated Pneumonitis 
Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear 
alternate etiology, including fatal cases, occurred with OPDIVO treatment.   
In patients receiving OPDIVO as a single agent, immune-mediated pneumonitis occurred 
in 3.1% (61/1994) of patients. The median time to onset of immune-mediated 
pneumonitis was 3.5 months (range: 1 day to 22.3 months). Immune-mediated 
pneumonitis led to permanent discontinuation of OPDIVO in 1.1%, and withholding of 
OPDIVO in 1.3% of patients.  Approximately 89% of patients with pneumonitis received 
high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median 
duration of 26 days (range: 1 day to 6 months).  Complete resolution of symptoms 
following corticosteroid taper occurred in 67% of patients.  Approximately 8% of 
patients had recurrence of pneumonitis after re-initiation of OPDIVO. 
1.7.3.3.2 
Immune-Mediated Colitis 
Immune-mediated colitis, defined as requiring use of corticosteroids with no clear 
alternate etiology, can occur with OPDIVO treatment.   
In patients receiving OPDIVO as a single agent, immune-mediated colitis occurred in 
2.9% (58/1994) of patients; the median time to onset was 5.3 months (range: 2 days to 
20.9 months).  Immune-mediated colitis led to permanent discontinuation of OPDIVO in 
0.7% and withholding of OPDIVO in 1% of patients. Approximately 91% of patients 
with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per 
day) for a median duration of 23 days (range: 1 day to 9.3 months). Four patients required 
addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% 
of patients. Approximately 16% of patients had recurrence of colitis after re-initiation of 
OPDIVO. 
1.7.3.3.3 
Immune-Mediated Hepatitis 
Immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear 
alternate etiology, can occur with OPDIVO treatment.   
In patients receiving OPDIVO 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). Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in 
0.7% and withholding of OPDIVO in 1% of patients. All patients with hepatitis received 
high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 
23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic 
acid to high-dose corticosteroids. Complete resolution occurred in 74% of patients. 
Approximately 29% of patients had recurrence of hepatitis after re-initiation of OPDIVO. 


 
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1.7.3.3.4 
Immune-Mediated Endocrinopathies 
Hypophysitis 
In patients receiving OPDIVO as a single agent, hypophysitis occurred in 0.6% (12/1994) 
of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months).  
Hypophysitis led to permanent discontinuation of OPDIVO in 0.1% and withholding of 
OPDIVO in 0.2% of patients. Approximately 67% of patients with hypophysitis received 
hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg 
prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days). 
Adrenal Insufficiency 
In patients receiving OPDIVO as a single agent, adrenal insufficiency occurred in 1% 
(20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 
months). Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% 
and withholding of OPDIVO in 0.5% of patients. Approximately 85% of patients with 
adrenal insufficiency received hormone replacement therapy and 25% received high-dose 
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 
11 days (range: 1 day to 1 month). 
Hypothyroidism and Hyperthyroidism 
In patients receiving OPDIVO 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). Approximately 79% of patients with 
hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution 
occurred in 35% of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients 
receiving OPDIVO as a single agent; the median time to onset was 1.5 months (range: 
1 day to 14.2 months). Approximately 26% of patients with hyperthyroidism received 
methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received 
corticosteroids. Resolution occurred in 76% of patients. 
Type 1 Diabetes Mellitus 
In patients receiving OPDIVO as a single agent, diabetes occurred in 0.9% (17/1994) of 
patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 
months (range: 15 days to 22 months). 
1.7.3.3.5 
Immune-Mediated Nephritis and Renal Dysfunction 
Immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased 
creatinine, requirement for corticosteroids, and no clear alternate etiology, can occur with 
OPDIVO treatment. 


 
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In patients receiving OPDIVO as a single agent, immune-mediated nephritis and renal 
dysfunction occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 
months (range: 23 days to 12.3 months). Immune-mediated nephritis and renal 
dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of 
OPDIVO in 0.8% of patients. All patients received high-dose corticosteroids (at least 
40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 
15.4 months). Complete resolution occurred in 48% of patients. No patients had 
recurrence of nephritis or renal dysfunction after reinitiation of OPDIVO. 
1.7.3.3.6 
Immune-Mediated Rash 
Immune-mediated rash including Stevens-Johnson syndrome (SJS) and toxic epidermal 
necrolysis (TEN) can occur with OPDIVO treatment.   
In patients receiving OPDIVO as a single agent, immune-mediated rash occurred in 9% 
(171/1994) of patients; the median time to onset was 2.8 months (range: <1 day to 25.8 
months). Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% 
and withholding of OPDIVO in 0.8% of patients. Approximately 16% of patients with 
rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) 
for a median duration of 12 days (range: 1 days to 8.9 months) and 85% received topical 
corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash 
occurred in 1.4% of patients who resumed OPDIVO after resolution of rash. 
1.7.3.3.7 
Immune-Mediated Encephalitis 
OPDIVO can cause immune-mediated encephalitis with no clear alternate etiology. 
Evaluation of patients with neurologic symptoms may include, but not be limited to, 
consultation with a neurologist, brain MRI, and lumbar puncture. 
In patients receiving OPDIVO as a single agent, encephalitis occurred in 0.2% (3/1994). 
Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite 
discontinuation of OPDIVO and administration of corticosteroids. In the other two 
patients encephalitis occurred post-allogeneic HSCT. 
1.7.3.3.8 
Other Immune-Mediated Adverse Reactions 
Other clinically significant immune-mediated adverse reactions can occur with OPDIVO.  
Immune-mediated adverse reactions may occur after discontinuation of OPDIVO 
therapy.  Across clinical trials of OPDIVO administered as a single agent or in 
combination with ipilimumab, the following clinically significant immune-mediated 
adverse reactions occurred in less than 1.0% of patients receiving OPDIVO: uveitis, iritis, 
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, 
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic 
inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic 
necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, 
rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome. 


 
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1.7.3.3.9 
Infusion Reactions 
Severe infusion reactions have been reported in less than 1.0% of patients in clinical trials 
of OPDIVO. 
In patients receiving OPDIVO as a single agent, infusion-related reactions occurred in 
6.4% (127/1994) of patients. 
1.7.3.4 
Overall Safety Reported in NSCLC Trial 
The safety of OPDIVO in metastatic NSCLC was evaluated in a randomized open-label, 
multicenter trial in patients with metastatic squamous NSCLC and progression on or after 
one prior platinum doublet-based chemotherapy regimen (Trial 2) and a randomized, 
open-label, multicenter trial in patients with metastatic non-squamous NSCLC and 
progression on or after one prior platinum doublet-based chemotherapy regimen (Trial 3).   
Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 
2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median 
duration of therapy in OPDIVO-treated patients in Trial 2 was 3.3 months (range: 1 day 
to 21.7+ months) and in Trial 3 2.6 months (range: 0 to 24.0+ months). In Trial 2, 36% of 
patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO 
for at least 1 year and in Trial 3, 30% of patients received OPDIVO for greater than 6 
months and 20% of patients received OPDIVO for greater than 1 year. 
Trial 2 and Trial 3 excluded patients with active autoimmune disease, medical conditions 
requiring systemic immunosuppression, or with symptomatic interstitial lung disease. 
Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 
85); 38% were ≥65 years of age, 61% were male, and 91% were white. Ten percent of 
patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).  
OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an 
adverse reaction. Serious adverse reactions occurred in 46% of patients receiving 
OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients 
receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural 
effusion, pneumonitis, and respiratory failure. In Trial 3, in the OPDIVO arm, seven 
deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, 
four were due to pulmonary embolism, and one death was due to limbic encephalitis. 
Across both trials, the most common adverse reactions (reported in at least 20% of 
patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. 
Other clinically important adverse reactions observed in patients treated with OPDIVO 
and which occurred at a similar incidence in docetaxel-treated patients and not listed 
elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), 
musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%). 


 
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1.8 
Expectations for Combination of Study Investigational Agents and 
Nivolumab 
1.8.1 
Potential for Drug-Drug Interactions 
The study investigational treatments glesatinib, sitravatinib or mocetinostat administered 
in combination with nivolumab are 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 the investigational 
agents are all small molecule therapeutics 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 
cytochrome P-450 (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.   
1.8.2 
Evaluation of Potential for Increased Toxicities with Combination 
Use of Nivolumab and Study Investigational Agents  
1.8.2.1 
All Investigational Study Treatments in Combination with Nivolumab 
Frequent adverse events, 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, glesatinib, sitravatinib and mocetinostat 
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, immune-related AEs (irAEs) of Special Interest based on observed 
safety events using nivolumab monotherapy include pneumonitis, colitis, hepatitis, 
endocrinopathy, nephritis/renal dysfunction, rash, and encephalitis.  While glesatinib, 
sitravatinib and mocetinostat may have immunostimulatory effects, autoimmune adverse 
effects have not been reported in clinical trials of these investigational study agents nor 
are they recognized as class effects for these agents.  However, the potential for the 
investigational study treatments to exacerbate or promote these adverse events when 
administered in combination with nivolumab should be borne in mind.   
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 the three investigational agents.  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 of uncertain etiology has been reported 
in approximately 55% of patients treated with glesatinib, 48% of patients treated with 
sitravatinib monotherapy, and 46% of patients treated with mocetinostat, most often 
beginning within the first month of the start of treatment.  Diarrhea (any grade) is less 


 
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common with nivolumab, occurring in approximately 8% (22/287) of NSCLC patients 
treated at 3 mg/kg Q2W in the CheckMate 057 clinical trial (USPI OPDIVO 
[nivolumab]).  The time to onset may be helpful in distinguishing diarrhea that may be 
attributed to autoimmune effects versus non specific toxicity.   
1.8.2.2 
Glesatinib and Nivolumab 
A clinically relevant overlap in toxicity may arise between the immune-related hepatitis 
attributed to nivolumab and the non-specific, most often mild to moderate elevation in 
liver enzymes observed with glesatinib.  Immune-mediated hepatitis was reported in 
0.3% (1/287) of NSCLC patients treated with nivolumab, with an onset of approximately 
8 months following initiation of therapy.  Increases in AST and ALT have been observed 
in approximately 18% and 12% of patients treated with glesatinib. 
1.8.2.3 
Sitravatinib and Nivolumab 
Hypothyroidism, including thyroiditis, was reported in 7% (20/287) of NSCLC patients 
treated with nivolumab.  Hypothyroidism has been reported in approximately 14% 
(22/153) of patients treated with sitravatinib monotherapy. 
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.  Immune-related rash has been reported in 6% (17/287) of NSCLC 
patients treated with nivolumab.  Rash of uncertain etiology has been reported in 10% 
(15/153) of patients treated with sitravatinib monotherapy.   
1.8.2.4 
Mocetinostat and Nivolumab 
Two AEs observed in previous clinical trials of mocetinostat for which causality and 
mechanism are unclear are cystitis and pericardial effusion.  Although the cause of these 
AEs is unknown, the potential for an immune-based mechanism exists, therefore 
increased risk may be associated with the combination of mocetinostat with nivolumab. 
Robust toxicity management guidelines are in place to address or manage any immune 
mediated adverse reactions and drug-related toxicities associated with the study 
treatments.   
1.9 
Study Rationale 
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated 
clinical activity in non-small cell lung cancer patients (Brahmer-2015, Borghaei-2015, 
Garon-2015).  While this therapy leads to durable clinical responses in a subset of 
patients, strategies to improve its clinical efficacy and overcome innate or acquired 
resistance to checkpoint inhibitor monotherapy are needed.  Combination therapy with 
agents that target the molecular and cellular mechanisms of resistance to checkpoint 


 
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inhibitor therapy is a rational approach to improving outcomes in both CIT-naïve and 
CIT-experienced patients. 
The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well established based on 
robust clinical efficacy achieved with well-tolerated inhibitors directed toward oncogenic 
tyrosine kinases.  In addition, selected TKIs have been shown to modulate the 
immunogenic status of tumors, improve tumor perfusion by reducing intratumoral 
pressure and modulate subsets of immune cells, increasing the frequency and function of 
effector immune elements, while decreasing the number and function of immune 
suppressor cells.  Taken together, these effects on the tumor microenvironment (TME) 
may lead to improved efficacy when TKIs are combined with checkpoint inhibitors.  The 
TAM (Tyro3, Axl and MERTK) receptor tyrosine kinases (RTKs) are expressed by select 
innate immune cell subpopulations including macrophages and dendritic cells 
(Lemke-2008).  The TAM receptors cooperate to create and maintain an 
immunosuppressive TME.  MERTK suppresses the M1 macrophage pro-inflammatory 
cytokine response involving IL‑12, IL‑6 and TNF and enhances M2 macrophage 
anti-inflammatory cytokine production involving IL‑10, IL-4, TGFβ and HGF 
(Camenisch-1999, Tibrewal-2008).  Given that anti-tumor host defense is usually 
mediated by cytotoxic T lymphocytes whose activation and stimulation is supported by 
Th1 type cytokines, the inhibition of Axl and MERTK are predicted to enhance an 
anti-tumor immune response.  Furthermore, both Axl and MERTK are expressed by 
natural killer (NK) cells and negatively regulate NK cell activity in the TME as part of a 
feedback regulatory mechanism resulting in decreased NK cell anti-tumor activity and 
enhanced tumor progression and metastasis (Paolino-2014).  Given the 
immunosuppressive function of TAM RTKs in the TME, inhibition of Axl and MERTK 
may complement PD-1/PD-L1 checkpoint inhibition to unleash the host anti-cancer 
immune response. 
The MET (Mesenchymal-Epithelial Transition) RTK is implicated in modification of 
tumor immune responses based on its role in mediating an immunosuppressive TME as 
well as its role in regulating antigen presenting cell (APC) function.  MET is expressed 
by immature CD14-positive monocytes and can induce an immunosuppressive phenotype 
when its ligand, hepatocyte growth factor (HGF), is secreted by tumor stroma and 
mesenchymal stem cells (MSCs) (Chen-2014).  Depletion of CD14-positive monocytes 
or neutralization of HGF secretion by MSCs reverses the suppression of T effector 
proliferation and triggers a shift back toward a Th1 activated T cell phenotype 
(Chen-2014).  MSCs are also implicated in expansion of immunosuppressive 
myeloid-derived suppressor cells (MDSCs), which are also dependent on the secretion of 
HGF (Yen-2013).  APCs (i.e., dendritic cells) also express MET and the activation of 
MET by HGF results in suppression of APC function including both antigen presenting 
capacity and antigen-dependent T cell responses (Okunishi-2005, Singhal-2011, 
Benkhoucha-2010).  Therefore, inhibition of MET may enhance the antitumor response 
by restoring APC function and reducing or eliminating MDSCs within the TME.   


 
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Glesatinib is an orally administered multi-targeted TKI that primarily targets the Axl and 
MET receptors.  Additional RTK targets potentially include the MERTK, DDR2, and 
PDGFR and  receptors.  The TKI profile of glesatinib suggests the potential for 
synergistic anti-tumor effect when administered in combination with a checkpoint 
inhibitor.   
Inhibition of the VEGF receptor family and KIT may further enhance antitumor 
immunoreactivity by depletion of immunosuppressive cellular subset from the TME 
including regulatory T cells and (MDSCs).  T regulatory cells express VEGFR2 and the 
inhibition of VEGFR2 utilizing a specific VEGFR2 antibody antagonist or VEGFA 
neutralizing antibody (but not a VEGFR1 antagonist) inhibited Treg proliferation in vitro 
and in tumor-bearing mice and patient peripheral blood (Terme-2013).  MDSCs notably 
express both KIT and VEGFR1 and the inhibition of these RTKs using pharmacologic or 
genetic approaches resulted in the inhibition of MDSC viability in vitro and depletion of 
this cell population in mouse tumor models (Ko-2009, Ozao-Choy-2009, Farsaci-2012). 
Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related 
spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR 
family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family 
members.  In addition to the immunostimulatory effects of Axl and MET inhibition, 
sitravatinib may further condition the TME in favor of antitumor activity by its 
immunomodulatory effects mediated through VEGFR and KIT inhibition.   
Taken together, TAM receptors, KIT, VEGFR family and MET activation work together 
to suppress anti-tumor immunity at several nodes and stages of the cancer-immunity 
cycle. The activation of TAM receptors functions as an innate immune cell checkpoint 
and inhibition of these receptors is predicted to complement and augment the activity 
observed with adaptive checkpoint inhibitor therapy (anti-PD-1) alone.  Since activation 
of the TAM receptors functions as a mechanism to limit inflammation during the natural 
course of an immune response, it is likely that differing levels of TAM-dependent 
immunosuppression exists in most tumors, thus providing a rationale for testing inhibitors 
of these “innate checkpoints” in combination with adaptive checkpoint inhibitor therapy 
(anti-PD-1) in cancer patients that are immunotherapy naïve. 
Histone deacetylases (HDACs) have been implicated in the epigenetic regulation of 
innate and adaptive immunity.  Increasing evidence supports the proposal that 
spectrum-selective inhibitors of class I HDACs can reverse immune evasion and elicit 
antitumor host response through immunostimulatory mechanisms.  The 
immunomodulatory properties of class I HDAC inhibitors are reported to be mediated 
through multiple mechanisms including: 1) induction of programmed cell death ligand 
1 (PD-L1) expression on the tumor cell surface, 2) induction of tumor associated antigens 
(TAAs) and MHC Class I and Class II molecules on tumor cells, 3) induction of 
immunogenic cell death via activation and cross-presentation of tumor antigens by 
antigen presenting cells (APCs), 4) enhanced function of T effector cells, and 5) 
decreased function of immunosuppressive cell subsets including Tregs and MDSCs.  In 


 
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addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell 
cycle progression and inducing apoptosis in tumor cells (Kroesen-2014, Leggatt-2012, 
West-2012).   
Mocetinostat is an orally administered spectrum-selective Class I/IV HDAC inhibitor 
specifically targeting HDACs 1, 2, 3 and 11.  Given these pleiotropic immune activating 
effects of class I HDAC inhibitors, combination therapy of mocetinostat with checkpoint 
inhibition may result in increased efficacy compared to immunotherapy alone.   
Nivolumab is a human immunoglobulin G4 (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. 
This study will evaluate the clinical activity of nivolumab in combination with 3 separate 
investigational agents, glesatinib, sitravatinib or mocetinostat.  The study will begin with 
a lead-in dose escalation evaluation in small cohorts of patients administered one of the 
investigational study treatments in combination with nivolumab.  Following identification 
of the dose level to be used in the Phase 2 evaluation for each investigational study 
treatment, full enrollment will proceed. 
 
2 STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objective 
 To evaluate the clinical activity of nivolumab in 3 combination regimens with the 
investigational agents glesatinib, sitravatinib, and mocetinostat, in patients with 
non-squamous NSCLC. 
2.1.2 
Secondary Objectives 
 To evaluate the safety and tolerability of the combination regimens in the selected 
population. 
 To evaluate secondary efficacy endpoints of the combination regimens in the selected 
population. 
 To evaluate the pharmacokinetics (PK) of the investigational agents administered in 
combination with nivolumab.  
 To evaluate the PK of different sitravatinib capsule formulations. 


 
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 To evaluate the PK of sitravatinib administered with food. 
2.1.3 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
ORR as defined by RECIST 1.1. 
2.2.2 
Secondary Endpoints 
 Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of adverse events and laboratory abnormalities. 
 Secondary efficacy endpoints: 
o DR; 
o CBR; 
o PFS; 
o 1-Year Survival Rate; and 
o OS. 
 Blood plasma concentrations of the investigational agents. 
2.2.3 
Exploratory Endpoints 
 
 
 
 
 
 
 
 


 
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3 STUDY DESIGN 
Study MRTX-500 is an open-label, parallel Phase 2 evaluation of nivolumab in 
combination with 3 investigational agents, glesatinib, sitravatinib or mocetinostat, in 
patients with locally advanced, unresectable or metastatic non-squamous NSCLC.  
Patients who have experienced progression of disease on or after treatment with a 
checkpoint inhibitor (CIT- experienced) as well as those who have experienced disease 
progression after platinum-based doublet chemotherapy (CIT- naïve) will be enrolled.  
The primary objective is to evaluate the clinical activity of the combination study 
treatments using ORR in accordance with RECIST 1.1.   
Secondary objectives include evaluation of safety, secondary efficacy endpoints, and PK 
for the investigational agents.  The Schedule of Assessments to be performed in the study 
is presented in Table 1.  Pharmacokinetic and blood biomarker sample collection and 
triplicate ECG assessment time points are presented in Table 2, Table 3, and Table 4.  
Specifics of two sitravatinib sub-studies are presented in appendices, including the PK 
evaluation of three sitravatinib capsule formulations (Appendix 5) and, the PK of 
sitravatinib administered with food (Appendix 6).  
The treatment arms included in this study are the following: 
1. Glesatinib plus nivolumab. 
2. Sitravatinib plus nivolumab. 
3. Mocetinostat plus nivolumab. 
To control bias in assignment of individual patients to treatment arms and to mitigate the 
risk of medication errors with the 3 investigational study treatments administered in 
specific regimens, study sites will be aligned with one specified treatment combination.  
Site alignment may change as patient cohorts are filled or patient recruitment factors shift 
at sites. 


 
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3.1 
Lead-In Dose Escalation Evaluation 
The study will begin with a lead-in dose escalation evaluation of two dose levels of each 
investigational agent in combination with nivolumab, in cohorts of 3 to 8 CIT-
experienced patients each.  The starting dose for each agent (labeled Dose Level 1 in 
Table 7) represents a full reduction step as typically used in single agent Phase 2 trials.  
Dose Level 2 in Table 7 is the typical dose used in single agent Phase 2 trials.  In 
addition, a dose de-escalation step may be undertaken as appropriate (labeled Dose Level 
-1 in Table 7).  Table 7 lists the planned dose levels for each agent.   
Table 7: 
Investigational Study Drug Starting Dose Levels for Cohorts of 
Patients in the Lead-In Dose Evaluation 
Drug 
Regimen 
Dose Level 
1 
2 
-1 
Glesatinib 
Tablets 
Twice Daily 
500 mg 
750 mg 
350 mg 
Sitravatinib 
Capsules  
Once Daily 
120 mg 
150 mg 
80 mg 
Mocetinostat 
Capsules 
Three Times 
Weekly 
70 mg 
90 mg 
50 mg 
 
Depending on experience in early cohorts of patients in the lead-in dose escalation 
evaluation, starting doses below those named in Table 7 may be implemented in new 
cohorts of patients after discussion among Investigators participating in the lead-in 
evaluation and the Sponsor. Depending on experience with early cohorts of patients, not 
all dose levels may be explored. 
Throughout the study, nivolumab will be administered in accordance with approved 
labeling.  Nivolumab is to be administered by intravenous infusion, using either regimen 
included in the approved label: 240 mg every 2 weeks (Q2W) or 480 every 4 weeks 
(Q4W).  Guidance for adverse event management and associated nivolumab treatment 
modifications are provided in product labeling and replicated in Section 5.2.   
3.1.1 
Definition of Dose Limiting Toxicity 
The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI 
CTCAE) version 4.03 will be used throughout this study.  The definition of DLT for the 
purpose of dose escalation decisions includes any of the following events considered to 
be causally related to treatment with an investigational study treatment in combination 
with nivolumab that occurs during the first 28-day treatment cycle: 
 Any Grade 4 non-hematological toxicity. 


