Clinical trial NCT02664181
Conditions: Lung Cancer Non-small Cell Lung Cancer
Keywords: Cancer Nivolumab Decitabine Tetrahydrouridine
Sponsor: Case Comprehensive Cancer Center
Start date: 2017-06-06; Completion date: 2024-05-19
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess whether treatment with the study drug tetrahydrouridine-decitabine (THU-Dec) in combination with nivolumab is more effective than treatment with nivolumab alone in patients with NSCLC.

Decitabine is an investigational (experimental) drug that works by depleting DNA methyltransferase 1 (DNMT1). DNMT1 is an enzyme, or protein that causes chemical changes, often increased in cancer. Blocking DNMT1 has been shown to reduce tumor formation. Decitabine is experimental in this study because it is not approved by the Food and Drug Administration (FDA) for patients with lung cancer. Decitabine is approved by the FDA for treating patients with a blood disease called myelodysplastic syndrome (MDS, a condition where the bone marrow does not make blood cells normally).

THU is an investigational (experimental) drug that works by blocking an enzyme that breaks down decitabine. This enzyme is highly expressed in solid tissues of the body, limiting the distribution of decitabine into these tissues, including solid cancer tissues. So, THU will increase the time cells are exposed to decitabine. The idea is that THU will also increase the time that the lung cancer cells are exposed to decitabine. THU is experimental because it is also not approved by the FDA, although it has been extensively used in clinical trials, including several cancer trials.

Detailed description:
Primary objective: To determine if non-cytotoxic oral THU-Dec when combined with nivolumab can improve objective response rates of nivolumab

Secondary objectives:

i) To evaluate clinical efficacy end points and toxicity of oral THU-Dec when combined with nivolumab ii) evaluate the induction of a T-cell response in patients with metastatic NSCLC iii) To evaluate hypotheses regarding mechanisms of resistance and predictive biomarkers for response to nivolumab

Study design: This is a Phase 2 randomized two arm trial of nivolumab alone or in combination with THU-Dec, in previously treated patients with stage IV Non-Small Cell Lung Cancer (NSCLC). The primary goal of this trial is to compare the efficacy of oral THU-Dec as a way of enhancing the anti-tumor immune response to nivolumab to that of nivolumab alone. The primary efficacy endpoint is overall RECIST-defined response. To accomplish this goal 60 patients will be randomized 2:1 to THU-Dec plus nivolumab or nivolumab only respectively.

Arms: arm 1: Oral THU \~10 mg/kg, followed by oral decitabine \~0.2 mg/kg 60 minutes after the THU, twice weekly on consecutive days. This drug combination is administered with Nivolumab 3mg/kg IV Q2 weeks until progression arm 2: Nivolumab 3mg/kg IV Q2 weeks until progression; This is the standard of care for patients with NSCLC who have progressed on prior chemotherapy.
Interventions: intervention 1: Nivolumab intervention 2: oral decitabine intervention 3: Tetrahydrouridine
Intervention descriptions: intervention 1: Nivolumab will be given at 3mg/kg by IV every two weeks until progression intervention 2: oral decitabine \~0.2 mg/kg 60 minutes after the THU, twice weekly on consecutive days. intervention 3: Oral THU \~10 mg/kg twice weekly on consecutive days

Protocol documents:
ICF_001.pdf: 
CASE 3516 
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CONSENT FOR CANCER RESEARCH 
Project Title:  CASE 3516:  Phase II Evaluation of Nivolumab, an Immune Checkpoint Inhibitor 
alone or in combination with Oral Decitabine/Tetrahydrouridine as Second Line Therapy for Non-
Small Cell Lung Cancer
Sponsor:  Yogen Saunthararajah, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, 
Cleveland, OH  44195
Principal Investigator(s):  Dr. Nathan Pennell  
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, 
University Hospitals and Case Western Reserve University (CWRU) through the NIH National 
Cancer Institute (NCI) designated Case Comprehensive Cancer Center (Case CCC).  The goal of 
this collaboration is to enhance cancer treatment and research in Northeast Ohio. This study is 
being offered at Cleveland Clinic (CC) and the National Institutes of Health (NIH). 
Conflict of Interest Disclosure  
Dr. Yogen Saunthararajah, the sponsor of this study and a Cleveland Clinic physician, is an 
inventor of the drug combination used in this study.  In the future, he may receive royalties for 
sales of that product.  He may benefit financially if this research is successful.  These financial 
interests are being managed and are within permissible limits established by the local 
institutional Conflict of Interest Policy.  If you have any questions regarding conflicts of interest, 
please ask you study doctor or call the Cleveland Clinic Institutional Review Board at (216) 444-
2924. 
What is the usual approach to my Non-Small Cell Lung Cancer (NSCLC)?
Current treatment options for non-small cell lung cancer that has worsened after initial platinum 
based chemotherapy include second-line treatment with immunotherapy drugs like Nivolumab. 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
 you may choose to have the usual approach described above 
 you may choose to take part in a different study, if one is available 
 or you may choose not to be treated for cancer. For example: comfort/palliative care 
Why is this study being done?
The purpose of this study is to assess whether treatment with the study drug tetrahydrouridine-
decitabine (THU-Dec) in combination with nivolumab is more effective than treatment with 
nivolumab alone in patients with NSCLC. 
Decitabine is an investigational (experimental) drug that works by depleting DNA 
methyltransferase 1 (DNMT1).  DNMT1 is an enzyme, or protein that causes chemical changes, 
often increased in cancer.  Blocking DNMT1 has been shown to reduce tumor formation. 
Decitabine is experimental in this study because it is not approved by the Food and Drug 
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019