 
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 Any Grade 3 non-hematological toxicity or Grade 3 or 4 hematological toxicity that 
does not recover to ≤ Grade 2 as indicated by symptoms within 3 days and/or as 
indicated by laboratory assessment within 8 days after onset of the event despite 
optimal medical management with or without corticosteroids. 
o A special case is provided for hepatic transaminases – increase over baseline by 
two-fold or more and meeting Grade 3 or 4 criteria. 
 Grade 2 pneumonitis or colitis that does not resolve to ≤ Grade 1 as indicated by 
symptoms within 3 days after onset of the event despite optimal medical management 
with or without corticosteroids. 
 Febrile neutropenia or neutropenia associated with systemic infection. 
 Any toxicity that requires suspension of treatment for more than 2 weeks. 
The definition of DLT excludes the following conditions:  
 Grade 3 fatigue lasting ≤ 7 days. 
 Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that can 
be effectively managed with hormone replacement therapy. 
 Acute infusion-related reaction. 
 Lymphopenia without infection. 
 Thrombocytopenia without clinically significant bleeding. 
3.1.2 
Enrollment and Dose Escalation Plan 
Patients meeting eligibility criteria as outlined in this protocol may enroll into the lead-in 
dose escalation evaluation, regardless of whether they did or did not experience clinical 
benefit during prior treatment with a checkpoint inhibitor.  Dose escalation cohorts are 
expected to include between 3 and 8 patients for each investigational study treatment and 
dose level evaluated.  The first patient to be treated at the starting dose and at each new 
higher dose of investigational study treatment will be observed for at least one week prior 
to enrollment of subsequent patients in the cohort.  As many as 5 patients may initially be 
enrolled into each cohort.  For a patient within a dose cohort to be considered evaluable 
for the dose-escalation decision, the patient must have either been on study for one full 
cycle and have received treatment with nivolumab and at least 75% of scheduled 
investigational study treatment doses in Cycle 1 or have experienced a DLT in Cycle 1.  
Decision making for cohort expansion and dose escalation or de-escalation will be in 
accordance with the mTPI method (Dose-Finding Spreadsheet presented in Appendix 2).  
To ensure sufficient patient experience at the dose to be used in the Phase 2 study, 
enrollment at any dose level under consideration may be expanded to include at least 
6 patients.   


 
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3.1.3 
Definition of Maximum Tolerated Dose 
The Maximum Tolerated Dose (MTD) is defined as the highest investigational study 
treatment dose administered in the combination regimen associated with the decision to 
“stay with the current dose” as determined from the Dose-Finding Spreadsheet 
(Appendix 2) using the experience of at least 6 patients during the first 28-day treatment 
cycle.   
3.1.4 
Selection of Phase 2 Dose for Investigational Study Drugs 
For each investigational study drug, the dose to be selected for use in the Phase 2 study 
will be the highest dose evaluated in the lead-in evaluation that is associated with: 
 sufficient safety/tolerability to anticipate that patients will typically be able to receive 
treatment with at least 75% of the intended dose intensity of investigational study 
treatment and 100% dose intensity of nivolumab; and 
 no observed ≥Grade 3 or serious irAEs causally related to the combination regimen. 
A dose level below the MTD may be selected for use in the Phase 2 study. 
3.2 
Phase 2 Study 
Following completion of the lead-in dose escalation evaluation, enrollment into the Phase 
2 study will proceed.   
The treatment arms included in this study are the following: 
1. Glesatinib plus nivolumab. 
2. Sitravatinib plus nivolumab. 
3. Mocetinostat plus nivolumab. 
For patients who have experienced progression of disease on or after treatment with a 
checkpoint inhibitor (CIT-experienced), enrollment into each treatment arm will be 
stratified by prior outcome of treatment with a checkpoint inhibitor: 
a. Clinical benefit (i.e., RECIST defined partial or complete response or stable disease 
for at least 12 weeks [-2 week window permitted for radiograph scheduling]) 
followed by radiographic progression of disease. 
b. No prior clinical benefit (i.e., radiographic progression of disease ≤ 12 weeks after 
initiation of treatment [+2 week window permitted for radiograph scheduling]).   
Thus, the study will include 6 parallel evaluations of clinical activity of nivolumab 
combination regimens (Figure 3) in patients with prior treatment with a checkpoint 


 
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inhibitor.  Patients enrolled in the lead-in dose escalation evaluation and receiving the 
dose of investigational study treatment chosen for the Phase 2 study will be included in 
the analysis of the Phase 2 endpoints. Patients who discontinue the study prior to the first 
on-study disease assessment for reasons other than disease progression may be replaced.  
For patients without prior checkpoint inhibitor therapy (CIT-naïve), each investigational 
study treatment arm (i.e., glesatinib, sitravatinib, and mocetinostat) will be stratified 
according to PD-L1 status: 
a. Having tumor with no/low PD-L1 expression. 
b. Having tumor with high PD-L1 expression. 
Tumor PD-L1 expression will be determined by the PD-L1 (28-8) companion diagnostics 
assay completed through the central laboratory.  No/low PD-L1 expression is defined as 
positivity < 5% of tumor cells; high PD-L1 expression is defined as positivity ≥ 5% of 
tumor cells.  Tumor samples used to establish PD-L1 expression for eligibility must have 
been collected after the most recent systemic therapy.   
Thus, the study will include 6 parallel evaluations of clinical activity of nivolumab 
combination regimens (Figure 3) in patients without prior treatment with a checkpoint 
inhibitor. 
Disease response and progression as documented by the Investigator in the Case Report 
Form (CRF) will be the basis for patient management and study expansion decision 
making.  Unconfirmed objective responses recorded in the CRF may be used as the initial 
basis for expansion of study enrollment; however, follow-up evaluations on patients with 
unconfirmed responses must continue to support the decision to continue to the full 
number of patients to be included in the next stage.  Disease assessments will be 
performed until objective disease progression is documented or subsequent anti-cancer 
therapy is begun.  Central radiology review for disease response and progression may be 
added to the study during Stage 2.  If this occurs, central review of all radiologic 
assessments performed in the study will be expected (including retrospective review of 
patients enrolled in Stage 1), and central radiology review for disease response will be the 
basis for the primary statistical analyses to estimate the objective response rate and its 
confidence interval, as well as the duration of response and PFS. 
Statistical Design Applied to CIT-Experienced and CIT-Naïve with No/Low PD-L1 
Expression 
This Phase 2 study will use a Predictive Probability Design (Lee-2008) in each treatment 
arm and strata.  In creating the statistical designs, the Type 1 error (α) is constrained to 
<0.05 and Power (1-β) is constrained to ≥0.90.   
The ORR using nivolumab in the population with advanced non-squamous NSCLC 
having prior disease progression on a checkpoint inhibitor or patients with non-squamous 
NSCLC without prior checkpoint inhibitor therapy with no/low PD-L1 expression is 


 
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assumed to be 5% (p0); thus this rate is considered uninteresting.  The target ORR using 
the investigational agents in combination with nivolumab in this study is 30% (p1).  Stage 
1 of enrollment will include a minimum of 9 evaluable patients in each treatment strata. 
With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective 
Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a 
total sample size of 17 evaluable patients.  If at least 3 Objective Responses are observed 
in a treatment stratum, further investigation may be warranted.  If the true ORR is 5% 
(null hypothesis), the probability of early termination during the study is 0.63; the Type 1 
error is equal to 0.0466 and the power is equal to 0.9045.   
Statistical Design Applied to CIT-Naïve with High PD-L1 Expression 
The ORR using nivolumab in the population with non-squamous NSCLC having high 
PD-L1 expression is assumed to be 27% (p0); thus this rate is considered uninteresting.  
The target ORR using the investigational agents in combination with nivolumab is 50% 
(p1).   
Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 
17 evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 27 
additional evaluable patients will be enrolled, for a total sample size of 44 evaluable 
patients.  If at least 18 Objective Responses are observed, further investigation may be 
warranted.  If the true ORR is 27% (null hypothesis), the probability of early termination 
during the study is 0.50; the Type 1 error is equal to 0.0303 and the power is equal to 
0.9018.   
The exact stopping rules for all cohorts will be calculated based on the Predictive 
Probability Design, once the exact number of patients evaluable at Stage 1 is known. The 
aim is to get a minimum of 9 evaluable patients at Stage 1 for CIT-experienced and CIT-
naïve with no/low PD-L1 expression cohorts and a minimum of 17 evaluable patients at 
Stage 1 for CIT-naïve with high PD-L1 expression cohort. 
In order to be part of the clinical activity evaluable population, the patient must have at 
least one on-study disease assessment or discontinue from treatment for progressive 
disease prior to this assessment.  Patients who discontinue treatment prior to the first on-
study disease assessment for an AE, toxicity, or withdraw consent are considered non-
evaluable for disease assessment. These patients will not be part of the clinical activity 
evaluable population. 
Expansion Beyond Stage 2 
The original protocol provided that if results in any strata were of high interest for 
efficacy, enrollment might be expanded to as many as 100 patients total in each cohort to 
narrow the 95% Confidence Interval (CI) around the ORR point estimate.  Protocol 
Amendment 3 (Version 4.0) eliminates enrollment expansion beyond Stage 2 except in 
the sitravatinib segment of the study enrolling patients with CIT-experience.   


 
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For the sitravatinib segment of the study enrolling patients with CIT-experience, 
expansion of enrollment beyond Stage 2 will be managed as one cohort that includes all 
patients, regardless of prior clinical benefit during treatment with CIT.  Based on 
preliminary clinical activity results as of June 2018 (described in Section 1.5.3.2.2), 
enrollment into the combined cohort will expand to as many as 125 patients total, to 
further evaluate safety and efficacy in this setting.   
Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not 
anticipated. 
 




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4 PATIENT 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 as applicable for phase of the 
study to be eligible for enrollment into the study: 
1. Histologically confirmed non-squamous NSCLC with metastatic or unresectable, 
locally advanced disease, not amenable to treatment with curative intent. 
2. Receipt of at least one prior treatment in the advanced disease setting.  
a) CIT-experienced: Most recent treatment must have included a checkpoint 
inhibitor (i.e., anti-PD-1 or anti-PD-L1 including nivolumab, pembrolizumab, 
durvalumab, atezolizumab or avelumab) with the result of progression of disease 
on or after treatment.  
Note: For the PK sub-studies as outlined within Appendix 5 and Appendix 6, 
treatment with a checkpoint inhibitor (i.e., anti-PD-1 or anti-PD-L1) does not 
need to be included in the most recent treatment. 
b) CIT-naïve: Receipt of prior platinum-based doublet chemotherapy.  
3. CIT-naïve: Molecular analysis of tumor sample collected following most recent 
therapy, assessed using the PD-L1 (28-8) CDx assay.  Inclusion in the treatment arm 
will be based on documented no/low PD-L1 expression (positivity < 5% of tumor 
cells) or high PD-L1 expression (positivity ≥ 5% of tumor cells). Note: This criterion 
does not apply to the PK sub-studies as outlined within Appendix 5 and Appendix 6. 
4. Measurable disease as per RECIST version 1.1.   
5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 
(Appendix 1). 
6. Adequate bone marrow and organ function demonstrated by:  
 Absolute neutrophil count  1,000/mm3 ( 1.0 × 109/L) 
 Platelet count ≥ 50 × 109/L (> 50,000 per mm3) 


 
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 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × Upper Limit of Normal (ULN), or ≤ 5.0 × ULN for patients with 
documented liver metastases.   
 Serum bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for patients with Gilbert Syndrome 
or documented liver metastases.   
 Serum creatinine ≤ 1.5 × ULN. 
7. ≥ 18 years of age. 
8. 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. 
9. Completed informed consent process, including signing IRB/EC-approved informed 
consent form. 
10. 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. Active brain metastases.  Patients are eligible if brain metastases are adequately 
treated and patients are neurologically stable (except for residual signs or symptoms 
related to the central nervous system (CNS) treatment) for at least 2 weeks prior to 
enrollment without the use of corticosteroids, or are on a stable or decreasing dose of 
≤10 mg daily prednisone (or equivalent). 
a. Patients with carcinomatous meningitis 
2. Patients with any history of tumors that test positive for EGFR, ROS1, ALK 
mutations or ALK fusions or any other well characterized driver mutations (e.g., RET 
fusion, TRK alterations, BRAF mutations). Note: The following modification to this 
criterion applies to the PK sub-studies as outlined within Appendix 5 and Appendix 
6: Patients with EGFR, ROS1, ALK mutations or ALK fusions are eligible if 
previously treated with targeted therapy and/or treatment with a targeted therapy is 
not indicated.  
3. Prior therapies: (Note: This exclusion criterion does not apply to the PK sub-studies 
as outlined within Appendix 5 and Appendix 6)  
a) Immunotherapies not previously specified, including anti-CTLA-4, anti-OX40 
and anti–CD137. 


 
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b) Combination therapy with a checkpoint inhibitor and cancer therapy having the 
same mechanism of action as the investigational agent intended for use in this 
study (e.g., tyrosine kinase target or HDAC inhibitor, except prior use of valproic 
acid for seizures). 
4. Unacceptable toxicity on prior checkpoint inhibitor treatment (CIT- experienced 
patients only): 
a. ≥ Grade 3 immune-related AE related to checkpoint inhibitor. 
b. Grade 2 immune-related AE associated with checkpoint inhibitor unless the AE 
resolved or was well controlled by withholding the checkpoint inhibitor and/or 
treatment with steroids, with the exception of prior colitis, myocarditis, and 
pneumonitis, which are exclusionary. 
c. CNS or ocular AE of any grade related to checkpoint inhibitor. 
NOTE: Patients with a prior endocrine AE are permitted to enroll if they are 
stably maintained on appropriate replacement therapy and are asymptomatic. 
5. Active or prior documented autoimmune disease: 
a. Inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). 
b. History of interstitial lung disease (ILD), drug-induced ILD, radiation 
pneumonitis which required steroid treatment, or any evidence of clinically active 
interstitial lung disease. 
c. Active or prior documented autoimmune disease within the past 2 years.  
NOTE: Patients with Type I diabetes, vitiligo, Grave’s disease, or psoriasis not 
requiring systemic treatment (within the past 2 years) are not excluded. 
6. Active or prior immunocompromising conditions: 
a. Current or prior use of immunosuppressive medication within 28 days before the 
first dose of study treatment, with the exceptions of topical, ocular, intranasal and 
inhaled corticosteroids (with minimal absorption) or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent corticosteroid. A brief course (≤ 3 days) of systemic corticosteroids 
>10 mg/day of prednisone (or equivalent corticosteroid) for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-immune conditions (e.g., delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted within the 
28 days. 
b. Known acute or chronic human immunodeficiency virus (HIV). 


 
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c. History of primary immunodeficiency. 
d. History of allogeneic transplant. 
7. Known acute or chronic hepatitis B or hepatitis C. Patients treated for hepatitis C with 
no detectable viral load are permitted. 
8. History of hypersensitivity to study treatment excipient.   
9. History of stroke or transient ischemic attack within the previous 6 months. 
10. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris. 
b. Congestive heart failure ≥ NYHA Class 3. 
c. QTc >480 milliseconds.   
d. Sitravatinib and mocetinostat treatment arms: 
i. LVEF <40% (sitravatinib and mocetinostat only). 
ii. Current or history of a small, moderate or large pericardial effusion, and/or 
hemodynamic compromise due to pericardial effusion of any size.  Minimal or 
trivial pericardial effusion is not excluded (mocetinostat only). 
11. Concomitant medication known to cause prolonged QT which cannot be discontinued 
or changed to a different medication prior to enrollment (Appendix 3). 
12. Known or suspected presence of another malignancy that could be mistaken for the 
malignancy under study during disease assessments. 
13. Pregnancy.  WOCBP must have a negative serum or urine pregnancy test documented 
within the screening period prior start of study drug. 
14. Breast-feeding or planning to breast feed during the study or within 6 months after 
study treatment. 
15. 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. 


 
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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 study-specific 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 Study Manual.  Each patient will be assigned a 
sequential number by the study site.  The patient number must be used on all 
documentation and correspondence with the Sponsor, Contract Research Organization 
(CRO) and laboratory vendors. 
For the evaluation of tumor PD-L1 expression for CIT-naive patients, a 14-day turn-
around time should be expected from the time of receipt of adequate samples at the 
central laboratory to test results returned to the study site. 
 


 
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5 STUDY TREATMENTS 
5.1 
Investigational Agents 
5.1.1 
Glesatinib 
5.1.1.1 
Glesatinib Formulation, Packaging and Storage 
Glesatinib will be supplied by the Sponsor as 100 and 250 mg unit dosage strength 
tablets.  The composition of the drug product consists of a blend of MGCD265 free base 
drug substance, hydroxypropylmethyl cellulose (HPMC), Avicel® (or equivalent), 
Kollidon® (or equivalent), sodium bicarbonate, sodium chloride, Syloid® (or equivalent), 
and magnesium stearate, as necessary.   
Glesatinib tablets will be supplied in high-density polyethylene (HDPE), white opaque 
bottles.  A tamper-proof heat induction seal and a child-resistant closure are used.  Tablet 
bottles will be received by the pharmacy in foil pouches that are to be kept intact until the 
bottles are dispensed to the patient.  The Sponsor provided bottles should be labeled for 
specific patient use and given to the patient.   
While stored in the study site pharmacy, glesatinib tablets should be at refrigerated 
conditions (suggested temperature range 2-8°C, 36-46°F).  Once dispensed to patients, 
tablets bottles should be stored at room temperature (suggested temperature range 
15-30°C, 59-86°F).   
Refer to the Pharmacy Study Manual for details on available unit dose strengths, bottle 
sizes, and number of units per bottle supplied. 
5.1.1.2 
Glesatinib Administration 
Glesatinib tablets will be administered orally, twice daily (BID), in a continuous regimen 
expressed in 28-day cycles.  The starting dose for glesatinib in the lead-in dose escalation 
evaluation will be 500 mg BID.  Depending on safety observations, the glesatinib dose in 
the subsequent cohort of patients may escalate to 750 mg BID or de-escalate to 350 mg 
BID.  Individual patients should not undergo dose escalation above their starting dose.   
The following guidelines should be followed for glesatinib administration: 
 Doses should be taken approximately every 12 hours at approximately the same times 
each day. 
 At the beginning of the study, tablets should be taken on an empty stomach (at least a 
1-hour fast before each dose and no food for a minimum of 1 hour after each dose).  
If results from an ongoing food-effect study indicate that fasting is unnecessary, an 
Administrative Letter to Investigators will communicate elimination of this guidance.  


 
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 Tablets should be taken with at least 200 mL (1 cup) of water. 
 Patients should swallow the tablets whole and not chew them. 
 If vomiting occurs after dosing, glesatinib doses should not be replaced.   
On days when glesatinib and nivolumab dosing are both scheduled, the first daily dose of 
glesatinib should precede nivolumab infusion for logistical reasons.  This order of dosing 
is of most interest on days when blood sampling is scheduled for glesatinib PK. 
5.1.1.3 
Glesatinib Dose Modification and Discontinuation 
In the event of adverse events attributed to glesatinib and deemed intolerable by the 
Investigator, treatment should be either temporarily or permanently discontinued.  For 
patients who temporarily discontinue treatment, treatment may resume following 
resolution of treatment-related adverse events to Grade 1 or baseline with the 
administration of glesatinib at a reduced dose level as outlined in Table 8.  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 glesatinib is interrupted for reasons other 
than toxicity, then treatment with the study drug may be resumed at the same dose.   
Table 8: 
Glesatinib Sequential Dose Reductions for Individual Patients 
750 mg twice daily 
500 mg twice daily 
350 mg twice daily 
250 mg twice daily 
 
Dose reduction below 250 mg BID may be undertaken after discussion with the Sponsor.  
If treatment with glesatinib is withheld for ≥ 28 consecutive days, then permanent 
discontinuation from this study drug should be considered. 
5.1.1.4 
Glesatinib Specific Adverse Event Management Guidelines 
See Section 5.1.4.2 for management guidelines for non-hematological or hematological 
toxicities commonly associated with cancer therapies, which will be applied to all three 
investigational study treatments in this study.   
The following are guidelines for management of potential adverse events more specific to 
treatment with glesatinib or agents in the same class of cancer treatment. 
5.1.1.4.1 
Diarrhea 
See Section 5.1.4.2.2 for treatment management guidelines in patients experiencing 
diarrhea during study treatment.  Patients treated with glesatinib should be made aware of 


 
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the potential of developing diarrhea while taking glesatinib.  Prophylactic anti-diarrheal 
treatment may be implemented at the discretion of the Investigator.  A regimen 
recommended for primary prophylaxis for diarrhea is loperamide 2-4 mg beginning with 
the first dose of glesatinib, followed by 2 mg every 6–8 hours.  Loperamide use may be 
subsequently titrated as needed.  If prophylactic treatment is not used, patients should 
start treatment with loperamide immediately upon the first sign of diarrhea.  If there is no 
improvement in severity of symptoms within 24 hours, additional anti-diarrheal 
medication in the form of Lomotil® should be added.  If this does not effectively control 
symptoms, patients should be instructed to contact their physician and their dose held 
until resolution of symptoms followed by a dose reduction as indicated per protocol.  
Patients with severe or prolonged diarrhea should be observed and treated for 
dehydration. 
5.1.2 
Sitravatinib  
5.1.2.1 
Sitravatinib Formulation, Packaging and Storage 
Two formulations of sitravatinib capsules are being utilized in this study.  The 
composition of the sitravatinib free base drug product consists of a blend of MGCD516 
free base drug substance, microcrystalline cellulose (Avicel® PH302) and polysorbate 
80 (Tween® 80) and Aerosil® 200 Pharma.   
Sites that are participating in one or both of the PK Sub-Studies as referenced in 
Appendix 5 and Appendix 6 of the protocol will also receive Sitravatinib (MGCD516) 
malate formulation capsules.  
Two manufacturing methods of the malate formulation were utilized to improve 
manufacturing process and scalability.  The composition of the sitravatinib malate direct 
blend drug product consists of a blend of MGCD516 malate drug substance, 
microcrystalline cellulose (Avicel® PH302), colloidal silicon dioxide (Cab-O-Sil), 
croscarmellose sodium (Ac-Di-Sol) and magnesium stearate. The composition of the 
sitravatinib malate roller compaction drug product consists of a blend of MGCD516 
malate drug substance, microcrystalline cellulose, mannitol, colloidal silicon dioxide, 
croscarmellose sodium, and magnesium stearate.  
Sitravatinib drug product in all formulations 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, or 
the pharmacy may re-dispense the needed number of capsules into Sponsor provided 
HDPE bottles. 
Sitravatinib capsule bottles should be stored under refrigerated conditions (2-8°C, 36-
46°F) at the pharmacy in according to instructions on the label.  After dispensing to the 
patient, bottles of sitravatinib capsules are to be stored at ambient room temperature for 
the duration of time specified in the Pharmacy Manual.   


 
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Refer to the Pharmacy Study Manual for details on available unit dose strengths, bottle 
sizes, and number of units per bottle supplied. 
5.1.2.2 
Sitravatinib Administration 
Sitravatinib capsules will be administered orally, once daily (QD), in a continuous 
regimen expressed in 28-day cycles.   
In the Phase 1 segment of the study, the starting dose for sitravatinib in the lead-in dose 
escalation evaluation will be 120 mg QD.  Depending on safety observations, the 
sitravatinib dose in the subsequent cohort of patients may escalate to 150 mg QD or 
de-escalate to 80 mg QD.  Individual patients should not undergo dose escalation above 
their starting dose. 
The sitravatinib recommended Phase 2 starting dose is 120 mg QD. 
The starting dose of sitravatinib for patients enrolled in the PK sub-studies is described in 
Appendix 5 and Appendix 6.  
The following guidelines should be followed for sitravatinib administration: 
 Dosing in the morning is preferred. 
 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).  Instructions to be followed for 
patients enrolled in the sub-study dedicated to evaluating sitravatinib administered 
with food are provided in Appendix 6.   
 Capsules should be taken with ~240 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. 
5.1.2.3 
Sitravatinib Dose Modification and Discontinuation 
In the event of adverse events attributed to sitravatinib and deemed intolerable by the 
Investigator, treatment should be either temporarily or permanently discontinued.  For 
patients who temporarily discontinue treatment, treatment may resume following 
resolution of treatment-related adverse events to Grade 1 or baseline with the 
administration of sitravatinib at a reduced dose level as outlined in Table 9.  Once the 
dose has been reduced, re-escalation is generally not recommended but may be 


 
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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 9: 
Sitravatinib Free Base Formulation Sequential Dose 
Reductions for Individual Patients 
150 mg once daily (eliminated after lead-in evaluation) 
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. 
Sitravatinib Malate Direct Blend Formulation Sequential Dose Reductions 
for Individual Patients 
60 mg once daily 
40 mg once daily 
 
Sitravatinib Malate Roller Compaction Formulation Sequential Dose 
Reductions for Individual Patients 
100 mg once daily 
80 mg once daily 
60 mg once daily 
40 mg once daily 
A two-step dose reduction (e.g. 100 mg to 60 mg once daily) is permitted at the discretion of the 
investigator 
In the event of sitravatinib-related AE, dose reduction with continuous treatment is 
preferred over repeated dose interruption.  Following sitravatinib dose reduction and 
control of adverse event, re-challenge at a higher sitravatinib dose is permitted at the 
discretion of the Investigator.  If treatment with sitravatinib is withheld for ≥ 28 
consecutive days, then permanent discontinuation from this study drug should be 
considered.  If one study drug is interrupted or discontinued, administration of the other 
study drug may continue at the discretion of the Investigator. 
5.1.2.4 
Sitravatinib Specific Adverse Event Management Guidelines 
See Section 5.1.4.2 for management guidelines for non-hematological or hematological 
toxicities commonly associated with cancer therapies which will be applied to all three 
investigational study treatments in this study.   


 
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The following are guidelines for management of potential adverse events more specific to 
treatment with sitravatinib or agents in the same class of cancer treatment. 
5.1.2.4.1 
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 10).  On the other hand, in cases of Grade 3 
hypertension with clinically significant increases in blood pressure (see Table 10), 
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 10). 
Table 10: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity 
Treatment Delay 
Reduction 
Grade 1 or 2 hypertension 
Investigator discretion, as per Table 15 
Grade 3 hypertension without clinically significant 
increases in BP as defined below 
Investigator discretion. Consider anti-
hypertensives per Section 5.1.2.4.1 
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 
5.1.2.4.2 
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. 


 
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5.1.2.4.3 
Diarrhea 
See Section 5.1.4.2.2 for treatment management guidelines in patients experiencing 
diarrhea during study treatment.  Diarrhea has been reported with sitravatinib treatment, 
though the mechanism remains unclear, as with other small molecule RTK inhibitors.  
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. 
5.1.2.4.4 
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.   
5.1.2.4.5 
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 patients who develop 
clinically significant thromboembolic complications such as acute myocardial infarction 
or severe pulmonary embolism. 
5.1.2.4.6 
Thyroid Dysfunction Other than Immune-Mediated 
Hypothyroidism and increases in 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. 
5.1.2.4.7 
Decreased Left Ventricular Ejection Fraction 
Decreased left ventricular ejection fraction (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.  The dose of 
sitravatinib should be interrupted and/or reduced in patients without clinical evidence of 
congestive heart failure (CHF) but with an ejection fraction <50% and >20% below 
baseline.  Discontinuation should be considered in more severe cases.  
5.1.2.4.8 
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 


 
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should be discontinued in the presence of ≥2 grams of proteinuria/24 hours and may 
restart when protein levels decrease to less than 2 grams/24 hours.  Patients who develop 
nephrotic syndrome should be withdrawn from treatment with sitravatinib. 
5.1.3 
Mocetinostat 
5.1.3.1 
Mocetinostat Formulation, Packaging and Storage 
Mocetinostat will be provided by the Sponsor as 10 mg (white opaque), 20 mg (white 
opaque), 25 mg (Swedish orange), and 50 mg (Swedish orange) unit dose strength 
capsules.  The composition of the drug product consists of the free-base form of 
MGCD0103 and inert excipients: microcrystalline cellulose, sodium starch glycolate, 
colloidal silicon dioxide and non-bovine magnesium stearate.   
Mocetinostat drug product is packaged in high-density polyethylene (HDPE), white 
opaque, bottles, with a desiccant packet.  A tamper-proof heat induction seal and a child-
resistant closure are used.  Refer to the Pharmacy Study Manual for details on available 
unit dose strengths, bottle sizes, and number of units per bottle supplied. 
Mocetinostat capsules should be stored protected from light, at room temperature 
(suggested range is 15-30°C, 59-86°F) according to instructions on the label.   
5.1.3.2 
Mocetinostat Administration 
Mocetinostat capsules will be administered orally, three times per week (TIW), in a 
continuous regimen expressed in 28-day cycles.  The starting dose for mocetinostat in the 
lead-in dose escalation evaluation will be 70 mg TIW.  Depending on safety 
observations, the mocetinostat dose in the subsequent cohort of patients may escalate to 
90 mg TIW or de-escalate to 50 mg TIW.  Individual patients should not undergo dose 
escalation above their starting dose.   
The following guidelines should be followed for mocetinostat administration: 
 Patients should be instructed to take the dose of mocetinostat three days per week 
(e.g., Monday/Wednesday/Friday), in the morning, at approximately the same time 
each day. 
 Mocetinostat capsules should be taken on an empty stomach (after an overnight fast 
or at least a 3-hour fast before each dose and no food for a minimum of 2 hours 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, mocetinostat doses should not be replaced.   


 
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 Mocetinostat doses should not be taken 2 days in a row and gaps longer than 3 days 
(~72 hours) should be avoided when possible. 
On days when mocetinostat and nivolumab dosing are both scheduled, the mocetinostat 
should precede nivolumab infusion for logistical reasons.  This order of dosing is of most 
interest on days when blood sampling is scheduled for mocetinostat PK.  Alignment of 
mocetinostat and nivolumab dosing days is not required.  For instance, mocetinostat may 
be routinely administered on Monday, Wednesday and Friday, and nivolumab 
administered in the clinic on a Thursday.   
5.1.3.3 
Mocetinostat Dose Modification and Discontinuation 
In the event of adverse events attributed to mocetinostat and deemed intolerable by the 
Investigator, treatment should be either temporarily or permanently discontinued.  For 
patients who temporarily discontinue treatment, treatment may resume following 
resolution of treatment-related adverse events to Grade 1 or baseline with the 
administration of mocetinostat at a reduced dose level as outlined in Table 11.  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 mocetinostat is interrupted 
for reasons other than toxicity, then treatment with the study drug may be resumed at the 
same dose.   
Table 11: 
Mocetinostat Sequential Dose Reductions for Individual 
Patients 
90 mg three times per week 
70 mg three times per week 
50 mg three times per week 
40 mg three times per week 
Dose reduction below 40 mg TIW may be undertaken after discussion with the Sponsor.  
If treatment with mocetinostat is withheld for ≥ 28 consecutive days, then permanent 
discontinuation from this study drug should be considered. 
5.1.3.4 
Mocetinostat Specific Adverse Event Management Guidelines 
5.1.3.4.1 
Mocetinostat Management of Pericardial Adverse Events 
Pericardial AEs will be defined as outlined in Table 12. 


 
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Table 12: 
Definitions of Pericardial Events 
Event Term 
Definition 
Characteristics/Diagnosis 
Pericarditis 
Inflammation of the 
pericardium 
The major clinical manifestations of acute pericarditis 
include: 1) chest pain, 2) pericardial friction rub, 3) ECG 
changes (with new, widespread ST elevation or PR 
depressions), and 4) pericardial effusion.  At least 2 of 
these features are usually considered necessary to make the 
diagnosis. 
Pericardial 
effusion 
Excess exudate, or fluid, 
in the pericardium 
Once a pericardial effusion is suspected, the diagnostic 
approach consists of 3 steps: 1) establish the presence of 
effusion, 2) assess the hemodynamic impact, and 
3) establish the cause.  Clinical evaluation and ECG 
findings may suggest the presence of a pericardial 
effusion, but imaging, usually ECHO, is required to 
establish a diagnosis. 
Hemodynamic  
Compromise 
Mechanical compression 
of the heart by large 
amounts of fluid or blood 
within the pericardial 
space that limits the 
normal range of motion 
and function of the heart 
The diagnosis of hemodynamic compromise is based upon 
clinical and imaging evidence.  The following physical 
findings 1) sinus tachycardia, 2) elevated jugular venous 
pressure, and 3) pulsus paradoxus are suggestive of frank 
tamponade.  Echocardiogram or other imaging of the 
pericardium is essential to the diagnosis of hemodynamic 
compromise. 
 
ECHOs will be used to assess and categorize pericardial fluid as minimal (or trivial), 
small, moderate or large and will assess for hemodynamic compromise.  Pericardial 
effusions will be assessed and managed as follows (Table 13). 
 
 


 
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Table 13: 
Pericardial Effusion and Patient Management Guidelines 
Category 
Definitions 
Patient Management 
Minimal 
(or trivial) 
A small echo-free space in the posterior 
atrioventricular groove that is visible only 
in systole when the heart has pulled away 
from the pericardium.  Typically 
represents a normal amount of pericardial 
fluid in a disease-free state. 
De novo (i.e., not present at baseline) 
pericardial effusion: 
 
Study treatment may be continued at 
the discretion of the Investigator. 
 
Increased ECHO and ECG monitoring 
weekly until effusion is no longer 
present or has not progressed over a 
period of 2 weeks. 
 
Regular assessment schedule 
afterwards. 
Small  
< 1 cm of posterior echo-free space, with 
or without fluid accumulation elsewhere, 
present throughout the cardiac cycle, 
including diastole (and not only systole). 
 
Study drug will not be discontinued in 
these Patients, at the discretion of the 
Investigator, unless the effusion 
progresses. 
 
Increased ECHO and ECG monitoring 
weekly for the first month after the 
new effusion first noted or until the 
effusion has regressed (if sooner).   
 
Treatment for the effusion may be 
administered at the discretion of the 
Investigator.   
Moderate 
1 to 2 cm of echo-free space.  Moderate 
effusions tend to be seen along the length 
of the posterior wall but not anteriorly. 
 
Remove immediately from study 
treatment. 
 
Manage according to the standard of 
care at the discretion of the 
Investigator. 
 
Refer to cardiologist for follow-up as 
clinically indicated, until resolution of 
stabilization. 
Large  
> 2 cm of maximal separation.  Large 
effusions tend to be seen circumferentially. 
Hemodynamic 
Compromise 
RV compression, IVC dilation without 
respiratory variation, abnormal flow 
variation across the AV valves without 
respiratory variation, enlarged or collapsed 
ventricles.  RA diastolic collapse in 
isolation is too non-specific to signal 
hemodynamic compromise, but should be 
considered consistent with this diagnosis 
when accompanied by other findings 
 
Remove immediately from study 
treatment. 
 
Refer to cardiologist for follow up as 
clinically indicated, until resolution or 
stabilization.   
 
Collect blood and test for anti-nuclear 
antibody (ANA) and anti-histone 
antibody. 
In exceptional circumstances where ECHO is not considered a technically optimal 
assessment of pericardial space (e.g., overweight patient), other methods (e.g., MRI) 
should be used for pericardial assessments.  In such cases, the guidelines provided in 
Table 13 would not apply, and the evaluation should be performed in consultation with 
the Sponsor.  In the event that a pericardial effusion is first identified by a method other 
than ECHO, efforts should be made to obtain an ECHO for assessment of effusion size. 


 
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5.1.4 
Instructions Common to Investigational Study Treatments 
5.1.4.1 
Clinical Trial Material Specifics and Management Common to the 
Investigational Study Treatments 
Investigational study treatment 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. 
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. 
Investigational study treatment clinical trial material should be stored in an area that is 
secure, with limited access and monitored for temperature using a calibrated thermostat.   
Study site personnel will dispense investigational study treatment tablets or capsules on 
Day 1 of each dose cycle for the first 12 cycles on study, and then may reduce the 
frequency to every 2 cycles, at the discretion of the Investigator.  Sufficient supply will 
be provided for each cycle and extra tablets/capsules may be provided to cover an 
additional 2 days in case of delayed clinic visits or lost tablets/capsules.  Study 
tablets/capsules will be dispensed in HDPE bottles provided by the Sponsor.   
All investigational 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 the specified investigational study 
treatment tablets or 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 tablet/capsule 
count.  Study site personnel will retain the bottle(s) until a monitor has completed 
reconciliation and retain dosing diaries with site study files.   
At the end of the study, all unused investigational study treatment 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. 


 
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5.1.4.2 
Adverse Event Management Guidelines Common to the 
Investigational Study Treatments 
Guidance on size of dose reduction steps in response to investigational study treatment 
toxicity are specified for glesatinib, sitravatinib and mocetinostat in Sections 5.1.1.3, 
5.1.2.3 and 5.1.3.3, respectively.   
Adverse event management guidance specific to investigational study treatments for 
glesatinib, sitravatinib and mocetinostat in Sections 5.1.1.4, 5.1.2.4 and 5.1.3.4, 
respectively. 
5.1.4.2.1 
Investigational Study Treatment Management in Event of 
Immune-Related Adverse Events 
None of the three investigational study treatments has been associated with 
immune-mediated AEs.  However, the potential exists for one or more of the treatments 
to contribute to immune-mediated AEs associated with nivolumab treatment.  In the 
event of an immune-related AE during study treatment, administration of the 
investigational study treatment and nivolumab should be interrupted until the event 
stabilizes to Grade ≤1 (consistent with guidance provided in the OPDIVO US Prescribing 
Information replicated in Section 5.2.5).  At the time of resumption of investigational 
study treatment dosing, a dose reduction may be implemented at the discretion of the 
Investigator.   
5.1.4.2.2 
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.  Non-specific, most often mild to moderate diarrhea has been 
observed with all three investigational study treatments and nivolumab.  Diarrhea has 
been reported in approximately 55% of patients treated with glesatinib, 23% of patients 
treated with sitravatinib, and 46% of patients treated with mocetinostat, most often 
beginning within the first month of treatment.  Diarrhea (any grade) is less common with 
nivolumab, occurring in approximately 8% (22/287) of patients treated for NSCLC with 
3 mg/kg Q2W in the CheckMate 057 clinical trial (USPI OPDIVO [nivolumab]).  
Immune-related colitis has been reported in 2.4% (7/287) of patients treated with 
nivolumab for NSCLC, with median time to onset of 2.7 months (range: 4 weeks to 
19 months).  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 glesatinib, sitravatinib or mocetinostat 
treatment-associated diarrhea.  The diarrhea observed with the investigational study 
treatments generally improves within several days of interrupting study medication and 
therefore dechallenge, 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 dechallenge, laboratory or radiologic tests suggests 


 
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the presence of immune-mediated colitis, all study medications should be withheld and 
treatment with immuno-suppressive therapy initiated as detailed in Table 17. 
5.1.4.2.3 
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.  Tyrosine kinase inhibitors in 
general, and MET inhibitors in particular, have been associated with non-specific, most 
often mild to moderate elevation in AST and ALT.  The observed effects of MET 
inhibitors likely reflect on-target impact on the ligand, hepatocyte growth factor (HGF).  
Among patients treated with glesatinib, increases in AST and ALT have been observed in 
approximately 18% and 12%, respectively.  Mild to moderate elevations in liver 
transaminases have also been observed in less than 10% of patient treated with 
sitravatinib.  The elevations observed with both glesatinib and sitravatinib generally 
occur within the first cycle of treatment and resolve with interruption of treatment.  
Nivolumab-related immune-mediated hepatitis was reported in 0.3% (1/287) of patients 
treated for NSCLC, with an onset of approximately 8 months following initiation of 
therapy.   
For cases where transaminases 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 are provided in Table 14.  
However, if any features of the clinical presentation, including timing of presentation, 
failure to improve with dechallenge, 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 Table 17. 
Table 14: 
Investigational Study Treatment Modification for Increased 
Hepatic Transaminase1 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 (>ULN to 3.0 × ULN) 
May be implemented based on Investigator and patient discretion 
Grade 2 (>3.0 to 5.0 × ULN) 
Not required 
Decrease by 1 dose level 
Grade 3/4 (>5.0 × ULN) 
Hold until ≤ Grade 1 or return to 
baseline 
Decrease by at least 2 dose 
levels for a first dose reduction; 
decrease by at least 1 dose level 
if dose is already reduced. 
1. 
See Sections 5.2.4 and 5.2.5 for guidelines on treatment modification for nivolumab 


 
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5.1.4.2.4 
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, investigational study treatment should be permanently discontinued. 
5.1.4.2.5 
Management of Investigational Study Treatment in Event of 
Non-Hematological Toxicities 
Per protocol, a complete review of adverse events should be conducted at each clinic 
visit.  Symptomatic Grade 2 sitravatinib-related non-hematological adverse events 
occurring any time on study, particularly early in treatment (e.g., Cycle 1 Day 15 or 
Cycle 2 Day 1), are recommended to be managed using dose reduction to the next lower 
dose level, per the reduction schedule outlined in Table 9, rather than continued dosing 
until interruption becomes necessary. 
Non-hematological toxicities ≥ Grade 3 and considered to be treatment-related should be 
managed with investigational study treatment interruption until resolution of toxicity to 
≤ Grade 1 or to baseline value.  If the toxicity is adequately managed by routine 
supportive care (such as electrolyte supplementation), treatment may be resumed at the 
same dose; if not, treatment may be resumed at a reduced dose (Table 15).  Treatment 
with sitravatinib may continue without dose modification (e.g., interruption or reduction) 
in cases of asymptomatic amylase and/or lipase increases in the absence of other clinical 
evidence of pancreatitis (e.g., symptoms, electrolyte abnormalities, radiographic changes) 
at the investigator’s discretion.  Recurrence of the toxicity may be managed similarly.  If 
treatment is interrupted for ≥ 28 days, permanent discontinuation from sitravatinib should 
be considered. 
Table 15: 
Investigational Study Treatment Dose Modifications – 
Non-Hematological Drug-Related Toxicities1, 2 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 
Continue treatment unchanged 
 Grade 2 Asymptomatic 
May be implemented based on Investigator or patient discretion2 
Grade 2 Symptomatic 
May be implemented based on Investigator or patient discretion2 
Early dose reduction to the next lower dose level is recommended over 
treatment interruption 
Grade 3 or 4 
Hold until ≤ Grade 1 or return to 
baseline2 
Resume at dose one or more levels 
below that inducing the toxicity. 
Exceptions presented in footnote.2,3  
1 
Management of selected adverse events for each investigational study treatment are presented in 
Sections 5.1.1.4, 5.1.2.4 and 5.1.3.4. 
2 
The current OPDIVO® US Prescribing Information (USPI OPDIVO [nivolumab]) must be 
consulted to determine appropriate dose modifications for nivolumab. 
3 
Patients may resume at the same dose in the following cases: 


 
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a. 
Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves 
spontaneously or with conventional medical treatment within 72 hours; 
b. Grade 3 amylase or lipase elevation that is not associated with symptoms or other clinical 
manifestations (e.g., electrolyte abnormalities, radiographic changes) of pancreatitis. 
5.1.4.2.6 
Management of Investigational Study Treatment in Event of 
Hematological Toxicities 
Hematological toxicities are not a frequent cause of treatment interruption or 
discontinuation with any of the three investigational study treatments.  Observed ≥ Grade 
3 hematological events that are considered to be causally related to the administered 
investigational study treatment should be managed using treatment interruption or dose 
reduction at the discretion of the Investigator.  If treatment is interrupted for ≥ 28 days, 
permanent discontinuation from study treatment should be considered. 
5.2 
Nivolumab Study Drug  
Nivolumab will be obtained from commercial sources and managed in accordance with 
the OPDIVO US Prescribing Information.  The following sections provide reprints of 
information and guidance included in the OPDIVO US Prescribing Information dated 
April 2018.  Refer to the current OPDIVO US Prescribing Information provided by the 
manufacturer for updates during the conduct of this clinical trial 
(https://packageinserts.bms.com/pi/pi opdivo.pdf). 
5.2.1 
Formulation and Packaging 
OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to 
pale-yellow liquid that may contain light (few) particles.  OPDIVO injection for 
intravenous infusion is supplied in single-dose vials.  Each mL of OPDIVO solution 
contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 
80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water 
for Injection, USP.  The formulation may contain hydrochloric acid and/or sodium 
hydroxide to adjust pH to 6. 
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 intravenous 
container. 
 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 


 
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1 mg/mL to 10 mg/mL.  For patients with weight less than 40 kg, the total volume of 
infusion must not exceed 4 mL/kg. 
 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 4 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 every 2 weeks (Q2W) or 480 mg every 4 
weeks (Q4W) administered as an intravenous infusion over approximately 30 minutes, 
until disease progression or unacceptable toxicity.  Administer the OPDIVO infusion 
through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-
line filter (pore size of 0.2 micrometer to 1.2 micrometer).  Flush the intravenous line at 
end of infusion. 
5.2.4 
Infusion Modification and Discontinuation 
There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 
Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.  
Discontinue OPDIVO in patients with severe or life-threatening infusion reactions.   
Dose modifications recommended in OPDIVO US Prescribing Information dated April 
2018 are reprinted in Table 16.  Required dose modifications (i.e., interruption 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 5.1.2.3.  
 
 


 
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Table 16: 
Recommended Dose Modifications for OPDIVO – Reprinted 
from OPDIVO US Prescribing Information 
Adverse 
Reaction 
Severity * 
Dose Modification 
Colitis 
Grade 2 diarrhea or colitis 
Withhold dose a 
Grade 3 diarrhea or colitis 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold dose a 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis 
Aspartate aminotransferase (AST)/or alanine 
aminotransferase (ALT) more than 3 and up to 5 
times the upper limit of normal or total bilirubin 
more than 1.5 and up to 3 times the upper limit of 
normal 
Withhold dose b 
AST or ALT more than 5 times the upper limit of 
normal or total bilirubin more than 3 times the 
upper limit of normal 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold dose a 
Grade 4 hypophysitis  
Permanently discontinue 
Adrenal 
Insufficiency 
Grade 2 adrenal insufficiency 
Withhold dose a 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 Diabetes 
Mellitus 
Grade 3 hyperglycemia 
Withhold dose a 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and 
Renal 
Dysfunction 
Serum creatinine more than 1.5 and up to 6 times 
the upper limit of normal 
Withhold dose a 
Serum creatinine more than 6 times the upper limit 
of normal 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal necrolysis 
(TEN) 
Withhold dose a 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New-onset moderate or severe neurologic signs or 
symptoms 
Withhold dose a 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction  
First occurrence  
Recurrence of same Grade 3 adverse reactions 
 
Withhold dose a 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions lasting 12 
weeks or longer 
Permanently discontinue 


 
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* 
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events. Version 4.0 (NCI CTCAE v4).   
a 
Resume treatment when adverse reaction returns to Grade 0 or 1. 
b 
Resume treatment when AST/ALT returns to baseline. 
5.2.5 
Nivolumab Adverse Event Management Guidelines 
Table 17 reproduces AE management guidelines provided in OPDIVO US Prescribing 
Information, Section 5.   
Table 17: 
Management of Nivolumab Immune-Related Adverse Events – 
Reprinted from OPDIVO US Prescribing Information 
Immune-mediated AE Defined as Requiring Use of Corticosteroids and no Clear Alternate 
Etiology 
Immune-mediated 
pneumonitis 
Monitor patients for signs with radiographic imaging and symptoms of 
pneumonitis.  Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone 
equivalents for moderate (Grade 2) or more severe pneumonitis, followed by 
corticosteroid taper.   
Permanently discontinue nivolumab for severe (Grade 3) or life-threatening 
(Grade 4) pneumonitis and withhold nivolumab until resolution for moderate 
(Grade 2) pneumonitis. 
Immune-mediated 
colitis 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) 
colitis.  Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of 
more than 5 days duration; if worsening or no improvement occurs despite 
initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone 
equivalents. 
Withhold OPDIVO for moderate or severe (Grade 2 or 3) colitis.  Permanently 
discontinue OPDIVO for life-threatening (Grade 4) or for recurrent colitis upon 
restarting OPDIVO. 
Immune-mediated 
hepatitis 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or 
without concomitant elevation in total bilirubin.  Administer corticosteroids at a 
dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) 
transaminase elevations. 
Withhold OPDIVO for moderate (Grade 2) and permanently discontinue 
OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated 
hepatitis. 
Immune-mediated endocrinopathies 
Hypophysitis 
Administer hormone replacement as clinically indicated and corticosteroids at a 
dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for 
moderate (Grade 2) or greater hypophysitis.  Withhold OPDIVO for moderate 
(Grade 2) or severe (Grade 3). Permanently discontinue OPDIVO for life-
threatening (Grade 4) hypophysitis. 
 