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Administration (FDA) for patients with NSCLC.  Decitabine is approved by the FDA for treating 
patients with a blood disease called myelodysplastic syndrome (MDS, a condition where the 
bone marrow does not make blood cells normally).   
THU is an investigational (experimental) drug that works by blocking an enzyme that breaks 
down decitabine.  So, THU will increase the time cells in your body are exposed to decitabine. 
THU is experimental because it is also not approved by the FDA, although it has been 
extensively used in clinical trials, including several cancer trials. 
What are the study groups?  
This study has two study groups. Group 1 will receive THU-Dec in combination with nivolumab
and Group 2 will receive nivolumab alone. 
A process (called randomization) will be used to assign you, by chance (like pulling your name 
out of a hat), to one of the study groups. Neither you nor your doctor can choose which group 
you are in. This is done by chance because no one knows if one study group is better or worse 
than the other. 
How long will I be in this study? 
You will receive the nivolumab with or without THU-Dec until your disease progresses or the 
study stops. After you finish treatment, your doctor will continue to watch you for side effects 
and follow your condition every 12 weeks. The study doctor may review your medical records, 
or contact you or your medical provider; you do not have to come to the clinic every 12 weeks. 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there may be some extra procedures that you will need to have if you take part 
in this study.
Immunebiomarker tests determine if your body’s immune system is mounting a response to the 
study drug. At Cycle 1 Day 1, Cycle 2 Day 15, Cycle 4 Day 15, Cycle 6 Day 15, Cycle 8 Day 15, 
and the first day of every cycle after Cycle 9 about 60 mL (approximately 4 tablespoons) of 
blood will be drawn for research purposes. At screening, Cycle 3 Day 1, Cycle 5 Day 1, and 
Cycle 7 Day 1, 32 mL (approximately 2 tablespoons) of blood will be drawn for research 
purposes. About 92 mL (approximately 6 tablespoons) of blood will be drawn at the end of 
treatment. 
Randomize 
(A process will 
randomly put you in a 
study group) 
Group 2 
nivolumab 
You agree to 
take part in the 
study 
Group 1 
 THU-Dec + 
nivolumab 
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Expiration Date: 8/11/2019