 


 
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Table 17: 
Management of Nivolumab Immune-Related Adverse Events – 
Reprinted from OPDIVO US Prescribing Information 
(Continued) 
Immune-mediated endocrinopathies (continued) 
Adrenal 
Insufficiency 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 
4) adrenal insufficiency.  Withhold OPDIVO for moderate (Grade 2) and 
permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 
4) adrenal insufficiency. 
Hypothyroidism 
and 
Hyperthyroidism 
Administer hormone-replacement therapy for hypothyroidism.  Initiate medical 
management for control of hyperthyroidism.  There are no recommended dose 
adjustments of OPDIVO for hypothyroidism or hyperthyroidism. 
Type 1 Diabetes 
Mellitus 
Withhold OPDIVO in cases of severe (Grade 3) hyperglycemia until metabolic 
control is achieved.  Permanently discontinue OPDIVO for life-threatening 
(Grade 4) hyperglycemia. 
Other Immune-mediated AEs 
Immune-Mediated 
Nephritis and 
Renal Dysfunction 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
followed by corticosteroid taper for life-threatening (Grade 4) increased serum 
creatinine.  Administer corticosteroids at a dose of 0.5 to 1 mg/lg/day prednisone 
equivalents for moderate (Grade 2) or severe (Grade 3) increased serum 
creatinine, if worsening or no improvement occurs, increase dose of 
corticosteroids to 1 to 2 mg/kg/day prednisone equivalents. 
Immune-Mediated 
Skin Adverse 
Reactions 
For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for 
specialized care for assessment and treatment. If SJS or TEN is confirmed, 
permanently discontinue OPDIVO. 
For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe 
(Grade 3) or life-threatening (Grade 4) rash.  Withhold OPDIVO for severe 
(Grade 3) rash and permanently discontinue OPDIVO for life-threatening (Grade 
4) rash. 
Immune-Mediated 
Encephalitis 
Withhold OPDIVO in patients with new-onset moderate to severe neurologic 
signs or symptoms and evaluate to rule out infectious or other causes of moderate 
to severe neurologic deterioration.  If other etiologies are ruled out, administer 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients 
with immune-mediated encephalitis, followed by corticosteroid taper.  
Permanently discontinue OPDIVO for immune-mediated encephalitis. 
Other Immune 
Mediated Adverse 
Reactions 
For any suspected immune-mediated adverse reactions, exclude other causes.  
Based on the severity of the adverse reaction, permanently discontinue or 
withhold OPDIVO, administer high-dose corticosteroids, and if appropriate, 
initiate hormone-replacement therapy.  Upon improvement to Grade 1 or less, 
initiate corticosteroid taper and continue to taper over at least 1 month.  Consider 
restarting OPDIVO after completion of corticosteroid taper based on the severity 
of the event. 
Infusion Reactions 
Discontinue OPDIVO in patients with severe or life-threatening infusion 
reactions.  Interrupt or slow the rate of infusion in patients with mild or moderate 
infusion reactions. 
 


 
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5.3 
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 Serious Adverse Event (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 glesatinib, 
sitravatinib, mocetinostat or nivolumab.  The Investigator will use clinical judgment to 
treat any overdose. 
5.4 
Concomitant Therapies 
5.4.1 
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 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. 
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.   
 Glesatinib specific – Patients treated with glesatinib may received prophylactic anti-
diarrheal treatment at the discretion of the Investigator.  A regimen recommended for 
primary prophylaxis for diarrhea is loperamide 2-4 mg beginning with the first dose 
of glesatinib, followed by 2 mg every 6–8 hours.  Loperamide use may be 
subsequently titrated as needed.   
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:  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 
investigational study treatment. 


 
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Medications with QTc Prolonging Activity (Sitravatinib and Mocetinostat only):  
The risk of QTc prolongation in patients receiving the investigational study treatments 
has not been characterized.  Use of medications known to prolong QTc and pose risk of 
Torsades de Pointes (examples listed in Appendix 3) is to be avoided.   
P-450 Considerations, Mocetinostat Specific: 
 Warfarin or Coumarin Derivatives – Therapeutic doses of warfarin or other 
coumarin derivative anticoagulants are not permitted in patients treated with 
mocetinostat.  Warfarin has a narrow therapeutic range and mocetinostat can have 
inhibitory effects on CYP2C9, the main metabolizing enzyme of warfarin.  Patients 
may adopt a different anticoagulant. 
 Contraceptives – Hormonal contraceptives may be affected by cytochrome P-450 
interactions, and are therefore not considered effective for this study, since induction 
of CYP3A4 may not be excluded in patients receiving mocetinostat. 
 Cautioned Medications – Caution should be used when mocetinostat is administered 
to patients taking medications metabolized by CYP2C9, or that inhibit or induce 
metabolism by CYP2E1 or CYA3A4.  See Appendix 3 for examples of medications 
of interest.  If a patient is taking a drug on one these lists, it is encouraged to 
substitute a different medication if possible. 
Herbal Medications/Preparations:  Herbal medications and preparations should be 
avoided throughout the study.  Herbal medications include, but are not limited to: St. 
John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe (yohimbine), saw palmetto, and ginseng.   
Transfusions: Patients may receive transfusions as necessary. 
Antibiotics:  Antibiotics should be used as needed.  Patients with neutropenic fever or 
infection should be treated promptly.   
Supportive Care/Palliative Care:  Supportive and palliative care for disease related 
symptoms may be administered at the Investigator’s discretion, including the use of 
analgesics.   
Growth Factors:  Therapeutic colony-stimulating factors should be used in accordance 
with ASCO guidelines.   
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 immune-mediated AEs and the extent required to manage comorbidities and 
symptoms of disease.   


 
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Vaccines:  Live attenuated vaccines within 100 days of nivolumab dosing are to be 
avoided.  Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
5.4.2 
Concomitant Surgery or Radiation Therapy 
The use of surgery to manage cancer lesions during study treatment is discouraged.  The 
impact of the investigation study treatments on wound healing has not yet been 
characterized.  For patients with bone involvement, any foreseeable need for palliative 
radiotherapy should be addressed before study entry, if possible and clinically appropriate 
(e.g., bone lesions at risk for spontaneous micro-fractures or painful lesions).  However, 
these treatments may be used in cases where it is medically necessary.  
In the event that major surgery is needed during study treatment, the patient should, if 
possible, interrupt dosing with the assigned investigational study treatment for the 
duration specified in Table 18. 
Table 18: 
Treatment Interruption for Major Surgery 
Drug 
Discontinue in 
Advance 
Resume Following 
Glesatinib Tablets 
1 week 
1 week 
Sitravatinib Capsules  
2 weeks 
2 weeks 
Mocetinostat Capsules 
1 week 
1 week 
 
5.4.3 
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. 
*Certain ongoing hormonal therapies taken to prevent recurrence of a malignancy not 
under study (e.g., tamoxifen/aromatase inhibitor for breast cancer) may be permitted after 
discussion with and agreement of the Sponsor’s Medical Monitor. 
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. 


 
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6.2 
Study Period 
For details on procedures during the study period, see Schedule of Assessments as shown 
in Table 1. 
6.3 
End of Treatment Assessment 
All patients will be followed for AEs for at least 28 days after the last dose of Study 
Treatment.  See the Schedule of Assessments (Table 1) for evaluations to be performed at 
the End of Treatment visit. 
6.4 
Long-Term Follow-up and End of Study Assessment 
Survival status and subsequent therapies will be collected during long term follow-up as 
outlined in the Schedule of Assessments (Table 1) until death or lost to follow-up.  
Beyond 28 days after last treatment, follow-up may be performed by telephone contact.  
Treatments received following participation in the study will be collected in the CRF. 
6.5 
Patient Discontinuation/Withdrawal 
Patients may discontinue from study treatment or from study follow-up 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 according to RECIST 1.1 as determined by the 
Investigator (patients who may derive clinical benefit may continue on treatment at 
the discretion of the Investigator); 
 Global deterioration of health status requiring discontinuation; 
 Adverse event; 
 Significant protocol violation; 
 Lost to follow-up; 
 Refusal for further treatment; 
 Study termination by Sponsor; 
 Death. 


 
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Reasons for discontinuation from study follow-up may include: 
 Study terminated by Sponsor; 
 Lost to follow-up; 
 Refusal for further follow-up for survival; 
 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 adverse events. 
If the patient withdraws from the study treatment and also withdraws consent for 
disclosure of future information, 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 such refusal for further follow-up. 
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 
outside of the control of the Investigator that may make it infeasible 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).  Screening/baseline tumor assessments should 
include CT or MRI of the chest, abdomen, and pelvis, whole body bone scan, MRI of the 
brain and evaluation of any superficial lesions.  On-study assessments will include all 
known and suspected sites of disease and will be performed at 8-week intervals until 
approximately 1-year and then every 16 weeks; bone scans may be performed half as 
often as other radiology evaluations (i.e., every 16 weeks).  The allowable windows for 
assessments are 4 weeks prior to first study treatment for screening/baseline assessments 
and 10 days for on-study disease assessments.  All known and suspected sites of disease 


 
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should be evaluated at each assessment.  Assessments will be performed until objective 
disease progression is documented or subsequent anti-cancer therapy is begun.   
CT scans should be performed with contrast agents unless contraindicated for medical 
reasons.  If intravenous 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.  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 and pelvis 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.   
For patients having effusions or ascites, cytological proof of malignancy should be 
obtained prior to selection of the effusion as a non-target lesion.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be 
considered to be cancer lesions. 
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer-2009).  
Appendix 4 provides guidance in using the response criteria and includes modifications 
to RECIST 1.1 to address potential temporary treatment effects such as tumor lesion 
cavitation or flare response.  Assessments will be performed until objective disease 
progression is documented by the Investigator, or subsequent anti-cancer therapy is 
begun.   
Patients experiencing tumor response (Partial Response [PR] or Complete Response 
[CR]) should undergo confirmatory assessment at least 4 weeks after initial 
documentation of response.  It is acceptable to perform confirmatory assessments at the 
next appointed evaluation per protocol.  Bone scan is required as an element of the 
confirmation of PR or CR if bone lesions were identified at the baseline assessment. 
The Investigator’s assessment of disease response and progression will be the basis for 
patient management and study expansion decision making.  Potential exists for individual 
tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time as 
the result of beneficial study treatment impact.  For example, tumor necrosis and 
cavitation may result in minor increase in overall individual lesion size or unclear tumor 
margins prior to recovery to a smaller lesion, development of scar tissue, or complete 
resolution.  For this reason, Investigators may delay reaching the conclusion of disease 
progression until subsequent on-study disease assessments are performed.   
Central radiology review to assess RECIST outcome may be undertaken after Stage 1 of 
the study.  Materials to be forwarded for independent review will be all imaging studies 
performed at screening and on study, preferably in digital format, using an electronic 


 
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transfer through a portal to the review vendor or transfer on compact disc or optical disc.  
All digital media must be in DICOM format.  Films may be forwarded for review if 
necessary; all films should be originals (second original films acceptable) rather than 
copies of films.   
7.2 
Safety Assessments 
7.2.1 
Adverse Events 
Assessment of adverse events will include type, incidence, severity (graded by the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE, Version 4.03]), timing, seriousness, and relatedness to study treatment. 
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 Day 1 of study treatment and 
onward throughout the study.  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. 
7.2.2 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and 
End of Treatment 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 were 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, thyroid tests, urinalysis and chemistry parameters presented in 
Table 19. 
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 adverse events, or as 
clinically indicated.   
 
 


 
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Table 19: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
Alkaline phosphatase 
Neutrophil count 
Total bilirubin (if Total bilirubin is ≥2×ULN and 
no evidence of Gilbert’s syndrome, then 
fractionate into direct and indirect 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 
Glucose (non-fasted) 
 
Albumin 
Thyroid Function Test 
Total Calcium 
Thyroid-stimulating hormone (TSH) 
Magnesium 
Free-T4 
Uric acid 
 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test 
will be performed by the local laboratory 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).  It is preferable that the machine used has a capacity to calculate 
the standard intervals automatically.  Assessments reported by automated read as 
prolongation of QTc should be over-read by a cardiologist to ensure accuracy of 
interpretation.   
7.2.5 
Echocardiogram (ECHO) 
Echocardiograms will be performed in the sitravatinib and mocetinostat treatment arms at 
screening, and thereafter as in the Schedule of Assessments (Table 1).  Additional 


 
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assessments of LVEF and evaluation of pericardial effusions may be performed as 
clinically indicated at the Investigator’s discretion if there are signs or symptoms of 
cardiotoxicity.  Where abnormalities indicating pericardial effusion exist, weekly 
assessments should be performed until normalization as described in Section 5.1.3.4.1.  
In exceptional circumstances where ECHO is not considered a technically optimal 
assessment of pericardial space (e.g., overweight patient), other methods (e.g., MRI) 
should be used for pericardial assessments.   
7.3 
Laboratory Studies 
Full details on sample collection, processing, storage and shipment are presented in the 
Study Laboratory Manual. 
7.3.1 
Pharmacokinetic Evaluation 
The PK of the investigational study treatments 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, Table 
3, and Table 4.  The actual time of each sample collection will be recorded on the source 
document and CRF.   
All plasma or serum 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 Tumor Tissue 
 
 
 
 
 
7.3.3 
Pharmacodynamic Evaluation in Blood 
 
 
 
 
 
.  


 
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7.3.4 
Circulating Tumor DNA 
 
 
   
 
 
   
 
   
7.3.5 
Sample Collection for PD-L1 Expression and Tumor Gene 
Alterations 
Tumor tissue testing for PD-L1 expression is required for patients enrolling in the CIT-
naïve patient cohort through the central laboratory.  The sample tested must have been 
collected following completion of the most recent systemic treatment regimen.   
For CIT-experienced patients, tumor tissue collection for testing for PD-L1 expression 
and/or evaluation of tumor gene alterations is an optional but highly desirable 
assessment.  Archival samples are acceptable if more recent tumor specimens are not 
available.   
Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy.  Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e., > 100 tumor cells) to 
allow for adequate PD-L1 immunohistochemistry analyses.   
Samples should be formalin fixed and embedded in paraffin.  Samples from fine needle 
aspirates (FNA) or decalcified bone are not appropriate for these evaluations. 
Further guidance on sample preparation and submission can be found in the Study 
Laboratory Manual. 
7.4 
Post-treatment Follow-up 
Survival status and subsequent therapies will be collected during long term follow-up as 
outlined in the Schedule of Assessments (Table 1) until death or lost to follow-up.  
Beyond 28 days after last treatment, follow-up may be performed by telephone contact.  
Treatments received following participation in the study will be collected in the CRF. 
 


 
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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 Study Manual. 
8.2 
Adverse Events 
An adverse event (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.  A treatment emergent AE (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 AE when available; 
follow all recorded AEs to resolution.  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). 
 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. 


 
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8.2.1 
Laboratory Abnormalities 
An abnormal laboratory test result 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. 
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 are 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.  Study drug should be permanently 
discontinued for a Hy’s Law case.   
8.2.2 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03).  
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 


 
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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 Events 
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: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o 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. 


 
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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 
preexisting 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 adverse event 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. 
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.   


 
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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 SAEs and AEs 
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 28 days post last administration of either therapy.  All SAEs will be 
followed until the event has resolved or stabilized to a chronic condition, whichever is 
later.  Death must be reported if it occurs during the active reporting period for SAEs 
regardless of whether a subsequent anticancer therapy is administered.  Serious adverse 
events 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 study drug.   
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 treatment 
and/or until recovery from all acute toxicities associated with the drug administration to a 
chronic condition, whichever is later.  If a patient begins a subsequent 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 Study Manual.  The 
24-hour timeframe also applies to additional new information (follow-up) on previously 


 
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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.   
All AEs (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.   
 
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. 
9.1 
Hypothesis and Sample Size 
9.1.1 
Lead-In Dose Escalation Evaluation 
Approximately 24 patients may be enrolled into the lead-in dose escalation portion of the 
study.  A precise sample size cannot be defined, as it is dependent on the number of dose 
escalations based on the mTPI method, and the number of patients enrolled in the 
expansion cohorts.   
The mTPI method (Ji-2013) will be employed in decision making concerning dose 
escalation within each regimen investigated.  The assumptions to be applied in 
establishing the mTPI methodology are: 
 each specific regimen exploration will include up to 30 patients; 
 the MTD is defined to have 0.25 probability of toxicity; and 
 the acceptable variance around the MTD is ± 0.05 (i.e., the region of the MTD is 
20% to 30% incidence of dose limiting toxicity).   


 
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9.1.2 
Phase 2 
This Phase 2 study will use a Predictive Probability Design (Lee-2008) in each treatment 
arm and strata.  In creating the statistical designs, the Type 1 error (α) is constrained to 
<0.05 and Power (1-β) is constrained to ≥0.90.   
Statistical Design Applied to CIT-Experienced and CIT-Naïve with No/Low PD-L1 
Expression 
The ORR using nivolumab in the population with advanced non-squamous NSCLC 
having prior disease progression on a checkpoint inhibitor or patients with non-squamous 
NSCLC without prior checkpoint inhibitor therapy with no/low PD-L1 expression is 
assumed to be 5% (p0); thus this rate is considered uninteresting.  The target ORR using 
the investigational agents in combination with nivolumab in this study is 30% (p1).  Stage 
1 of enrollment will include a minimum of 9 evaluable patients in each treatment strata. 
With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective 
Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a 
total sample size of 17 evaluable patients.  If at least 3 Objective Responses are observed 
in a treatment stratum, further investigation may be warranted.  If the true ORR is 5% 
(null hypothesis), the probability of early termination during the study is 0.63; the Type 1 
error is equal to 0.0466 and the power is equal to 0.9045.   
Statistical Design Applied to CIT-Naïve with High PD-L1 Expression 
The ORR using nivolumab in the population with non-squamous NSCLC having high 
PD-L1 expression is assumed to be 27% (p0); thus this rate is considered uninteresting.  
The target ORR using the investigational agents in combination with nivolumab is 50% 
(p1).   
Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 
17 evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 
27 additional evaluable patients will be enrolled, for a total sample size of 44 evaluable 
patients.  If at least 18 Objective Responses are observed, further investigation may be 
warranted.  If the true ORR is 27% (null hypothesis), the probability of early termination 
during the study is 0.50; the Type 1 error is equal to 0.0303 and the power is equal to 
0.9018.  The exact stopping rules for all cohorts will be calculated based on the 
Predictive Probability Design, once the exact number of patients evaluable at Stage 1 is 
known. The aim is to get a minimum of 9 evaluable patients at Stage 1 for CIT-
experienced and CIT-naïve with lo/no PD-L1 expression cohorts and a minimum of 
17 evaluable patients at Stage 1 for CIT-naïve with high PD-L1 expression cohort. 


 
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Expansion Beyond Stage 2 
For the sitravatinib segment of the study enrolling patients with CIT-experience, 
expansion of enrollment beyond Stage 2 will be managed as one cohort that includes all 
patients, regardless of prior clinical benefit during treatment with CIT.  Based on 
preliminary clinical activity results as of June 2018 (described in Section 1.5.3.2.2), 
enrollment into the combined cohort will expand to approximately 125 patients total.  
The purpose for enrollment expansion is to further evaluate safety and efficacy in this 
setting. 
Expansion of sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not 
anticipated. 
Table 20 presents estimates of the 95% CI around the observed ORR for several potential 
outcomes using the sample size of 125 patients, and the Clopper-Pearson method. 
Table 20: 
Estimates of 95% CI Using Clopper-Pearson After Enrollment 
of 125 Patients 
Number of  
Observed Responses  
Among 125 Patients 
ORR 
95% CI 
19 
15% 
9.4-22.7 
25 
20% 
13.4-28.1 
31 
25% 
17.5-33.3 
38 
30% 
22.5-39.3 
44 
35% 
26.9-44.3 
50 
40% 
31.3-49.1 
63 
50% 
41.3-59.5 
 
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. 


 
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9.3 
Analysis Populations 
9.3.1 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (mITT) population is defined as all patients who receive 
treatment with both an investigational study treatment and nivolumab on this study. 
The primary efficacy analyses of the primary and secondary efficacy endpoints will be 
performed in the mITT population.  In addition, the mITT population will be used in 
making decisions to expand the study to the next stage of enrollment. 
9.3.2 
Clinical Activity Evaluable Population 
In order to be considered eligible for the clinical activity evaluable population, the patient 
must have at least one on-study disease assessment or discontinue from treatment for 
progressive disease.  Patients who discontinue treatment prior to the first on-study disease 
assessment for an AE, toxicity, or withdraw consent are considered non-evaluable for 
disease assessment and will not be part of the clinical activity evaluable population. 
This population will be used to present tumor responses as well as to make decision on 
the Predictive Probability design. 
9.3.3 
Safety Population 
The Safety population is defined as all patients who received at least 1 dose of either 
investigational study treatment or nivolumab.  The Safety population will be used for all 
safety analyses. 
9.3.4 
Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at 
least one dose of either investigational study treatment or nivolumab for whom PD-L1 
expression or circulating PD-L1 results are available. 
9.3.5 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic evaluable population will consist of all patients who received 
treatment with an investigational study drug and had sufficient concentration-time data to 
permit calculation of PK parameters for the investigational agent.  For patients who were 
noncompliant with respect to administration of investigational agent, or for patients with 
incomplete data, a decision as to their inclusion in the analysis will be made on a 
case-by-case basis. 
9.3.6 
Pharmacodynamic Evaluable Population 
The Pharmacodynamic evaluable population will consist of all patients who receive at 
least one dose of investigational agent or nivolumab for whom PD results are available. 


 
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9.4 
Efficacy Endpoint Definitions and Analyses 
9.4.1 
Objective Response Rate 
Objective disease response will be categorized in accordance with RECIST v1.1 
(Appendix 4).  Objective Response Rate (ORR) is defined as the percent of patients 
documented to have a confirmed Complete Response (CR) or Partial Response (PR).  If 
central review of disease response is undertaken, ORR as reported by the central 
radiology review laboratory will be used to calculate ORR and the exact 95% confidence 
intervals (CI).  ORR as reported by the Investigator will be used in study expansion 
decision making (PPD design) and supportive analyses. 
Descriptive statistics (frequency and percentage) for ORR, CR, and PR 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: ORR ≤ 5% against H1: ORR 
> 5%.  Other details will be described in the SAP. 
9.4.2 
Clinical Benefit Rate 
Clinical Benefit Rate (CBR) is defined as the percent of patients documented to have a 
confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) 
documented during at least 2 on-study assessments and including at least 14 weeks on 
study (e.g., allowance for 2-week window around Week 17 assessment).   
9.4.3 
Duration of Response 
Duration of Response (DR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of Objective Progression 
of Disease (PD) or to death due to any cause in the absence of documented PD.  
Censoring for the DR endpoint will be assigned on the date of the last tumor assessment 
if no assessment of tumor progression is identified and the patient does not die while on 
study.  DR will only be calculated for the subgroup of patients with an objective 
response.  The Kaplan-Meier method will be used to obtain the estimate of median DR.   
9.4.4 
Progression Free Survival 
Progression-free survival (PFS) is defined as the time from date of first study treatment to 
first PD or death due to any cause in the absence of documented PD.  Censoring for the 
PFS endpoint will be assigned on the date of the last tumor assessment if no assessment 
of tumor progression is identified and the patient does not die while on study.  For 
patients in whom two or more sequential assessments are missed, followed by the finding 
of tumor progression, the PFS endpoint will be censored on the date of the last tumor 
assessment before the gap.  Patients lacking an evaluation of disease after first study 
treatment will have their PFS time censored on the date of first dose with duration of 
1 day.  Patients who start a new anti-cancer therapy prior to documented PD will have the 
endpoint censored at the date of the last tumor assessment prior to the start of the new 


 
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therapy.  The Kaplan-Meier method will be used to obtain the estimate of median 
progression-free survival time.   
9.4.5 
Overall Survival 
Time to death is defined as the time from date of first study treatment to death due to any 
cause.  Censoring for the survival endpoint will be assigned on the date of the last 
on-study follow-up that the patient is reported to be alive.  The Kaplan-Meier method 
will be used to estimate the median OS and 1-year Survival Rate; the 95% confidence 
interval of the 1-year survival rate will also be reported.   
9.5 
Safety Data Presentations and Summaries 
9.5.1 
Adverse Events 
Adverse events 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).   
9.5.2 
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.   
9.5.3 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, 
coagulation, urinalysis, thyroid function tests and chemistry), vital signs, ECHO 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 v.4.03 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 Fridericia’s formula applied 
programmatically to the ECG data collected in CRFs.   


 
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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 
by treatment group. 
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 
 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 cycles 
administered, the median (range) of cycles administered for each agent separately and for 
the combination, dose intensity, and reasons for the deviations from planned therapy. 
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 for each investigational agent.  Pharmacokinetic 
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 dose level, Day and Cycle.  The 
exposure levels as well as the PK parameters of the investigational drugs reported in 
earlier studies will be compared to the current study PK exposure and parameters to 
evaluate the potential effect of nivolumab on investigation drugs’ PK.  Details of this 
analysis will be provided in the PKAP.  Possible relationships between PK parameters, 
PD variables, safety, and clinical activity may be examined. 


 
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9.6.2 
Pharmacodynamic and Exploratory Analyses 
 
 
 
   
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. 
 
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), ICH E6 (R2) 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; 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). 


 
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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. 
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 full access to 
the study and source documents. 
10.3 Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC) 
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 
for written approval.  The Investigator will provide the Sponsor with a copy of the 
IRB/EC’s written approval, as well as the membership list or a compliance statement 
from the IRB/EC.  The Investigator is responsible for notifying the IRB/EC of any 
Sponsor-approved amendments to the protocol or ICF, SAEs occurring in patients treated 
at the study site in accordance with local IRB/EC 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 patient 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 


 
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and otherwise except in accordance with applicable law or regulations.  However, 
authorized regulatory officials, IRB/EC 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. 
 
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. 
 


 
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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 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 
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 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 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. 


 
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If in the judgment of the IRB/EC, 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 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.   
 
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 
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, drug safety concerns, or at the 
discretion of the Sponsor.  In addition, the Sponsor retains the right to discontinue 
development of glesatinib, sitravatinib or mocetinostat 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 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. 


 
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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. DOSE-FINDING SPREADSHEET OF THE MODIFIED TOXICITY PROBABILITY INTERVAL (MTPI) 
METHOD 
 
Number of Patients Treated at Current Dose 
Number of Dose Limiting Toxicities 
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 
26 
27 
28 
29 
30 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
U 
D 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
4 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
5 
U 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
6 
U 
U 
U 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
7 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
8 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
9 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U  
U  
U  
S 
S 
S 
S 
S 
S 
S 
S 
10 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
11 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
12 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
13 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
14 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
15 
E = Escalate to the next higher dose 
S = Stay at the current dose 
D = De-escalate to the next lower dose 
U = The current dose is unacceptably toxic 
MTD = 0.25 
Sample Size = 30 
ɛ1 = 0.05 
ɛ2 = 0.05 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
16 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
17 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
18 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
19 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
20 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
21 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
22 
U 
U 
U 
U 
U 
U 
U 
U 
U 
23 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
U 
U 
24 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
U 
25 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
26 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
27 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
28 
 
 
 
 
 
 
 
 
U 
U 
U 
29 
U 
U 
30 
U 


 
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Appendix 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING STUDY TREATMENT 
Bold font indicates medications or substances 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 mocetinostat and 
sitravatinib for management of a concurrent illness. 
DRUGS THAT MAY PROLONG QT INTERVAL 
Drugs To 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, cisapride (off US market), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone 
(not on US market), dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, halofantrine, haloperidol, ibutilide, 
levomethadyl (off US market), mesoridazine (off US market), 
methadone, moxifloxacin, ondansetron, pentamidine, pimozide, 
probucol (off US market), procainamide, quinidine, sevoflurane, 
sotalol, sparfloxacin (off US market), sulpiride (not on US 
market), terfenadine (off US market), thioridazine, vandetanib. 
 
Drugs To Be Used with Caution  
Drugs with a 
Conditional Risk 
of Torsades de 
Pointes 
Amantadine, amisulpride, amitriptyline, amoxapine, chloral 
hydrate, ciprofloxacin, clomipramine, desipramine, 
diphenhydramine, doxepin, fluconazole, fluoxetine, 
furosemide, galantamine, hydrochlorothiazide, imipramine 
(melipramine), indapamide, itraconazole, ivabradine, 
ketoconazole, metronidazole, nelfinavir, nortriptyline, 
paroxetine, posaconazole, protriptyline, quinine sulfate, 
ritonavir, sertraline, solifenacin, telaprevir, trazodone, 
trimethoprim-sulfa, trimipramine, voriconazole. 
 
 
 


 
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CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS AND 
SUBSTANCES DURING TREATMENT WITH MOCETINOSTAT 
Enzyme 
Inhibitor of 
CYP 2E1 
Disulfiram   
Inducers of 
CYP 2E1 
Ethanol, isoniazid, tobacco 
Strong Inhibitors 
of CYP 3A4 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil (withdrawn from US market), nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole 
Strong Inducers 
of CYP 3A4 
Carbamazepine, phenytoin, rifampin 
Substrates of 
CYP 2C9 
Celecoxib, diclofenac, fluvastatin, glipizide, ibuprofen, 
irbesartan, losartan, naproxen, phenytoin, piroxicam, 
rosiglitazone, sulfamethoxazole, tamoxifen, tolbutamide, 
torsemide 
 
 


 
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Appendix 4. ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES  
A modification to RECIST 1.1 has been made to account for the possibility of temporary 
changes resulting from the potentially beneficial treatment responses of tumor necrosis, 
cavitation or flare response.   
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 patiented to other local treatment) are 
non-measurable unless it they have progressed since completion of treatment. 
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.   


 
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 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. 
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’). 
 
 


 
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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  
o one or more target lesions have not been assessed,  
o or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
o or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure), 
o or one or more target lesions were excised or irradiated and have not reappeared 
or increased.   
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.   


 
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 PD: Unequivocal progression of preexisting 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. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flare 
response to treatment or become otherwise difficult to evaluate for a period of time as the 
result of beneficial study treatment impact.  For example, tumor necrosis, cavitation or 
flare may result in increase in overall size of individual lesions or unclear tumor margins 
prior to recovery to smaller lesions, development of scar tissue, or complete resolution.  
The true tumor measurements of lesions should be recorded but the conclusion of 
progressive disease may be suspended until continued assessment clarifies the nature of 
the tumor change.  If repeat assessments indicate progression of disease, then PD should 
be recorded on the date of the first assessment giving the impression of progression.  If 
repeat assessments indicate that the change was a process of transition, then NE (not 
evaluable) should be recorded during the period of transition, and PR or CR may be 
recorded for subsequent evaluations.  The CRF will collect information on the 
observations during the period of transition to support the assessment conclusions.   
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. 
 
 


 
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Best Objective Response 
Target 
Lesions 
Non-Target 
Lesions 
New Lesion 
Point in Time 
Response 
Best Response 
CR 
CR 
No 
CR 
CR and PR require 
confirmation at least 
4 weeks after first 
observation 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
SD requires an on-study 
assessment after at least 
6weeks on treatment. 
Unconfirmed PR or CR are 
reported as SD. 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Patientive 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 treatment CRF as off treatment due to Global Deterioration of 
Health Status.   
 
 


 
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Appendix 5. SITRAVATINIB SUB-STUDY TO EVALUATE THE 
PHARMACOKINETICS OF THREE FORMULATIONS  
This sub-study within Study MRTX-500 will be conducted at selected study sites.  It is an 
open-label evaluation of sitravatinib PK using three formulations of capsules. The 
sitravatinib formulations to be studied are free base hard gelatin capsules with 10% 
polysorbate 80 (Tween® 80), the formulation used in the main study and reference 
product, and as many as two new malate formulations: malate capsules, and free base 
softgel capsules.  Investigation of alternative formulations is for the purpose of 
optimizing product characteristics and manufacturing efficiency.  This investigation is 
being performed within the context of Study MRTX-500 to enable evaluation in one of 
the patient populations of interest for future sitravatinib clinical trials and in patients 
whose steady-state PK may be evaluated, and long-term sparse PK samples may be 
collected.  
In preparation for this sub-study, a non-clinical PK study was conducted in dogs after 
administration of single and multiple doses of the three sitravatinib capsule formulations.  
Groups of 6 dogs (3 male and 3 female) were included in each evaluation.  PK sampling 
was performed on Day 1 and at steady state on Day 7.  The PK parameters Cmax, AUC0-24, 
and AUC0-∞ (for Day 1 only) were estimated (Table 21).  The ratios of the geometric 
means were used to compare the free base Tween capsule (reference product) to the 
malate salt capsule and the free base softgel capsule.  Preliminary data indicate that the 
malate salt capsule to reference product ratios were 2.52, 2.19, and 2.15 for Cmax, AUC0-
24, and AUC0-∞, respectively, on Day 1 and, 1.85 and 1.65 for Cmax and AUC0-24, 
respectively, on Day 7.  The free base softgel capsule to reference product ratios were 
2.18, 2.29, and 2.26 for Cmax, AUC0-24, and AUC0-∞, respectively, on Day 1 and, 1.70 and 
1.81 for Cmax and AUC0-24, respectively, on Day 7.  Concentration time profiles for the 
formulations were comparable, with a median tmax of 4, 3 and 4 hrs and a mean half-life 
of 5.6, 4.9 and 5.1 hrs for the reference product, malate salt capsule and free base softgel 
capsule, respectively.  The new formulations showed lower variability as compared to the 
reference product, expressed as lower geometric mean CV% values for all the PK 
parameters. 
 
 


 
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Table 21: 
Pharmacokinetic Parameters in Dog Following Oral 
Administration of Three Sitravatinib Capsule Formulations 
 
Dose (mg) 
Cmax 
AUC0-24 
AUC0-inf 
Day 
(Formulation) 
(ng/mL) 
(ng·hr/mL) 
(ng·hr/mL) 
Day 1 
20 
Geo. Mean 
57.61 
451.22 
470.64 
Malate Salt Capsule 
Geo. CV% 
51.4 
45.5 
44.7 
N 
6 
6 
6 
 
 
 
 
 
20 
Geo. Mean 
49.91 
472.04 
495.13 
Free Base Softgel Capsule 
Geo. CV% 
21.3 
18.6 
21.0 
 
N 
6 
6 
6 
 
 
 
 
 
20 
Geo. Mean 
22.85 
205.82 
219.28 
Free Base 10% Tween Capsule 
Geo. CV% 
110.0 
118.7 
125.5 
N 
6 
6 
6 
 
 
 
 
 
Malate Salt to: 
 
 
 
 
Free Base 10% Tween 
Ratioa 
2.52 
2.19 
2.15 
 
 
 
 
 
Free Base Softgel to: 
 
 
 
 
Free Base 10% Tween 
Ratioa 
2.18 
2.29 
2.26 
 
 
 
 
 
Day 7 
20 
Geo. Mean 
73.85 
637.62 
 
Malate Salt Capsule 
Geo. CV% 
44.8 
41.2 
 
 
N 
6 
6 
 
 
 
 
 
 
20 
Geo. Mean 
67.98 
698.55 
 
Free Base Softgel Capsule 
Geo. CV% 
32.2 
32.3 
 
 
N 
6 
6 
 
 
 
 
 
 
20 
Geo. Mean 
39.92 
385.99 
 
Free Base 10% Tween Capsule 
Geo. CV% 
115.1 
130.2 
 
 
N 
6 
6 
 
 
 
 
 
 
Malate Salt to: 
 
 
 
 
Free Base 10% Tween 
Ratioa 
1.85 
1.65 
 
 
 
 
 
 
Free Base Softgel to: 
 
 
 
 
Free Base 10% Tween 
Ratioa 
1.70 
1.81 
 
 
 
 
 
 
a Ratio calculated based on Geo. Mean. 
The exposure levels observed in the dog study were higher for both of the new 
formulations as compared to the reference product.  For this reason, a dose escalation 
approach will be implemented in this sub-study for the new formulations.  The starting 
dose for each was determined by applying the Day 1 and Day 7 (steady state) exposure 
ratios to the starting dose using the reference product in the main study (120 mg QD).  If 


 
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the exposure ratios observed in dogs reflect exposure in patients, administration of 50-70 
mg of either new formulation would be expected to result in exposure comparable to the 
reference product (free base 10% Tween capsule) administered at 120 mg QD.  The 
starting dose for the malate direct blend formulation will be 60 mg QD.  This is 
considered conservative for two reasons, 1) the magnitude of exposure differences 
between oral formulations observed in dogs is most often attenuated when subsequently 
studied in humans, and 2) sitravatinib has been administered at 150 mg QD in a clinical 
trial (Study 516-001) and was tolerated.  As described below, each new formulation may 
also be evaluated at a higher dose level.   
As described in Section 1.8.1 of this protocol, sitravatinib administered in combination 
with nivolumab is unlikely to result in a clinically relevant drug-drug interaction 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 cytochrome P-
450 (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. 
This sub-study will include dedicated patient cohorts for the free base formulation, 
malate direct blend formulation and malate roller compaction formulation.  Data 
evaluable for PK are needed from as many as 10 patients in each cohort; as many as 12 
patients may be enrolled into each cohort to ensure sufficient PK data are evaluable.  
Patients eligible for this sub-study will meet applicable entry criteria in the main study.  
Specifically, patients will have locally advanced, unresectable or metastatic non-
squamous NSCLC and will have experienced progression of disease on or after at least 
one prior treatment in the advanced disease setting.   
Enrollment of the cohort of patients to receive the sitravatinib free base 10% Tween 
capsule formulation (reference product) may proceed upon approval of Protocol 
Amendment 4 (Version 5.0) by the IRB/EC.  Enrollment into cohorts evaluating the new 
formulations is expected to begin in the fourth-quarter 2018.  The sitravatinib malate salt 
capsule formulation is expected to be evaluated first, with evaluation of the free base 
softgel capsule undertaken if results using the malate salt are unfavorable.     
Reference sitravatinib exposure data using the sitravatinib free-base 10% Tween capsule 
formulation administered at 120 mg QD will be generated in one cohort of patients.  Due 
to the observation in the dog study of increased exposure using the two new sitravatinib 
capsule formulations, two dose levels are planned for each of these formulations.  The 
starting dose for both the malate salt capsule and free base softgel capsule formulation 
will be 60 mg QD, as described above.  The PK data generated using the starting dose in 
patients will be used to extrapolate the dose of each capsule formulation needed to 
achieve exposure comparable to the reference product administered at 120 mg QD.   


 
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The potential patient cohorts are listed below: 
1. Sitravatinib free base 10% Tween (free base) capsule formulation – 120 mg QD. 
2. Sitravatinib malate direct blend salt capsule formulation – 60 mg QD. 
3. Sitravatinib malate roller compaction capsule formulation – 100 mg QD. 
This starting dose of 100 mg sitravatinib malate roller compaction capsule is extrapolated 
based on the safety and PK results in Cohort 2. The 60 mg QD sitravatinib malate 
exposure was compared to the 120 mg sitravatinib free base exposure and the 100 mg QD 
of sitravatinib malate is projected to achieve exposure comparable to the 120 mg QD 
sitravatinib free base.  
The following patient cohorts will no longer be explored and hence patient enrollment 
within these cohorts will not open at this time. 
4. Sitravatinib free base softgel capsule formulation – 60 mg QD. 
5. Sitravatinib free base softgel capsule formulation – dose to be extrapolated based on 
results in Cohort 4 to achieve exposure comparable to Cohort 1.    
In the event that early results at a dose level are not within the exposure range expected, 
adaptations, including truncated enrollment into a cohort or addition of a limited number 
of cohorts may be undertaken after discussion between the Investigators participating in 
the sub-study and the Sponsor.  
Sitravatinib Administration and PK/ECG Timepoints 
The sub-study will begin with a 7-day lead-in period comprised of a single dose of the 
assigned sitravatinib formulation/dose followed by sample collection for PK analysis 
over a 168-hour period as defined in Table 22.  
At only the Lead-in Day 1 and C1D15 visits: following an overnight fast of at least 10 
hours, patients enrolled in this sub-study will receive the assigned sitravatinib capsule 
formulation administered with ~240 mL (a cup) of water. Patients will continue to fast 
for at least 4 hours before the next meal. Water is allowed as desired except for one hour 
before and one hour after sitravatinib administration.  
All other doses of sitravatinib (with the exception of Lead-in Day 1 and C1D15) should 
be taken, at the assigned daily dose, in the modified fasted state, specifically, at least a 2-
hour fast before each dose and no food for a minimum of 1 hour after each dose.  On days 
of PK sampling, patients should delay taking the daily sitravatinib dose until the pre-dose 
PK sample has been collected in the clinic.   






 
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Appendix 6. SITRAVATINIB SUB-STUDY TO EVALUATE 
PHARMACOKINETICS WHEN ADMINISTERED WITH FOOD 
This sub-study within Study MRTX-500 will be conducted at selected study sites.  It is an 
open-label evaluation of PK when sitravatinib capsules are administered orally in the fed 
state.  The potential to administer sitravatinib in the fed or fasted state is being 
investigated to provide flexibility and convenience for future patients enrolling in 
sitravatinib clinical trials.  Reference data in the fasted state will be generated in the sub-
study described in Appendix 5.  Depending on timing of availability of drug product for 
different sitravatinib capsule formulations and results from the formulation PK sub-study, 
evaluation of sitravatinib PK in the fed state may be undertaken with one or more capsule 
formulation(s).   
Sitravatinib administered in combination with nivolumab is unlikely to result in a 
clinically relevant drug-drug interaction 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 cytochrome P-450 (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. 
This sub-study will be conducted in as many as three dedicated patient cohorts.  Data 
evaluable for PK are needed from at least 6 patients in each cohort; as many as 8-10 
patients may be enrolled into each cohort to ensure 6 patients are evaluable for PK.  The 
sitravatinib dose to be administered using either of the new capsule formulations will be 
determined in the PK sub-study described in Appendix 5.   
Patients eligible for the sub-study will meet applicable entry criteria in the main study.  
Specifically, patients will have locally advanced, unresectable or metastatic non-
squamous NSCLC and will have experienced progression of disease on or after at least 
one prior treatment in the advanced disease setting.   
The definition of the fed state for the purpose of this sub-study is consumption of a high-
fat (approximately 50% of total caloric content of the meal), high-calorie (800-1000 
calories) meal at the time of sitravatinib dosing.  For the purposes of this sub-study, a 
high-fat meal consists of approximately 150, 250, 500-600 calories from protein, 
carbohydrates and fat respectively. An example meal consists of two eggs fried with 
butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown 
potatoes and eight ounces of whole milk. The nutritionist at the study site may 
recommend an alternative meal that follows the guidance for fat and calorie content.  
 
 


 
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Sitravatinib Administration and High-Fat Meal/PK/ECG Timepoints 
The sub-study will begin with a 7-day lead-in period comprised of a single dose of the 
assigned sitravatinib formulation followed by sample collection for PK analysis over a 
168-hour period (Table 24).  
At only Lead-in Day 1 and C1D15 visits: Patients will be seen in clinic at the end of an 
overnight fast of at least 10 hours. The pre-dose PK sample will be obtained and then the 
patient will consume a high-fat, high-calorie meal (as described above). Patients should 
start the recommended meal 30 minutes prior to sitravatinib dosing. Patients should eat 
this meal in 30 minutes or less. Sitravatinib is to be administered 30 minutes after the 
start of the meal with ~240 mL of water. If the meal is not finished in 30 minutes, 
patients should not complete the meal post sitravatinib administration. No food should be 
consumed for at least 4 hours after the dose. Water can be allowed as desired except for 1 
hour before and 1 hour after the drug administration.  
C1D1 to C1D14: Patients should consume their typical meal within 30 minutes prior to 
each dose of sitravatinib. Sitravatinib should be taken with ~240 mL of water. 
C1D16 and beyond: Sitravatinib should be taken in the modified fasted state, specifically, 
at least a 2-hour fast before each dose and no food for a minimum of 1 hour after each 
dose.  On days of PK sampling, patients should delay taking the daily sitravatinib dose 
until the pre-dose PK sample has been collected in the clinic. 
Patients enrolled in this sub-study will receive sitravatinib administered orally at the daily 
dose of 120 mg QD for the reference product and, for the new capsule formulations, at 
the dose recommended after conduct of the PK sub-study described in Appendix 5.  
Several changes to the assessment schedule outlined in the main study will apply to 
patients enrolled in this sub-study. 
1 Patients enrolled in this sub-study are exempt from sample collection for the 
purposes of flow cytometry and protein or cytokine biomarker studies. 
2 Triplicate ECGs will be performed on Day 1 of the lead-in period as described in 
Table 22 instead of later, on Cycle 1 Day 1, as described in Table 3. 
3 The PK sample collection schedule describe in Table 22 and Table 23 are to be 
followed up to Cycle 1 Day 15, after which the sparse sampling schedule described 
in Table 3 applies. 
PK blood samples will each collect 4 mL of blood.  PK samples collected during this sub-
study will be analyzed by the central laboratory in convenient batches.  See the Study 
Manual for instructions concerning sample transfer.    




 
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The PK evaluable population will consist of all patients who received treatment with 
sitravatinib and had sufficient concentration-time data to permit calculation of PK 
parameters for sitravatinib.  For patients who were noncompliant with respect to 
administration of sitravatinib or prescribed food regimen, or for patients with incomplete 
data, a decision as to their inclusion in the analysis will be made on a case-by-case basis. 
After completion of the food effect sub-study specific assessments and depending on the 
duration of treatment of individual patients and the long-term availability of various 
sitravatinib capsule formulations, patients may be transferred from the formulation 
assigned at the time of study entry to a different formulation to alleviate supply concerns.  
The need for any such transfers will be communicated to Investigators by the Sponsor in 
writing (to be retained with patient source documents).   
PK concentration and parameter data will be descriptively derived and displayed.  A 
descriptive comparison will be conducted using AUC0-t, AUC(0-∞), Cmax, Tmax, t1/2, and 
steady state PK exposure parameters.  The effect of food will be assessed based on the 
clinical relevance.  Steady state exposure comparison will also be assessed and accounted 
for.  Descriptive statistics will be used to summarize patient characteristics, treatment 
administration and safety variables between fed and fasted groups.  Details of this 
analysis will be provided in the PKAP. 