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Research biopsies
Tumor biopsies will be done prior to study enrollment to check for a protein called PD-L1 (this 
is considered standard of care) however an additional research biopsy will be performed during 
Cycle 2 to help understand the effects of the drug on the tumor and the interaction with the 
immune system and to identify factors in the tumor that might influence tumors response or 
resistance to the drug. A tumor biopsy is the removal of a small piece of tumor using a needle 
biopsy typically using an ultrasound or a CT or a bronchoscope approach. 
An optional biopsy at the time of cancer progression may be requested; the purpose of this is to 
determine reasons why the treatment is not working. You will be given more information about 
this optional biopsy and an opportunity to indicate your preference for participation at the end of 
this consent form.
Before you begin the study: 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there may be some extra exams and procedures that you will need to have if 
you take part in this study 
Screening  
Exams and tests will be used to determine your ability to participate in this study, after you sign 
this informed consent form. All evaluations must be completed within 4 weeks before the first 
dose of study treatment. 
x
Informed Consent (signing this form) 
x
ECOG Performance Status (this describes how well you are functioning in your daily 
activities)
x
Height and Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature
x
Medical History  
x
Complete physical examination 
x
If you are a female who could become pregnant you will have a blood pregnancy test. 
x
Blood samples will be collected for safety and diagnostic tests. 
x
Tissue samples will be collected from a tumor biopsy 
x
CT scan of the chest, abdomen, and pelvis to measure the disease in your body. Magnetic 
Resonance Imaging (MRI) is also acceptable.
During the study the following will be additional research procedures: 
If these tests show that you are eligible and you agree to participate in the study, you will come 
to the clinic for procedures described in the schedule of study visits and assessments listed 
below: 
Treatment Period 
x
Treatment cycles are 28 days long.  If you are randomized to Group 1 (THU-Dec + 
nivolumab), you will be asked to take your study medication two days in a row each 
week.  On treatment dosing days, you should take your required number of THU oral 
capsules with or without food (as you wish).  Then 60 minutes later, you should take your 
required number of Decitabine oral capsules with or without food (as you wish).  A 
member of your study team will provide you with a diary to keep track of the days you 
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take your study medication.  Please bring this diary with you to all scheduled 
appointments.  
Cycle 1 Day 1 
x
ECOG Performance Status
x
Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature
x
Directed physical examination 
x
Blood samples will be collected for safety and diagnostic tests. 
x
We will ask you about any side effects you may be having.  
x
Start treatment
Odd Cycles (1, 3, 5, etc) Day 15 
x
ECOG Performance Status
x
Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature
x
Directed physical examination 
x
Blood samples will be collected for safety and diagnostic tests. 
x
We will ask you about any side effects you may be having.  
x
Continue treatment
Cycle 2 Day 1 
x
ECOG Performance Status
x
Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature 
x
Directed physical examination 
x
Blood samples will be collected for safety and diagnostic tests. 
x
Collection of tissue samples from a biopsy. 
x
We will ask you about any side effects you may be having.  
x
Continue treatment
Even Cycles (2, 4, 6, etc) Day 15 
x
ECOG Performance Status
x
Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature
x
Directed physical examination 
x
Blood samples will be collected for safety and diagnostic tests. 
x
Blood samples will be collected for research purposes 
x
We will ask you about any side effects you may be having.  
x
Continue treatment
Odd Cycles (3, 5, 7, etc) Day 1 
x
ECOG Performance Status
x
Weight 
x
Vital signs including: blood pressure, pulse, respiratory rate and temperature 
x
Directed physical examination 
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x
Blood samples will be collected for safety and diagnostic tests. 
x
Blood samples will be drawn for research purposes 
x
CT scan of the chest, abdomen, and pelvis to measure the disease in your body Magnetic 
Resonance Imaging (MRI) is also acceptable
x
We will ask you about any side effects you may be having.  
x
Continue treatment
If your disease worsens or you no longer tolerate treatment, your treatment will be discontinued.  
If your disease progresses while you are on this study, you will be asked to have the following 
assessments 
x
Blood samples will be collected for research purposes 
x
Directed physical examination   
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
 You may lose time at work or home and spend more time in the hospital or doctor’s office 
than usual 
 You may be asked sensitive or private questions which you normally do not discuss 
 The study drug may not be better, and could possibly be worse, than the usual approach for 
your cancer. 
The drugs used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 

The study doctors do not know who will or will not have side effects. 

Some side effects may go away soon, some may last a long time, or some may never go 
away. 

Some side effects may interfere with your ability to have children. 

Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 

The study doctor may be able to treat some side effects. 

The study doctor may adjust the study drugs to try to reduce side effects. 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
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Expiration Date: 8/11/2019


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The possible side effects of decitabine listed below. 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving decitabine, more than 20 and up to 100 may have:

Slight decrease in the number of white cells (blood cells that fight infection) 

Slight increase in the number of platelets (blood cells that form blood clots)

Testicular toxicity.  Studies in animals suggest an effect on sperm counts even with low 
doses of decitabine.  This toxicity appears reversible. 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving decitabine, from 4 to 20 may have: 

Moderate decrease in the number of white cells (blood cells that fight infection) 

Moderate decrease in the number of platelets (blood cells that help blood to clot) 

Nausea 

Changes in bowel habits (diarrhea or constipation) 
RARE, SOME MAY BE SERIOUS 
In 100 people receiving decitabine, 3 or fewer may have:

Infection.  We will monitor your blood counts to avoid too low white cell counts; 
however, it is possible that an infection could result from a decreased white cell count.