SAP_001.pdf: 
Protocol Number: MRTX-500 
Official Title: A Parallel Phase 2 Study of Glesatinib, 
Sitravatinib or Mocetinostat in Combination With Nivolumab 
in Advanced or Metastatic Non-Small Cell Lung Cancer 
NCT Number: NCT02954991 
Document Date: 10-January-2022 




Sponsor: Mirati Therapeutics, Inc
Statistical Analysis Plan
Protocol no: MRTX-500
Version Date: 10-Jan-2022
PRS 005 T 17 F
Page 2 of 44
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved.
Table of Contents
Approvals.................................................................................................................................................................................... 1
Purpose....................................................................................................................................................................................... 5
Scope .......................................................................................................................................................................................... 5
Introduction................................................................................................................................................................................ 5
4.1 Changes from Protocol
5
4.1.1 Glesatinib
5
4.1.2 Mocetinostat
5
4.1.3 Analysis Populations
6
4.1.4 Clinical Benefit Rate (CBR)
6
4.1.5 Sitravatinib Pharmacokinetic Sub-Studies
6
4.2 Study Treatment Definitions
6
4.2.1 Study Drug
6
4.2.2 Treatment Arm
7
Study Objectives and Endpoints ................................................................................................................................................. 7
5.1 Objectives
7
5.1.1 Primary Objective
7
5.1.2 Secondary Objectives
7
5.1.3 Exploratory Objectives
7
5.2 Endpoints
7
5.2.1 Primary Endpoint
7
5.2.2 Secondary Endpoints
7
5.2.3 Exploratory Endpoints
8
Study Design ............................................................................................................................................................................... 8
6.1 Lead-in Dose Escalation Evaluation
16
6.1.1 Definition of Dose Limiting Toxicity (DLT)
16
6.1.2 Enrollment and Dose Escalation Plan
17
6.1.3 Definition of Maximum Tolerated Dose (MTD)
17
6.1.4 Selection of Phase 2 Dose for Investigational Study Drugs
17
6.2 Phase 2 Study
18
6.2.1 Sample Size Considerations
19
6.3 Randomization
20
Analysis Populations ................................................................................................................................................................. 22
7.1 Enrolled Population
22
7.2 Full Analysis Set (FAS)
22
7.3 Clinical Activity Evaluable (CAE) Population
22
7.4 Safety Population
22
7.5 DLT Evaluable Population
22
7.6 PK Sub-Study Population
22
Endpoint Definitions ................................................................................................................................................................. 22
8.1 Baseline Characteristics
22
8.1.1 Baseline
22
8.1.2 Age
23
8.1.3 Time Since Diagnosis
23
8.2 Efficacy Variables
23
8.2.1 Objective Response Rate (ORR)
23
8.2.2 Duration of Response (DoR)
24


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8.2.3 Clinical Benefit Rate (CBR)
25
8.2.4 Progression-Free Survival (PFS)
25
8.2.5 Overall Survival (OS)
25
8.3 Study Drug Exposure Variables
25
8.3.1 Study Treatment Duration
25
8.3.2 Cumulative Dose Administered
25
8.3.3 Cycles Started
25
8.3.4 Dose Intensity
26
8.3.5 Compliance
26
8.3.6 Days on Study Drug
26
8.4 Safety Variables
26
8.4.1 Adverse Events
26
8.4.2 Immune-Related Adverse Event (irAE)
27
8.4.3 Adverse Events of Special Interest (AESI)
27
8.4.4 Physical Examinations
27
8.4.5 Vital Signs
27
8.4.6 Clinical Laboratory Assessments
27
8.4.7 Electrocardiograms
27
8.4.8 Echocardiograms
27
8.4.9 Prior and Concomitant Medications
28
8.5 Predetermined Covariates and Prognostic Factors
28
Data Handling ........................................................................................................................................................................... 28
9.1 Missing Dates
28
9.1.1 Imputation of Partial Adverse Event or Medication Dates
28
9.1.2 Imputation of Partial Subsequent Anti-Cancer Therapy Dates
29
9.2 Laboratory Values Beyond the Limits of Quantification
30
9.3 Important Protocol Deviations
30
Interim Analyses ..................................................................................................................................................................... 30
Planned Analysis ..................................................................................................................................................................... 30
11.1 Analysis for Main Study (non PK sub-studies)
31
11.1.1 Patient Disposition
31
11.1.2 Important Protocol Deviations
31
11.1.3 Demographic and Baseline Characteristics
31
11.1.4 Prior and Concomitant Medications and Procedures
31
11.1.5 Medical History
32
11.1.6 Efficacy Analyses
32
11.1.6.1 Primary Variable
32
11.1.6.2 Secondary Variables
32
11.1.7 Safety Analyses
33
11.1.7.1 Extent of Study Drug Exposure
34
11.1.7.2 Treatment Emergent Adverse Events (TEAEs)
34
11.1.7.3 Serious Adverse Events (SAEs) and Deaths
35
11.1.7.4 Laboratory Data
36
11.1.7.5 Vital Signs
39
11.1.7.6 Physical Examinations, ECGs, and Other Observations Related to Safety
40


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11.2 Analysis for PK Sub-Studies
41
Validation................................................................................................................................................................................ 41
References .............................................................................................................................................................................. 42
Appendix: Glossary of Abbreviations.............................................................................................................................................. 43


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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 MRTX-500.
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 SAP will be described in the Clinical Study Report (CSR).
Introduction
This SAP describes the statistical methods to be used during the analysis and reporting of data collected under 
Mirati Therapeutics, Inc. Protocol MRTX-500.
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 v6.0 dated 11-Feb-2020 and CRF v4.0 dated 07-Jan-2020. Any further changes 
to the protocol or CRF may necessitate updates to the SAP.
The stable version of the SAP will be approved based on the current protocol and CRF, allowing programming to 
be initiated. A final version of the SAP will be issued for approval prior to database lock.
Each version of the SAP requires approval by the sponsor.
4.1 Changes from Protocol
4.1.1 Glesatinib 
Enrollment into Glesatinib cohorts was discontinued in November 2017 as a result of Sponsor portfolio 
reprioritization. The analysis and reporting of this treatment arm is limited to the Lead-in phase only, and will be 
summarized for patient disposition, demographics, primary disease history, prior primary disease treatment, 
medical history, prior/concomitant medications and a single AE table only. Any other data will appear in listings 
only.
4.1.2 Mocetinostat 
Enrollment into Mocetinostat cohorts was never initiated and therefore no analysis or reporting of this treatment arm
is necessary.  The reference to Mocetinostat will only remain in the SAP where text is copied verbatim from the 
protocol. 


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4.1.3 Analysis Populations
The modified Intent-to-Treat (mITT) population as defined in Section 9.3.1 of the protocol has been renamed as the 
Full Analysis Set (FAS).
Section 3.2 of the protocol described that for patients to be part of the Clinical Activity Evaluable (CAE) population 
they “…must have at least one on-study disease assessment or discontinue from treatment for progressive disease 
(PD) prior to this assessment.” This definition was modified by Mirati to be as described in Section 7.3 of this SAP, 
where it includes “patients with measurable disease (per RECIST 1.1) at baseline and have received at least one 
dose of both investigational study drug and Nivolumab, must have at least one on-study disease assessment or 
discontinue from treatment for PD.” 
4.1.4 Clinical Benefit Rate (CBR)
Section 9.4.2 of the protocol states that “Clinical Benefit Rate (CBR) is defined as the percent of patients 
documented to have a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD)
documented during at least 2 on-study assessments and including at least 14 weeks on study (e.g., allowance for 
2-week window around Week 17 assessment).”
Amendments have been made to the later part of this definition to allow for at least one on-study assessment at 
least 42 days on study. This change is aligned with the definitions laid out in Section 8.2 in this SAP.
4.1.5 Sitravatinib Pharmacokinetic Sub-Studies
Two Sitravatinib sub-studies were added to protocol v4.0, however as per the project administrative letter, dated 
July 15th 2020;
x
PK Formulations of capsules (Appendix 5 of protocol v6): 
This was intended to be an evaluation of Sitravatinib PK using three formulations of capsules. The 
objective of this sub-study was fulfilled in a healthy volunteer study (516-006) which demonstrated 
bioequivalence between the 100 mg Sitravatinib malate capsule formulation (test) and the 120 mg 
Sitravatinib free base capsule formulation (reference). Therefore, no additional data are needed.
x
PK Food sub-study (Appendix 6 of protocol v6): 
This was intended to be an evaluation of PK when Sitravatinib capsules are administered orally in 
the fed state. Mirati Therapeutics has decided to conduct a separate study to evaluate the 
pharmacokinetics of Sitravatinib with and without food. Therefore, the Pharmacokinetic Food Effect 
Sub-Study (Appendix 6) will be closed.
As a result, the PK sub-study component of this study will be comprised of selected Demographic and Safety 
summaries, as described in Section 11.2. Patients from these PK sub-studies will be excluded from the main study 
summaries, their data will be listed separately.
4.2 Study Treatment Definitions
4.2.1 Study Drug 
The investigational agents of primary interest (Glesatinib, Sitravatinib, Mocetinostat) are referred to in the protocol 
as both study drugs and study treatments. Within the context of this SAP these terms are used interchangeably.




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-
Duration of Response (DoR)
-
CBR
-
Progression-Free Survival (PFS)
-
1-Year Survival Rate
-
Overall Survival (OS)
x
Blood plasma concentrations of the investigational agents.
5.2.3 Exploratory Endpoints
Study Design
Study MRTX-500 is an open-label, parallel Phase 2 evaluation of Nivolumab
in combination with 
three investigational agents, Glesatinib, Sitravatinib or Mocetinostat, in patients with locally advanced, unresectable 
or metastatic non-squamous NSCLC. Patients who have experienced progression of disease on or after treatment 
with a checkpoint inhibitor (checkpoint inhibitor therapy [CIT]-experienced) as well as those who have experienced 
disease progression after platinum-based doublet chemotherapy (CIT-naïve) will be enrolled. The primary objective 
is to evaluate the clinical activity of the combination study treatments using ORR in accordance with RECIST 1.1.
Secondary objectives include evaluation of safety, secondary efficacy endpoints, and PK for the investigational 
agents. The Schedule of Assessments to be performed in the study is presented in Table 1.  Pharmacokinetic and 
blood biomarker sample collection and triplicate Electrocardiogram (ECG) assessment time points are presented 
in Table 2, Table 3, and Table 4.
Specifics of two Sitravatinib sub-studies are presented in the protocol appendices, including the PK evaluation of 
three Sitravatinib capsule formulations (Appendix 5) and the PK of Sitravatinib administered with food (Appendix 
6).
The treatment arms included in this study are the following:
1.
Glesatinib plus Nivolumab.
2.
Sitravatinib plus Nivolumab.
3.
Mocetinostat plus Nivolumab.
To control bias in assignment of individual patients to treatment arms and to mitigate the risk of medication errors 
with the three investigational study treatments administered in specific regimens, study sites will be aligned with 
one specified treatment combination. Site alignment may change as patient cohorts are filled or patient recruitment 
factors shift at sites.


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Table 1:
Schedule of Assessments
Assessments
Screen/
Baseline
Cycle 1
Cycle 2 and 3
 Cycle 4
End of Treatment15
Within 28 
days
Day 1
Day 15
(± 2 days)
Day 1
(± 2 days)
Day 15
(± 2 days)
Day 1
(± 2 days)
Day 15
(± 2 days)
End of 
Treatment/ 
Withdrawal
Post 
Treatment 
Follow Up
Study Participation 
Informed Consent1
Before study 
specific 
assessments
Tumor Tissue Collection for 
PD-L1 Expression and 
Tumor Gene Alterations2
X
Medical History, Disease 
History, Prior Therapy 
X
ECOG Performance Status
X
Physical Exam3
X
X
Abbreviated Physical Exam3
X
X
X
X
X
X
Vital Signs4
X
X
X
X
X
X
X
X
Pregnancy Test5
X
As clinically indicated
Hematology6,7
X
X
X
X
X
X
X


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Table 1:
Schedule of Assessments (Continued)
Assessments
Screen/
Baseline
Cycle 1
Cycle 2 and 3
 Cycle 4
End of Treatment15
Within 28 
days
Day 1
Day 15
(± 2 days)
Day 1
(± 2 days)
Day 15  
(± 2 days)
Day 1
(± 2 days)
Day 15
(± 2 days)
End of 
Treatment/ 
Withdrawal
Post 
Treatment 
Follow Up
Coagulation6,7
X
As clinically indicated
Urinalysis6,7
X
As clinically indicated
Serum Chemistry6,7
X
X
X
X
X
X
X
Thyroid Function Test6,7
X
X
X
X
X
Blood for 
Pharmacokinetics8
See Table 2, Table 3, and Table 4 and Table 22, Table 23, Table 24, Table 25 from the protocol sub-
study appendix 5 and appendix 6 for PK sub-studies 
Biopsy of Tumor for 
Biomarker Studies 
(Optional)9
Pre-dose 
X
Cycle 2 
Only
X
X
Blood Samples – Flow 
Cytometry10
X
See Table 2, Table 3, and Table 4
X
Blood Samples – Protein 
and Cytokine Biomarkers10
See Table 2, Table 3, and Table 4
X
ctDNA blood sample11
X
Time of confirmation of disease response PR or CR
X
Single 12-Lead ECG12
X
As clinically indicated except –
Mocetinostat arm: Day 1 of each treatment cycle
X
Triplicate 12-Lead ECG12
See Table 2, Table 3, and Table 4


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Table 1:
Schedule of Assessments (Continued)
Assessments
Screen/
Baseline
Cycle 1
Cycle 2 and 3
 Cycle 4
End of Treatment15
Within 28 
days
Day 1
Day 15
(± 2 days)
Day 1
(± 2 days)
Day 15
(± 2 days)
Day 1
(± 2 days)
Day 15
(± 2 days)
End of 
Treatment/ 
Withdrawal
Post 
Treatment 
Follow Up
Echocardiogram
(Mocetinostat and 
Sitravatinib Treatment 
Arms Only)
X
X
Mocetinostat 
arm only
X
Cycle 3 only
X
Mocetinostat 
arm only
X
Disease Evaluation13
X
Every 8 weeks (± 10 days) for ~1 year 
and then every 16 weeks
Investigational Agent 
Dispensing and/or 
Reconciliation
X
X
X
Nivolumab Administration
X
X if Q2W
X
X if Q2W
X
X if Q2W
Adverse Events14 and 
Concomitant Medications
SAEs only
Throughout
Long Term Follow-up16
X
1
Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to initiation of 
any study specific assessments.
2
Tumor Testing for PD-L1 Expression and Tumor Gene Alterations: Encouraged for all patients. Archival tumor tissue allowed. For patients enrolled in CIT 
Naïve cohorts, the sample must have been collected following the completion of the most recent systemic treatment regimen and the central laboratory testing is 
to begin prior to study entry. Biopsy may precede informed consent if performed as Standard of Care (SOC) or to assess eligibility for a different clinical trial.
3
Physical Examinations: A complete physical examination required at Screening and End of Treatment only.  Height will be recorded at screening only. All other 
evaluations will be symptom-directed, abbreviated evaluations.
4
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated.
5
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.
6
Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.
7
Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 19 in the protocol) will be performed 
by local laboratories.


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8
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2, Table 3, and Table 4.  In 
addition, 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 the investigational agent.
9
Tumor Biopsy for Biomarker Studies:  Consent for serial sampling of tumor tissue (preferably the same lesion) is requested but is not mandatory for study entry.  
If tumor biopsy has been performed during screening, then that biopsy may be used for the baseline assessment.  Markers of interest in tumor tissue include PD-
L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) including proliferating (Ki67+) CD8+ cells, natural killer cells (NK-cells), T regulatory cells (Tregs), 
macrophages and myeloid derived suppressor cells (MDSCs).  Gene expression analyses may also be performed.
10
Blood Samples for Biomarker Studies:  Blood samples for flow cytometry and protein/cytokine assays will be collected as outlined in Table 2, Table 3, and Table 
4.  Markers of interest in circulation include circulating PD-L1, Tregs, MDSCs, NK-cells, flow cytometry for T- and B-cell including CD4, CD8 and Ki67, 
monocytes and selected cytokines including &'$ *=0% ,)1Ȗ &;&/ CXCL10, CXCL11, and TBX21.  Patients participating in the Sitravatinib
formulation and food effect sub-studies described in protocol Appendix 5 and Appendix 6 are exempt from sample collection for biomarker studies, including 
flow cytometry and protein/cytokine assays.
11
Blood samples for ctDNA analysis:  Blood will be collected in two 10ml Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and stability at 
ambient temperatures.
12
12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 2, Table 3, and Table 4.  Only for the Mocetinostat containing treatment 
arm, ECGs are to be performed on Day 1 of each cycle, either as a triplicate ECG accompanying PK or as a single ECG.  In addition, ECGs are to be performed 
as clinically indicated.  Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and QTc intervals.  rRR interval should be recorded 
during each ECG assessment in order to calculate QTcF.
13
Disease Evaluations: To be performed at screening (28 day window allowed) and every 8 weeks from Cycle 1 Day 1 ( ± 10 days window for all other 
assessments except screening) until Week 49 (~1 year) and then every 16 weeks.  All on-study disease evaluations should be based on a calendar beginning from 
the first day of dosing.  At screening/baseline, assessments are to include CT with contrast of the chest, abdomen and pelvis, as well as brain Magnetic 
Resonance Imaging (MRI) with and without gadolinium or Computed Tomography Scan (CT) with contrast, a whole body bone scan and evaluation of any 
superficial lesions.  Subsequent disease assessments should include all sites of disease identified at baseline or suspected to have developed; bone scans may be 
performed half as often (every 16 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease response.  More 
detailed guidance on exceptional circumstances is provided in the protocol.
14
Adverse Events: SAEs will be reported from the time of informed consent until at least 28 days after the last administration of investigational agent or 
Nivolumab.  Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution or 
stabilization of acute AEs and/or ongoing SAEs.
15
End of Treatment: All patients will be followed for AEs for at least 28 days after the last dose of Study Treatment. Assessments that have been completed in the 
previous 4 weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule).
16
Long Term Follow-up: Survival status and subsequent therapies will be collected during long term follow-up every 2 months (±14 days) from the End of 
Treatment visit until death or lost to follow-up. Follow-up may be performed by telephone contact.


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Table 2:
Glesatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments
Screen/
Baseline
Cycle 1 Day 1
Cycle 1 
Day 15
(± 2 days)
Cycle 2, 3, 5 
Day 1
(± 2 days)
Cycle 2 
Day 15 
(± 2 days)
Collection Time and Allowable 
Window
Within 28 
days
Pre-dose
(-0.5-0 hour)
30 min
(± 10 min)
3 hour 
(2-4 hour)
6 hour
(5-8 hour)
Pre-dose
(-0.5-0 hour)
Pre-dose
(-0.5-0 hour)
Pre-dose
(-0.5-0 hour)
PK Sample 1
X
X
X
X
X
X
X
Flow Cytometry 2
X
X
X
Protein and Cytokine Biomarkers 2
X
X
Triplicate ECG 3
X
X
X
X
X
1
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Glesatinib dosing and sampling should precede Nivolumab infusion.
2
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day 
as the pre-dose Cycle 1 Day 1 sample.
3
ECGs should be taken in triplicate, each reading at least 2 minutes apart.  On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 minutes prior 
to dosing (e.g., at 15 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.


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Table 3:
Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments
Screen/
Baseline
Cycle 1 Day 1
Cycle 1 
Day 15
(± 2 days)
Cycle 2, 3, 5 
Day 1
(± 2 days)
Cycle 2
Day 15
(± 2 days)
Collection Time and 
Allowable Window
Within 
28 days
Pre-dose
(-0.5-0 hour)
30 min
(± 10 
min)
4 hour
(3-5 hour)
6 hour
(5.5-8 hour)
Pre-dose
(-0.5-0 hour)
Pre-dose
(-0.5-0 hour)
Pre-dose
(-0.5-0 hour)
PK Sample 1, 4
X
X
X
X
X
X
X
Flow Cytometry 2, 5
X
X
X
Protein and Cytokine 
Biomarkers 2, 5
X
X
Triplicate ECG 3, 6
X
(-1 hour)
X
(-0.5 hour)
X
X
X
X
1
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede Nivolumab infusion.
2
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day 
as the pre-dose Cycle 1 Day 1 sample. 
3
ECGs should be taken in triplicate, each reading approximately 2 minutes apart. On Cycle 1 Day 1 only, two sets of triplicate ECGs should be done within 1 hour 
prior to dosing (e.g., at 30 minute intervals prior to dosing) to firmly establish the baseline for the patient. One set of triplicate ECGs is required at all other time 
points. In general, ECGs should be performed prior to the respective PK blood collection. Examples of the schedule are presented below:
o Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK)
o Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK).
4
Sample schedules for Sitravatinib formulation and food effect evaluations are presented in protocol Appendix 5 and Appendix 6, Table 22, Table 23, Table 24, 
and Table 25. 
5
Patients participating in the Sitravatinib formulation and food effect sub-studies described in protocol Appendix 5 and Appendix 6 are exempt from sample 
collection for biomarker studies, including flow cytometry and protein/cytokine assays.
6
Patients participating in the Sitravatinib formulation and food effect sub-studies described in protocol Appendix 5 and Appendix 6 will undergo evaluation by 
triplicate ECG on Lead-In Day 1 instead of Cycle 1 Day 1.


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Table 4:
Mocetinostat Schedule of PK, Biomarker Samples and Triplicate ECG Assessments (Study arm not
initiated)
Screen/
Baseline
Cycle 1 Day 1
Cycle 1 Day 15 (± 2 days)
Cycle 2, 3, 5
Day 1 (± 2 days)
Collection Time 
and Allowable 
Window
Within 28 
days
Pre-dose
(-0.5-0 hour)
1 hour 
(0.5-1.5 hour)
3 hour
(2-4 hour)
7 hour
(6-8
hour)
Pre-dose
(-0.5-0 hour)
1 hour 
(0.5-1.5 hour)
Pre-dose
(-0.5-0 hour)
1 hour 
(0.5-1.5 hour)
PK Sample 1
X
X
X
X
X
X
X
X
Flow Cytometry 2
X
X
X
Protein and Cytokine 
Biomarkers 2
X
X
Triplicate ECG 3
X
X
X
X
X
1
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  On days Mocetinostat and Nivolumab are both administered and scheduled 
for PK assessment, Mocetinostat dosing and sampling should precede Nivolumab infusion.
2
The Day 1 blood samples for biomarker studies may be drawn up to 2 hours before dosing. The screen/baseline sample should not be collected on the same day 
as the pre-dose Cycle 1 Day 1 sample.  
3
ECGs should be taken in triplicate, with readings at least 2 minutes apart. On Cycle 1 Day 1, two sets of triplicate ECGs should be done within 30 minutes prior 
to dosing (e.g., at 15 minute intervals) to firmly establish the baseline.  In general, ECGs should be performed prior (within -30 to -5 minutes) to the respective 
PK blood collection.


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6.1 Lead-in Dose Escalation Evaluation
The study will begin with a lead-in phase dose escalation evaluation of two dose levels of each investigational agent 
in combination with Nivolumab, in cohorts of 3 to 8 CIT-experienced patients each. Table 5 lists the planned dose 
levels for each agent, with the starting dose for each agent shown as Dose Level 1.
Patients may be escalated to Dose Level 2 or de-escalated to Dose Level -1, depending on safety observations. 
Table 5:
Investigational Study Drug Starting Dose Levels for Cohorts of Patients in 
the Lead-In Phase Dose Evaluation
Drug
Regimen
Dose Level
1
2
-1
Glesatinib Tablets
Twice Daily
500 mg
750 mg
350 mg
Sitravatinib 
Capsules 
Once Daily
120 mg
150 mg
80 mg
Mocetinostat 
Capsules
Three Times 
Weekly
70 mg
90 mg
50 mg
Depending on experience in early cohorts of patients in the lead-in phase dose escalation evaluation, doses below 
those shown in Table 5 may be implemented in subsequent cohorts of patients after discussion among Investigators 
participating in the lead-in phase evaluation and the Sponsor. Depending on experience with early cohorts of 
patients, not all dose levels may be explored.
Throughout the study, Nivolumab will be administered in accordance with approved labeling. Nivolumab is to be 
administered by intravenous infusion, using either regimen included in the approved label: 240 mg every 2 weeks 
(Q2W) or 480 every 4 weeks (Q4W). Guidance for adverse event management and associated Nivolumab treatment 
modifications are provided in the product labeling and replicated in Section 5.2 of the protocol.
6.1.1 Definition of Dose Limiting Toxicity (DLT)
The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.03 will be used for the 
evaluation of safety observations throughout this study. The definition of DLT for the purpose of dose escalation 
decisions includes any of the following events considered to be causally related to treatment with an investigational 
study drug in combination with Nivolumab that occurs during the first 28-day treatment cycle:
x
Any Grade 4 non-hematological toxicity.
x
Any Grade 3 non-KHPDWRORJLFDO WR[LFLW\ RU *UDGH  RU  KHPDWRORJLFDO WR[LFLW\ WKDW GRHV QRW UHFRYHU WR 
Grade 2 as indicated by symptoms within 3 days and/or as indicated by laboratory assessment within 8 
days after onset of the event despite optimal medical management with or without corticosteroids.
-
A special case is provided for hepatic transaminases – increase over baseline by two-fold or more and 
meeting Grade 3 or 4 criteria.
x
Grade 2 pneumonitis or colitis that does not reVROYH WR  *UDGH  DV LQGLFDWHG E\ V\PSWRPV ZLWKLQ  GD\V
after onset of the event despite optimal medical management with or without corticosteroids.
x
Febrile neutropenia or neutropenia associated with systemic infection.


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x
Any toxicity that requires suspension of treatment for more than 2 weeks.
The definition of DLT excludes the following conditions:
x
*UDGH  IDWLJXH ODVWLQJ   GD\V
x
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that can be effectively managed 
with hormone replacement therapy.
x
Acute infusion-related reaction.
x
Lymphopenia without infection.
x
Thrombocytopenia without clinically significant bleeding.
6.1.2 Enrollment and Dose Escalation Plan
Patients meeting eligibility criteria as outlined in the protocol may enroll into the lead-in phase dose escalation 
evaluation, regardless of whether they did or did not experience clinical benefit during prior treatment with a 
checkpoint inhibitor. 
Dose escalation cohorts are expected to include between 3 and 8 patients for each investigational study treatment 
and dose level evaluated. The first patient to be treated at the starting dose and at each new higher dose of 
investigational study drug will be observed for at least 1 week prior to enrollment of subsequent patients in the 
cohort. As many as 5 patients may initially be enrolled into each cohort. For a patient within a dose cohort to be 
considered evaluable for the dose-escalation decision, the patient must have either been on study for 1 full cycle 
and have received treatment with Nivolumab and at least 75% of scheduled investigational study drug doses in 
Cycle 1 or have experienced a DLT in Cycle 1. 
Decision making for cohort expansion and dose escalation or de-escalation will be in accordance with the modified 
toxicity probability interval (mTPI) method (Dose-Finding Spreadsheet presented in Appendix 2 of the protocol). To 
ensure sufficient patient experience at the dose to be used in the Phase 2 study, enrollment at any dose level under 
consideration may be expanded to include at least 6 patients.
6.1.3 Definition of Maximum Tolerated Dose (MTD)
The Maximum Tolerated Dose (MTD) for each combination regimen is defined as the highest investigational study 
drug dose administered in the combination regimen associated with the decision to “stay with the current dose” as 
determined from the Dose-Finding Spreadsheet (Appendix 2 of the protocol) using the experience of at least 
6 patients during the first 28-day treatment cycle.
6.1.4 Selection of Phase 2 Dose for Investigational Study Drugs
For each investigational study drug, the dose to be selected for use in the Phase 2 study will be the highest dose 
evaluated in the lead-in phase evaluation that is associated with:
x
sufficient safety/tolerability to anticipate that patients will typically be able to receive treatment with at 
least 75% of the intended dose intensity of investigational study drug and 100% dose intensity of 
Nivolumab; and
x
QR REVHUYHG *UDGH 3 or serious immune-related adverse events (irAEs) causally related to the 
combination regimen.


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A dose level below the MTD may be selected for use in the Phase 2 study.
6.2 Phase 2 Study
Following completion of the lead-in phase dose escalation evaluation, enrollment into the Phase 2 study will 
proceed. The treatment arms included in this study are the following:
1.
Glesatinib plus Nivolumab
2.
Sitravatinib plus Nivolumab
3.
Mocetinostat plus Nivolumab
For patients who have experienced progression of disease on or after treatment with a checkpoint inhibitor (CIT-
experienced) enrollment into each treatment arm will be stratified by prior outcome of treatment with a checkpoint 
inhibitor:
a.
Clinical benefit (i.e., RECIST defined CR, PR or SD for at least 12 weeks [-2 week window permitted for 
radiograph scheduling]) followed by radiographic progression of disease.
b.
No prior clinical benefit (i.e., radiographic SURJUHVVLRQ RI GLVHDVH   weeks after initiation of treatment 
[+2 week window permitted for radiograph scheduling].
Thus, the study will include 6 parallel evaluations of clinical activity of Nivolumab combination regimens (Figure 1)
in patients with prior treatment with a checkpoint inhibitor. Patients enrolled in the lead-in phase dose escalation 
evaluation and receiving the dose of investigational study drug chosen for the Phase 2 study will be included in the 
analysis of the Phase 2 endpoints. Patients who discontinue the study prior to the first on-study disease assessment 
for reasons other than disease progression may be replaced.
For patients without prior CIT (CIT-naïve), each investigational study treatment arm (i.e., Glesatinib and
Sitravatinib) will be stratified according to PD-L1 status:
a.
Having tumor with no/low PD-L1 expression.
b.
Having tumor with high PD-L1 expression.
Tumor PD-L1 expression will be determined by the PD-L1 (28-8) companion diagnostics assay completed through 
the central laboratory. No/low PD-L1 expression is defined as positivity < 5% of tumor cells; high PD-L1 expression 
LV GHILQHG DV SRVLWLYLW\   RI WXPRU FHOOV 7XPRU VDPSOHV XVHG WR HVWDEOLVK 3'-L1 expression for eligibility must 
have been collected after the most recent systemic therapy.
Thus, the study will include 6 parallel evaluations of clinical activity of Nivolumab combination regimens (Figure 1) 
in patients without prior treatment with a checkpoint inhibitor.
Disease response and progression as documented by the Investigator in the CRF will be the basis for patient 
management and study expansion decision making. Unconfirmed objective responses recorded in the CRF may 
be used as the initial basis for expansion of study enrollment; however, follow-up evaluations on patients with 
unconfirmed responses must continue to support the decision to continue to the full number of patients to be 
included in the next stage. Disease assessments will be performed until objective disease progression is 
documented or subsequent anti-cancer therapy is begun. Central radiology review for disease response and 
progression may be added to the study during Stage 2. If this occurs, central review of all radiologic assessments 
performed in the study will be conducted (including retrospective review of patients enrolled in Stage 1), and central 
radiology review for disease response will be the basis for the primary statistical analyses to estimate the objective 
response rate and its confidence interval (CI), as well as the DoR and PFS.


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6.2.1 Sample Size Considerations
Approximately 24 patients may be enrolled into the lead-in phase of the study. A precise sample size cannot be 
defined as it is dependent on the number of dose escalations based on the mTPI (Ji 2013) method, and the number 
of patients enrolled in the expansion cohorts
6.2.1.1 Lead-In Phase
The mTPI method will be employed in decision making concerning dose escalation within each regimen 
investigated. The assumptions to be applied in establishing the mTPI methodology are:
x
Each specific regimen exploration will include up to 30 patients
x
The MTD is defined to have 0.25 probability of toxicity; and
x
The acceptable variance around the MTD is ± 0.05 (i.e., the region of the MTD is 20% to 30% incidence of 
DLT).
6.2.1.2 Phase 2 CIT-experienced and CIT-naïve with no/low PD-L1 expression
This Phase 2 study will use a Predictive Probability Design (Lee 2008) in each treatment arm and strata. In creating 
the statistical GHVLJQV WKH 7\SH  HUURU Į LV FRQVWUDLQHG WR  DQG power (1-ȕ LV FRQVWUDLQHG WR 
The ORR using Nivolumab in the population with advanced non-squamous NSCLC having prior disease 
progression on a checkpoint inhibitor or patients with non-squamous NSCLC without prior CIT with no/low PD-L1 
expression is assumed to be 5% (p0); thus this rate is considered uninteresting. The target ORR using the 
investigational agents in combination with Nivolumab in this study is 30% (p1). Stage 1 of enrollment will include a 
minimum of 9 evaluable patients in each treatment strata. With exactly 9 evaluable patients at Stage 1, if at least 
1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the treatment stratum, for a 
total sample size of 17 evaluable patients. If at least 3 Objective Responses are observed in a treatment stratum, 
further investigation may be warranted. If the true ORR is 5% (null hypothesis), the probability of early termination 
during the study is 0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.
6.2.1.3 Phase 2 CIT-naïve with high PD-L1 expression
The ORR using Nivolumab in the population with non-squamous NSCLC having high PD-L1 expression is assumed 
to be 27% (p0); thus this rate is considered uninteresting. The target ORR using the investigational agents in 
combination with Nivolumab is 50% (p1).
Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 17 evaluable patients at 
Stage 1, if at least 5 patients have Objective Responses, 27 additional evaluable patients will be enrolled, for a total 
sample size of 44 evaluable patients. If at least 18 Objective Responses are observed, further investigation may be 
warranted. If the true ORR is 27% (null hypothesis), the probability of early termination during the study is 0.50; the 
Type 1 error is equal to 0.0303 and the power is equal to 0.9018.
The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, once the exact 
number of patients evaluable at Stage 1 is known. The aim is to get a minimum of 9 evaluable patients at Stage 1 
for CIT-experienced and CIT-naïve with no/low PD-L1 expression cohorts and a minimum of 17 evaluable patients 
at Stage 1 for CIT-naïve with high PD-L1 expression cohort.


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The original protocol provided that if results in any strata were of high interest for efficacy, enrollment might be 
expanded to as many as 100 patients total in each cohort to narrow the 95% CI around the ORR point estimate.  
Protocol Amendment 3 (v4.0) eliminates enrollment expansion beyond Stage 2 except in the Sitravatinib segment 
of the study enrolling patients with CIT-experience.  
6.2.1.4 Expansion Beyond Phase 2
For the Sitravatinib segment of the study enrolling patients with CIT-experience, expansion of enrollment beyond 
Stage 2 will be managed as one cohort that includes all patients, regardless of prior clinical benefit during treatment 
with CIT. Based on preliminary clinical activity results as of June 2018 (described in Section 1.5.3.2.2 of the 
protocol), enrollment into the combined cohort will expand to as many as 125 patients total, to further evaluate 
safety and efficacy in this setting.  
Expansion of Sitravatinib CIT-naïve cohorts beyond Stage 2 of enrollment is not anticipated.
6.3 Randomization
Random assignment to treatment arms is not being used in this study. Treatment arm assignment will be determined 
by the site where the patient is enrolled as described in Section 6.0.


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Figure 1:
Phase 2 Portion Study Diagram


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Analysis Populations
Patients who consent to be part of the PK sub-studies will be excluded from all populations, with the exception of 
the enrolled population and the PK sub-study population.
7.1 Enrolled Population
The Enrolled Population is defined as all patients who sign an informed consent and are determined by the 
Investigator to meet all eligibility criteria during screening assessments. Percentages in the disposition summaries 
will be displayed using the Enrolled Population as the denominator.
7.2 Full Analysis Set (FAS)
The FAS is defined as all patients who receive at least one dose of both investigational study drug and Nivolumab.
The analyses of the primary and secondary efficacy endpoints will be performed using the FAS.
7.3 Clinical Activity Evaluable (CAE) Population
The CAE Population is defined as all patients who have received at least one dose of both investigational study 
drug and Nivolumab, have evaluable baseline tumor assessment and at least one post-baseline tumor assessment.
This population will be used for the supportive analysis of tumor responses.
7.4 Safety Population
The Safety Population is defined as all patients who received at least 1 dose of either investigational study drug or 
Nivolumab. The Safety Population will be used for all safety analyses.
7.5 DLT Evaluable Population
The DLT evaluable population is defined as any patient who is enrolled in a cohort in the lead-in phase of the study
and who either has been on study for one full cycle and has received treatment with Nivolumab and at least 75% of 
scheduled investigational study treatment doses in Cycle 1 or who has experienced a DLT in Cycle 1.
7.6 PK Sub-Study Population
The PK sub-study population is defined as any patient consenting to be part of either the PK formulation or the PK 
food effect sub-studies. Consent will be identified programmatically from the Study Treatment Assignment page of 
the CRF.
Endpoint Definitions
8.1 Baseline Characteristics
8.1.1 Baseline
Baseline is defined as the last non-missing value prior to first dose. In most cases this will be Cycle 1 Day 1, however 
values from the Screening/Baseline visit may be used if Cycle 1 Day 1 is missing, or after first dose.


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8.1.2 Age 
Age (years) is calculated relative to the date of signing informed consent;
Age (years) = (Date of Informed Consent - Date of Birth) + 1 / 365.25.
8.1.3 Time Since Diagnosis
Time since diagnosis is calculated relative to the date of first dose of any study drug. Missing or partial dates of 
diagnosis will not be imputed.
Time Since Diagnosis (Years) = (Date of First Dose – Date of Diagnosis) +1/365.25.
8.2 Efficacy Variables
With regard to efficacy endpoints, the term “on-study” includes the period from the first dose of any study drug until 
the end of study. The term “baseline” will include screening and Cycle 1 Day 1 pre-dose assessment which would 
represent a 29-day window. Unscheduled visits assessments preceding Cycle 1 Day 1 will be also considered for 
baseline.
Disease assessments involving radiographic evaluations may be performed over the course of a few days. The 
date of response (CR, PR, SD, PD or Not Evaluable [NE]) will be recorded as the date of the last radiographic 
evaluation included in the series for that time point assessment. For the investigator assessment, the date will be 
determined using the latest Date of Assessment recorded among the radiologic modalities included for the 
applicable Time Point Assessment.
8.2.1 Objective Response Rate (ORR)
Objective disease response will be categorized in accordance with RECIST v1.1. ORR is defined as the proportion 
of patients documented to have a confirmed CR or PR. ORR as reported by the investigator will be used in decision 
making for study expansion (Predictive Probability Design).
Best Overall Response (BOR) is defined as the best response among all overall responses (in the order CR, PR, 
SD, PD then NE) recorded from the start of study drug until disease progression/recurrence or start of subsequent 
anti-cancer therapy, whichever comes first. The status of best response of CR or PR must be confirmed by repeat 
tumor assessment within no less than 4 weeks according to RECIST v1.1. If the status of CR or PR cannot be 
confirmed by repeat tumor assessment, the BOR of unconfirmed CR and PR will be SD or NE. The status of BOR
of SD requires an on-study assessment after at least 42 days from first dose date of treatment.


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Confirmed Response Based on Subsequent Assessments*;
First Time Point 
Response**
Second Time Point 
Response
Confirmed Response
(Best Response)*
PD
No further evaluation
PD
NE
PD
PD
CR
PD
SD or PD (1)
PR
PD
SD or PD (1)
SD
PD
SD or PD (1)
CR
CR
CR
CR
NE **
SD or NE (2)
PR
CR
PR
PR
PR
PR
PR
SD (3)**
SD
PR
NE **
SD or NE (2)
SD
CR
SD
SD
PR
SD
SD
SD
SD
SD
NE
SD or NE (2)
NE
CR
SD
NE
PR
SD
NE
SD
SD
NE
NE
NE
*     A Best Response of SD can only be made after the patient is on-study for a minimum of 42 days. If the 
patient is on-study less than 42 days, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
**    Subsequent documentation of CR may provide confirmation of a previously identified CR for patients where 
the second integrated response was NE. Subsequent documentation of PR may provide confirmation of a 
previously identified PR for patients where the second integrated response was NE or SD. If the third 
response confirms the CR (or PR) then the confirmed response will be CR (or PR).
For example: CR NE CR = CR; PR NE PR = PR.
Additionally, one SD is allowed between PRs (e.g., PR SD PR = PR).
(1)
Best response will be SD if the first response is after 42 days on-treatment.  Otherwise, the best response 
will be PD.
(2)
Best response will be SD if the first response is after 42 days on-study.  Otherwise, the best response will 
be NE.
(3)
Response is SD if the increase from the first to the second assessment does not qualify for PD.
For patients with unconfirmed CR/PR that can’t be confirmed due to dropping off study, the best overall 
response will be SD.
8.2.2 Duration of Response (DoR)
DoR is defined as the time in months from date of the first documentation of objective response (CR or PR) to the 
first documentation of objective PD or to death due to any cause in the absence of documented PD (i.e., min (PD 
date, death date) – date of the first observation of response +1). DoR will only be calculated for the subgroup of 
patients achieving a confirmed CR or PR.


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DOR = (Min(PD Date, Death Date) – Date of the First Observation of Response +1)/30.4375
8.2.3 Clinical Benefit Rate (CBR)
CBR will be categorized in accordance with RECIST v1.1. CBR is defined as the proportion of patients documented 
to have a confirmed CR or PR, or SD.
8.2.4 Progression-Free Survival (PFS)
PFS is defined as the time from the first dose of study drug to the date of PD or death due to any cause in the 
absence of documented PD, whichever occurs first.
PFS (in months) = (First Event Date – First Dose Date +1)/30.4375.
8.2.5 Overall Survival (OS)
OS is defined as the time from first dose of study drug to the date of death due to any cause. 
OS (in months) = (Date of DHDWK í Date of First Dose of Study Drug +1)/30.4375.
8.3 Study Drug Exposure Variables
The term study drug in the exposure definitions below, refers to Glesatinib and Sitravatinib unless otherwise 
specified.
8.3.1 Study Treatment Duration
Study treatment duration will be summarized separately for each study drug and Nivolumab and is defined as;
x
Study Treatment Duration (weeks) = (Last Dose Date – First Dose Date +1)/7.
8.3.2 Cumulative Dose Administered
Dose modifications should be accounted for in the cumulative dose administered calculations below;
x
Cumulative dose received for Nivolumab (mg) is defined as the total amount of Nivolumab a patient receives 
during the study as recorded on the Nivolumab Administration CRF forms. Nivolumab is planned to be 
administered at a dose of 240 mg once every 2 weeks or 480 once every 4 weeks.
x
Cumulative dose received for study drug (mg) is defined as the total amount of the study drug a patient 
receives during the study;
The Sum of [(Last Dose Date – First Dose Date + 1) * Total Dose (mg per administration) * Dose Frequency] 
as recorded on the Study Drug Administration CRF forms.
8.3.3 Cycles Started
A patient is considered to have started a cycle if they received at least one dose of either study drug or Nivolumab
in that cycle, per the Study Drug Administration CRF page.


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8.3.4 Dose Intensity
x
Relative dose intensity should apply to both Sitravatinib (Phase 2 only) and Nivolumab, from Cycle 1 Day 
1,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 in days.
o
For Nivolumab: [cumulative Nivolumab dose administered (mg)] / cumulative planned Nivolumab
dose (mg)] * 100, where the cumulative planned total dose is:
240݉݃ݔܴ݋ݑ݊݀ቆܦݑݎܽݐ݅݋݊݋݂ܰ݅ݒ݋ݑܾ݉ܽ(ݓ݁݁݇ݏ) + ܺ
2
ቇ
Where X is 2 weeks for subjects who took 240mg as their last dose, and 4 weeks for subjects who 
took 480mg as their last dose.
8.3.5 Compliance
Compliance is only calculated for Sitravatinib (Phase 2 only), from Cycle 1 Day 1, defined as:
Compliance (%) = Cumulative Dose Received (mg) / Adjusted Cumulative Planned Dose (mg) * 100, where
Treatment Duration (Days) = Last Dose Date - First Dose Date +1, and 
Adjusted Cumulative Planned Dose (mg) = Planned Dose * (Treatment Duration – Duration of 
Interruptions and/or Dose ReductLRQV GXH WR $(  (DFK 3ODQQHG ,QWHUUXSWLRQ DQGRU 'RVH
Reduction (mg) * Duration of the given Planned Interruption/Reduction due to AE).
8.3.6 Days on Study Drug
Days on study drug is defined as the total number of days that a patient received treatment, after subtracting for 
interruptions or drug missed, that is:
x
The [(Last Dose Date – First Dose Date captured on the Study Drug Administration CRF page) – number 
of days with 0 mg dose +1].
8.4 Safety Variables
With regard to safety summaries, the term “on-treatment” is the period from first dose until either last dose + 28 
days or the start of anti-cancer therapy, whichever is earlier. 
AEs, laboratory values and ECGs will be graded according to the NCI CTCAE v4.03 (see Section 13.0 for link to 
the criteria) , ECGs will also be graded according to International Conference on Harmonisation (ICH) E14.
8.4.1 Adverse Events
8.4.1.1 Treatment-Emergent AEs (TEAEs)
TEAEs are those that first occur or increase in severity after the first dose of study treatment and not more than 28 
days after the last dose of study treatment and prior to the initiation of subsequent anti-cancer therapy. Any ongoing 
TEAE (or any baseline sign/symptom recorded as part of Medical History) that changes in attribution or increases 
in severity is captured as a new AE.


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8.4.1.2 Serious Adverse Events (SAEs)
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. All SAEs ongoing 28 days after the last dose should be followed until resolution, stabilization to a chronic 
condition or administration of alternative cancer treatment, whichever occurs first.
8.4.2 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 by the Investigator on 
the adverse events CRF page.
8.4.3 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 
and may require close monitoring and rapid communication by the Investigator to the sponsor. AESIs will be 
identified by the medical team based on coded terms.
8.4.4 Physical Examinations
A physical examination including all major body systems is mandated at Screening and End of Treatment Visits 
only. During study treatment, symptom directed physical examinations are performed.
8.4.5 Vital Signs
Vital signs: systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature, height and weight.
Height will be recorded at screening only.
8.4.6 Clinical Laboratory Assessments
Clinical laboratory parameters to be collected routinely for hematology, chemistry, urinalysis and thyroid function
are listed in Table 6 in Section 11.1.7.4 .
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test will be performed by the 
local laboratory at screening. Pregnancy tests will also be done whenever pregnancy is suspected during the study.
8.4.7 Electrocardiograms
Single and triplicate 12-Lead ECG parameters will be collected as shown in Table 1-4. Assessments include rhythm, 
heart rate, PR, QRS, QT and RR, the QT interval will be corrected for heart rate using Fridericia’s formula (QTcF).
The Investigator’s overall interpretation will also be collected. 
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 Cycle 1 Day 1 (-1 hour and -0.5 hours pre-dose). If any of the 6 values are missing, the mean 
will be calculated using the observed values.
8.4.8 Echocardiograms
Echocardiograms will be performed in the Sitravatinib treatment arm at screening, and thereafter as shown in Table 
1. Additional assessments of left ventricular ejection fraction (LVEF) and evaluation of pericardial effusions may be 


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performed as clinically indicated at the Investigator’s discretion if there are signs or symptoms of cardiotoxicity. 
Where abnormalities indicating pericardial effusion exist, weekly assessments will be performed until normalization 
as described in Section 5.1.3.4.1 of the protocol.
8.4.9 Prior and Concomitant Medications
Medications administered to study participants 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 both prior and concomitant medications, unless the end 
date is prior to first dose, in which case it would be considered prior only. 
Medications with a missing start date but an observed end date after first dose of study treatment, will be considered 
as concomitant medication. 
Concomitant medications are defined as medications administered to study participants on or after the first dose of 
study treatment, or a prior medication with an end date after the first dose of study treatment.
A medication can be considered both prior and concomitant.
8.5 Predetermined Covariates and Prognostic Factors
Enrollment into each treatment arm of the CIT-experienced patients will be stratified by prior outcome of treatment 
with a checkpoint inhibitor (prior clinical benefit, no prior clinical benefit). Each combination of treatment arm and 
prior clinical benefit stratum, including overall, will be analyzed separately.
Enrollment into each treatment arm of the CIT-naïve patients will be stratified according to the patient’s PD-L1 status 
(No/Low, High). Each combination of treatment arm and PD-L1 status, including overall, will be analyzed separately.
Data Handling
9.1 Missing Dates
9.1.1 Imputation of Partial Adverse Event or Medication Dates
The rules to impute missing start and stop dates will be applied as follows;
Start Date
If the start date is completely missing (i.e., the day, month, and year are all unknown) the start date will not 
be imputed.
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 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


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x
The day will be treated as also 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 not the same as the year of the first dose date, then January 1 
will be assigned to the missing fields.
x
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
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 December 31 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.
9.1.2 Imputation of Partial Subsequent Anti-Cancer Therapy Dates
The following rules will be applied to impute missing subsequent anti-cancer therapy dates.
Missing Day Only
x
If the month and year of the incomplete date are the same as the month and year of the last dose 
date, then the last dose date + 1 will be assigned to the missing day.  
x
If the month and year of the incomplete date are after the month and year of the last dose date, then 
the first day of the month will be assigned to the missing day.
Missing Month Only
x
The day will be set as missing and treated as missing Day and Month.
Missing Day and Month
x
If the year of the incomplete date is the same as the year of the last dose date, then the last dose 
date + 1 will be assigned to the missing day and month.  
x
If the year of the incomplete date is after the year of the last dose date, then January 01 will be 
assigned to the missing fields.


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9.2 Laboratory Values Beyond the Limits of Quantification
Laboratory values of the form of “< x” (i.e., below the lower limit of quantification) or “> x” (i.e., above the upper limit 
of quantification) will be imputed as “x” for the purpose of calculating summary statistics and comparing to normal 
ranges. These values will remain as “< x” or “> x” in the listings.
9.3 Important 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, safety assessment, efficacy assessment, visit window, 
informed consent, prohibited medication, 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.
Interim Analyses
There are no formal interim analyses in the study. Tumor responses will be reviewed for the CAE population to 
make decisions per the Predictive Probability Design on whether a cohort should be stopped for lack of tumor 
response as detailed in Section 6.2.
Planned Analysis
PK sub-study patients will be excluded from any main study summaries and will be presented in PK sub-study 
specific summaries only. Screen Failures will be summarized in a Screen Failure table, but otherwise excluded from 
all tables and listings. Listings will include all relevant derived variables.
All data collected during this study will be displayed in data listings, unless otherwise specified. Data listings will be 
presented separately for enrolled patients in the main study and those in the PK sub-studies. 
Descriptive statistics (mean, median, standard deviations [STD] or standard error, first quartile [Q1], third quartile 
[Q3], 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 values 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.
Safety summaries will be presented for assessments on-treatment (as defined in Section 8.4) and will include 
patients from both the safety lead-in and phase 2 parts of the study. Efficacy summaries will be presented for 
assessments on-study (defined in Section 8.2) and will include patients receiving the recommended phase 2 dose 
(120mg QD) only. All tables will be presented by treatment arm and strata.
Unless otherwise noted, missing data will not be imputed or carried forward.
All data summaries and tabulations will be prepared with SAS v9.4 or higher.


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11.1 Analysis for Main Study (non PK sub-studies)
11.1.1 Patient Disposition
The number and percentage of patients in each analysis population will be presented, along with the patients who 
withdrew from the study, discontinued Nivolumab or the investigational study drug, with the breakdown of 
corresponding withdrawal/discontinuation reasons. The number and percentage of deaths, including cause of death 
and the duration on treatment (time from first dose date to end of treatment, in months) will also be presented.
The number of patients enrolled by site and overall will be presented. 
Disposition will be summarized descriptively by treatment arm and strata.
11.1.2 Important Protocol Deviations
Important protocol deviations (see definition in Section 9.3) for patients in the Enrolled Population will be listed only.
A listing of patients who enroll with inclusion or exclusion criteria exceptions will also be provided.
11.1.3 Demographic and Baseline Characteristics
Demographic and baseline data will be summarized descriptively using the Safety population. 
Demographic variables to be summarized include sex, reproductive status for female, race, ethnicity, age (years), 
baseline weight (kg), baseline height (m), baseline Eastern Cooperative Oncology Group (ECOG) status, and 
smoking history.
Primary disease history will summarize Histology (Adenocarcinoma, Large Cell Carcinoma, and Other), Current 
Stage (Locally Advanced, Metastatic), the time since diagnosis and the time since metastatic diagnosis.
Prior primary disease treatment (systemic therapies including platinum therapies and checkpoint inhibitors, 
radiotherapy, and surgery) will summarize the following:
x
Prior Systemic Therapy - Platinum Agent Received (Cisplatin, Carboplatin, Other)
x
Prior Checkpoint Inhibitor - (Nivolumab, Pembrolizumab, Durvalumab, Atezolizumab, Avelumab, Other)
x
Best Response to Prior Checkpoint Inhibitor
x
Prior Regimens (Number of Regimens and Type)
x
Prior Radiotherapy - Type (Adjuvant, Palliative)
x
Prior Surgery - Location (Lung, Liver, Lymph Node, Adrenal, Brain, Other)
Demographic, primary disease history, and prior primary disease treatment data will also be listed by patient.
11.1.4 Prior and Concomitant Medications and Procedures
Concomitant medications will be coded using World Health Organization (WHO) Drug Enhanced (Version: March 
2016).
Prior and concomitant medications will be tabulated separately for the Safety Population by Anatomical Therapeutic 
Chemical (ATC) Classification (2nd Level) and preferred drug name using counts and percentages. The number and 
percentage of patients using at least one medication will be summarized.
Prior and concomitant medications along with concomitant procedures will be listed.


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11.1.5 Medical History
Medical history will be tabulated using the Safety Population by system organ class (SOC) and preferred term (PT).
Medical history will also be listed by patient.
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.
11.1.6 Efficacy Analyses
All efficacy analyses will be presented by planned treatment arm and strata, as described in Section 8.5. 
The 120mg dose of Sitravatinib was given to patients in both the lead-in phase and in phase 2, hence the efficacy 
results will be presented for all subjects receiving this dose combined across phases.
If a treatment arm includes patients only in the lead-in phase and not in phase 2, then only listings will be presented 
for this treatment arm. If a treatment arm was not initiated, then no efficacy results will be presented.
11.1.6.1 Primary Variable
Descriptive statistics for ORR and BOR (CR, PR, SD, PD and NE) based on the response assessments by the 
Investigator will be presented by treatment arm and strata. Exact 95% Clopper-Pearson CIs for ORR will also be 
presented.
An exact test for single proportion (one-VLGHG Į 0.025) will be performed to test H0 255 5% against H1: ORR >5% 
for CIT-experienced and PD-L1 no/low or CIT naïve for each treatment arm which proceeds to Phase 2 and test 
H0 255 27% against H1: ORR >27% for PD-L1 high of CIT naïve. 
Patients who cannot be assessed for response will be counted as non-responders.
The primary analysis will be conducted using the FAS with supportive analyses presented using the CAE population.
11.1.6.2 Secondary Variables
DoR, CBR, and PFS will be based on the response assessments by the Investigator. Secondary analyses will be 
conducted using either the CAE population or the FAS as described within each variable section below.
11.1.6.2.1 Clinical Benefit Rate (CBR)
Descriptive statistics for CBR, confirmed CR, PR or SD based on the response assessments by the Investigator 
will be presented by strata and treatment arm using both the FAS and the CAE population. Exact 95% Clopper-
Pearson CIs for CBR will also be presented.
11.1.6.2.2 Duration of Response (DoR)
DoR will be summarized descriptively using a subset of the CAE population (patients who have confirmed CR or 
PR), presenting Kaplan-Meier (KM) estimates for the median, 25th and 75th percentiles and their two sided 95% CIs 
(Brookmeyer and Crowley, 1982) where appropriate. In addition, minimum and maximum values will also be 
displayed. 
DoR will be listed and KM plots will also be provided.
Censoring Rules for DoR


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x
Patients without documented PD will be censored at the date of the last evaluable tumor assessment prior 
to the start of the new therapy (if received any), unless they die within 122 days of last evaluable tumor 
assessment, in which case they will be assessed as having an event on the date of death.
11.1.6.2.3 Progression-Free Survival (PFS)
PFS will be summarized in the same manner as DoR, though conducted using the FAS. In addition, the PFS rate 
at 3, 6 and 9 months will be analyzed using KM methodology (Greenwood’s formula, Kalbfleisch and Prentice, 
1980).
Censoring Rules for PFS
x
Event time will be censored on the date of first dose with duration of 1 day for;
o
No Disease Assessments Performed On-Study
i.e. Patients lacking evaluation of disease after first study treatment, unless they die within 2 tumor 
assessments of baseline (on or prior to week 16, i.e. Cycle 5 Day 1 plus the 10 day window, which 
is Study Day 122]), then they will be treated as experiencing an event with date of death as the 
event date.
o
Patients with baseline or post-baseline assessments inadequate to apply RECIST v1.1 criteria.
x
Patients without documented PD will be censored at the date of the last evaluable tumor assessment prior 
to the start of the new therapy (if received any), unless they die within 122 days of last evaluable tumor 
assessment, in which case they will be assessed as having an event on the date of death.
11.1.6.2.4 Overall Survival (OS)
OS will be summarized similarly to PFS. Additionally, the 1-year OS rate (proportion and 95% CI) will be analyzed 
using KM methodology (Greenwood’s formula, Kalbfleisch and Prentice, 1980).
Censoring Rules for OS
For patients who are continuing the study at the time of an analysis, lost to follow-up, or who withdrew consent, the 
OS endpoint will be censored on the last date that patients were known to be alive. The date last known to be alive 
is derived from the CRF and may include but not limited to the latest visit date for patients ongoing in the study or 
the latest Date of Contact on the Long-Term Follow-up/Survival Status page, whichever occurs latest. For patients 
with no follow-up after the first dose of study drug, OS will be censored at the date of first dose.
11.1.6.2.5 Extent of Follow-Up
The median extent of follow-up with 95% CI will be calculated and presented in a dedicated table using a reverse 
KM approach (reversing the OS censoring).
11.1.7 Safety Analyses
All safety analyses will be summarized by actual treatment arm.
DLTs will be presented using the DLT Evaluable Population, all other safety parameters will be presented using the 
Safety Population.


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11.1.7.1 Extent of Study Drug Exposure
Descriptive statistics will be provided separately for each study drug, for the duration of exposure (weeks) and the 
total number of cycles started. The number of doses administered, cumulative dose administered (mg), relative 
dose intensity and overall compliance will be presented for Sitravatinib only.
For Glesatinib and Sitravatinib, the number and percentage of patients will also be presented for patients with at 
least one dose reduced from the previous dose, and at least one dose interrupted, along with all associated reasons.
For Nivolumab the number and percentage of patients will also be presented for patients with at least one dose 
interrupted or delayed from the previous, and at least one infusion interrupted along with all associated reasons.
Information regarding patients’ dosing regimens will be listed separately for each investigational study drug.
11.1.7.2 Treatment Emergent Adverse Events (TEAEs)
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) v19.0 dictionary by 
SOC, PT, and severity grade using NCI CTCAE v4.03.
An overall summary of TEAEs will be presented, with supporting tables summarizing TEAEs by SOC and PT, as 
well as PT only. Counts will be presented by patient rather than event and those experiencing multiple instances of 
the same event will be counted only once within each SOC or PT.
The following summaries will be presented by SOC and PT for the Sitravatinib plus Nivolumab treatment arm, using 
the Safety Population, unless otherwise specified. 
x
Any TEAEs 
x
Any DLTs (DLT Evaluable Population)
x
Any Treatment-Related TEAEs
x
Any Nivolumab-Related TEAEs 
x
Any Sitravatinib-Related TEAEs
x
Any TEAE leading to dose reduction or interruption of either study drug
x
Any Treatment-Related TEAE leading to dose reduction or interruption of either study drug
x
Any TEAE leading to drug discontinuation of either study drug 
x
Any TEAE leading to Nivolumab discontinuation 
x
Any TEAE leading to Sitravatinib discontinuation
x
Any Treatment-Related TEAE leading to drug discontinuation of either study drug 
x
Any Nivolumab-Related TEAE leading to Nivolumab discontinuation 
x
Any Sitravatinib-Related TEAE leading to Sitravatinib discontinuation
x
Any TEAE leading to study discontinuation
x
Any TEAEs by Maximum CTCAE Grade
x
Any Treatment-Related TEAEs by Maximum CTCAE Grade
x
Any Nivolumab-Related TEAEs by Maximum CTCAE Grade
x
Any Sitravatiib-Related TEAEs by Maximum CTCAE Grade
x
Any irAEs


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x
Any AESIs (if at least one AESI is identified)
For the Glesatinib and Nivolumab treatment arm, a single summary table by SOC and PT will be presented. 
x
Any Glesatinib-Related TEAEs 
In addition to the SOC and PT summaries, the following summaries will also be presented by PT only for the 
Sitravatinib plus Nivolumab treatment arm 
x
Any TEAEs 
x
Any TEAEs by Maximum CTCAE Grade (Any Grade, Grade 3, Grade 4, Grade 5)
x
Any Treatment-Related TEAEs by Maximum CTCAE Grade (Any Grade, Grade 3, Grade 4, Grade 5)
x
Any Nivolumab-Related TEAEs by Maximum CTCAE Grade (Any Grade, Grade 3, Grade 4, Grade 5)
x
Any Sitravatinib-Related TEAEs by Maximum CTCAE Grade (Any Grade, Grade 3, Grade 4, Grade 5)
All TEAEs will be listed, separate listings for irAEs and TEAEs leading to study drug discontinuation (TEAEs and 
related TEAEs) will also be presented.
11.1.7.3 Serious Adverse Events (SAEs) and Deaths
The following summaries of treatment emergent SAEs, including TEAEs that lead to death, will be presented by 
SOC and PT for the Sitravatinib plus Nivolumab treatment arm, using the Safety Population:
x
Any Treatment-Emergent SAEs
x
Any Treatment-Related Treatment-Emergent SAEs
x
Any Nivolumab-Related Treatment-Emergent SAEs
x
Any Sitravatinib-Related Treatment-Emergent SAEs
x
Any TEAE with an outcome of death
In addition to the SOC and PT summaries, the following summaries will also be presented by PT only for the 
Sitravatinib plus Nivolumab treatment arm 
x
Any Treatment-Emergent SAEs 
x
Any Treatment-Related Treatment-Emergent SAEs 
All treatment emergent SAEs and TEAEs with an outcome of death will be listed.


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11.1.7.4 Laboratory Data
Laboratory data will be presented for hematology, chemistry, urinalysis and thyroid function tests (see Table 6 for 
a list of specific parameters under each category), by scheduled visit using the Safety Population for patients with 
at least 1 measurement for each parameter, regardless of whether or not a baseline assessment is present.
Unscheduled visits will be included in any presentation of minimum, maximum or worst case summaries across all 
cycles.
All laboratory data will be summarized in International System (SI) units, with selected chemistry parameters 
repeated using British imperial units commonly used in the United States. The conversion factors from conventional 
units to SI units are documented in the Lab Loader Specification (v1.0 October 13th 2020) for this study. 
Descriptive statistics will be provided for each parameter result and associated changes from baseline by cycle. 
Multiple measurements taken during a given visit for a patient will be represented by the most severe value for each 
parameter. Criteria for selecting the most severe value in these cases are described in the category specific sections 
below.
Shift tables for selected parameters will present shifts in CTCAE grades from baseline to each post-baseline 
scheduled visit, to the maximum post-baseline grade (including unscheduled visits), and to the last assessment.
All clinical laboratory results will be listed, with any laboratory values meeting NCI CTCAE Grade 3 or 4 criteria 
being listed separately.
CTCAE Coding of Laboratory Data
Grades are applied based only on the numeric SI value of the parameter assessed; clinical signs and symptoms 
are not considered. For example, Grade 4 hyperglycemia will be assigned based solely on the value of the glucose 
measurement, and acidosis will not be 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: 
x
Hematology:  hemoglobin, WBC, lymphocyte, neutrophils, and platelets.
x
Chemistry:  ALT, albumin, alkaline phosphatase, AST, total bilirubin, calcium, creatinine, 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.




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x
If the values are all within the normal range, select the value closest to the normal limit (in either direction) 
x
If at least one value is outside the normal range, select the value most distant from the normal limit (in either 
direction)
In the event that this algorithm does not allow for determining the most severe (e.g. a tie), select the first 
chronological value. 
Low values are considered the most severe for all hematology parameters, unless otherwise noted in Section 8.4.6
and the notation High or Low within Table 6.
Shift tables will present shifts in CTCAE grades from baseline for the following hematology parameters;
x
Hemoglobin (Anemia and Hemoglobin Increased), 
x
Neutrophils (Neutrophil Count Decreased), 
x
Platelets (Platelet Count Decreased)
x
Lymphocyte Count (Lymphocyte Count Decreased and Lymphocyte Count Increased)
Patients who develop a  Grade 3 toxicity will be also listed separately.
11.1.7.4.2 Chemistry 
Selected chemistry parameters will be repeated using British imperial units commonly used in the US, refer to 
Section 8.4.6 and the notation IU within Table 6.
If a patient has multiple measurements taken during the visit for a patient will be represented by the most severe 
value for each chemistry parameter. The most severe value will be determined using the following criteria;
High values are considered the most severe for all chemistry parameters, unless otherwise noted in Section 8.4.6
and the notation Low or High or Low within Table 6. The most severe value will be determined using the same criteria 
described for Hematology parameters, 
Shift tables will present shifts in CTCAE grades from baseline for the following selected chemistry parameters;
x
AST (AST Increased), 
x
ALT (ALT Increased), 
x
Creatinine (Creatinine Increased), 
x
Sodium (both Hyponatremia and Hypernatremia), 
x
Potassium (both Hypokalemia and Hyperkalemia),
x
Phosphate (Hypophosphatemia), 
x
Uric Acid (Hyperuricemia).
For parameters where separate grading criteria exists, all low values will be included in the Grade 0 group when 
summarizing high values as being most severe and vice versa (all high values will be included in the Grade 0 group 
when summarizing low values as being most severe).


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Patients who develop a Grade 3 toxicity will be also listed separately.
11.1.7.4.3 Hy’s Law
+HSDWLF IXQFWLRQ DEQRUPDOLW\ GHILQHG E\ DQ LQFUHDVH LQ $67 DQGRU $/7 WR  x ULN concurrent with an increase in 
WRWDO ELOLUXELQ WR  x ULN but without increase in alkaline phosphatase (i.e., alkaline phosphatase < 2x 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 set of evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) figures displaying patients who reach 3xULN 
for ALT or AST, plus 2x ULN for Total Bilirubin and thus, are at risk for a drug induced liver injury according to Hy’s 
law will be presented for all patients. A listing of patients at risk will also be presented.
11.1.7.4.4 Urinalysis
Urinalysis results for the parameters blood and protein will be listed only.
11.1.7.4.5 Thyroid
Results for TSH and Free-T4 will be listed only.
11.1.7.5 Vital Signs
The following vital signs will be summarized: pulse rate (bpm), systolic blood pressure (SBP; mmHg), diastolic blood 
pressure (DBP; mmHg), respiration rate (breaths/min), body temperature (C), and weight (kg). 
Vital signs and change from baseline will be summarized descriptively. All vital signs and change from baseline 
through the last Cycle will be summarized. In these tables, baseline will generally be the Cycle 1 Day 1 
measurement for all comparisons. This will include a summary of the minimum and maximum values observed 
while the patient was on treatment and change from baseline to that observed value.
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. 
Potentially clinically important (PCI) values will also be summarized based on the thresholds detail in the table 
below.
Vital Signs Parameter
PCI Thresholds
SBP
x
 160 mmHg 
x
 180 mmHg
x
 200 mmHg 
DBP
x
 100 mmHg
x
 120 mmHg
Weight
x
   5% increase from baseline
x
   10% decrease from baseline
All vital signs including baseline ECOG performance status will be listed.


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11.1.7.6 Physical Examinations, ECGs, and Other Observations Related to Safety
Physical Examination
Complete physical examinations will be conducted during screening and at the End of Treatment visit. Abbreviated 
physical examinations will be performed on Day 1 and Day 15 of all cycles. Any new abnormal physical exam 
findings will be collected as AEs. Physical Examination data will be listed for the Safety population.
Electrocardiogram
A summary of ECG parameters including heart rate (beats/min), QT interval (msec), QTcF (msec), PR (msec), QRS 
(msec) 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. 
Where triplicates of ECG parameters are collected, the values will be averaged before use in any analysis.
In addition, listings and summaries will be generated for patients by Maximum ICH E14 Category for absolute value 
(<450 msec, 4 WR  ! WR  PVHF DQG ! PVHF DQG FKDQJH IURP EDVHOLQH  PVHF ! WR 
msec and >60 msec). Patients with PR value >220 msec and change from baseline >25%, as well as patients with 
QRS >110 msec and change from baseline >25%, will also be summarized and presented in listings.
QTcF will be graded per CTCAE (v4.03). The grades are as follows:
x
Grade 0: QTcF <450 msec
x
Grade 1: QTcF 450 to 480 msec
x
Grade 2: QTcF >480 to 500 msec 
x
Grade 3: QTcF >500 or increase from baseline >60 msec
A shift from baseline to worst CTCAE grade summary will also be presented.
A separate listing of the ECG results along with the overall interpretation will be presented.
Echocardiogram 
Descriptive statistics of the observed values and changes from baseline will be presented for LVEF data from the 
echocardiogram or multigated acquisition (MUGA) scan at Screening, Cycle 3 Day 1 and end of treatment. 
Additionally, patients who have at least one on-treatment decrease will be summarized using the following 
categories: 
x
decrease from baseline of 10% and absolute on-treatment value 40%, 
x
decrease from baseline of 10% and absolute on-treatment value <40%,
x
decrease from baseline of 20% and absolute on-treatment value 40%, 
x
decrease from baseline of 20% and absolute on-treatment value <40%,
where on-treatment is defined as the period of time after the first dose of study treatment and not more than 
28 days after the last dose of study treatment and prior to the initiation of subsequent systemic anti-cancer 
therapy.
All echocardiogram results will be listed.




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Statistical Analysis Plan
Protocol no: MRTX-500
Version Date: 10-Jan-2022
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References
1.
Ji 2013: Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More Reliable Method 
than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol. 2013;31(14):1785-1791. 
doi:10.1200/JCO.2012.45.7903.
2.
Lee 2008: Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical Trials 
2008; 5: 93–106.
3.
Brookmeyer, R and Crowley, J. A confidence interval for mean survival time. Biometrics, 1982, 38, 29-41.
4.
Kalbfleisch, JD and Prentice, RL. The statistical analysis of time failure data. 1980, New York: John Wiley.
5.
NCI Common Terminology Criteria for Adverse Events (CTCAE) data files: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
6.
U.S. Department of Health and Human Services, FDA 2005: Guidance for Industry E14 Clinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs




Sponsor: Mirati Therapeutics, Inc
Statistical Analysis Plan
Protocol no: MRTX-500
Version Date: 10-Jan-2022
PRS 005 T 17 F
Page 44 of 44
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved.
NE
Not Evaluable
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
PCI
Potentially Clinically Important 
PD
Progressive Disease
PD-L1
Programmed Cell Death Ligand 1
PFS
Progression-Free Survival
PK
Pharmacokinetic
PR
Partial Response
PT
Preferred Term
PTT
Partial Thromboplastin Time
Q1
First Quartile
Q3
Third Quartile
QTcF
Fridericia’s corrected QT Interval
QxW
Every x Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Stable Disease
SI
International System
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