Blood clots. We anticipate that your platelet count will increase with treatment.  
Platelets normally form blood clots when there is injury to prevent excessive bleeding.  
We do not think that this elevated platelet count will cause a blood clot inside your 
body, but this is a possibility that we cannot rule out. 

DNA alteration.  In test tubes, decitabine, like other chemotherapy drugs, sometimes 
alters the DNA (genetic roadmap) of cells.  In theory, these changes have the rare 
possibility of leading to cancer. 

Allergic reaction. Some people have allergic reactions to decitabine.  If you have a 
very bad allergic reaction, you could die.  Some things that happen during an allergic 
reaction that could be a sign or symptom of a life-threatening allergic reaction 
(anaphylaxis) are: 
o
a rash 
o
hives 
o
having a hard time breathing 
o
wheezing when you breathe 
o
a sudden drop in blood pressure (making you feel dizzy or lightheaded) 
o
swelling around the face, mouth, lips, tongue, throat, or eyes 
o
a fast pulse 
o
sweating
Possible side effects of tetrahydrouridine 
There have been no risks or side effects identified with tetrahydrouridine by itself.  It has been 
used in other clinical studies in combination with other anti-cancer drugs, and no specific risks of 
tetrahydrouridine have been identified. 
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When tetrahydrouridine is taken together with other drugs, the risks resemble having more of the 
other drug it is being given with.  In other words, the risks from taking tetrahydrouridine together 
with decitabine are the risks that would be expected from taking a higher amount of decitabine. 
Possible side effects of nivolumab, which is the usual approach for this type of cancer: 
VERY COMMON, SOME MAY BE SERIOUS 
In 100 people receiving nivolumab, more than 10 may have:

Fatigue  

Rash 
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COMMON, AND SERIOUS 
In 100 people receiving nivolumab, more than 1 and up to 10 may have:
x
Abdominal pain 
x
Alkaline phosphatase increased: lab test result associated with liver or bone 
abnormalities 
x
ALT increased: lab test result associated with abnormal liver function 
x
Amylase increased: lab test result associated with pancreas inflammation 
x
AST increased: lab test result associated with abnormal liver function 
x
Chills 
x
Constipation 
x
Cough 
x
Creatinine increased: lab test result associated with decreased kidney function 
x
Decreased appetite 
x
Diarrhea 
x
Dry mouth 
x
Dry skin 
x
Fever 
x
Headache 
x
Lipase increased: lab test result associated with pancreas inflammation  
x
Inflammation of the colon 
x
Inflammation of the mouth 
x
Infusion related reaction 
x
Itching 
x
Joint pain or stiffness 
x
Loss of color (pigment) from areas of skin 
x
Lung inflammation (pneumonitis - see details below) 
x
Musculoskeletal pain 
x
Nausea 
x
Shortness of breath 
x
Swelling, including face, arms, and legs 
x
Thyroid gland function decreased 
x
Thyroid gland function increased 
x
Thyroid stimulating hormone increased: lab test result associated with abnormal 
thyroid function 
x
Tingling, burning, numbness or weakness, possibly in arms, legs, hands and feet 
x
Vomiting 
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UNCOMMON, AND SERIOUS 
As few as 1 in 1000 people to as many as 1 in 100 people receiving nivolumab may have:
x
Adrenal gland function decreased 
x
Allergic reaction 
x
Bilirubin (liver function blood test) increased 
x
Bronchitis 
x
Cranial nerve disorder 
x
Diabetes 
x
Dizziness 
x
Dry eye 
x
Hair loss 
x
Heart rate increased 
x
Heart rhythm abnormal 
x
High blood pressure 
x
Hives 
x
Increased blood sugar 
x
Inflammation of the eye 
x
Inflammation of the heart 
x
Inflammation of the kidney 
x
Inflammation of the pancreas 
x
Inflammation of the pituitary gland 
x
Inflammation of the stomach 
x
Inflammation of the thyroid gland 
x
Liver inflammation 
x
Low blood pressure 
x
Pituitary gland function decreased 
x
Psoriasis: characterized by patches of abnormal, scaly skin 
x
Redness 
x
Renal failure 
x
Respiratory failure 
x
Sodium levels in blood low 
x
Upper respiratory tract infection 
x
Vertigo 
x
Vision blurred 
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RARE, AND SERIOUS 
As few as 1 in 10,000 people to as many as 1 in 1000 people receiving nivolumab may have:
x
Anaphylactic reaction (severe allergic reaction) 
x
Damage to the protective covering of the nerves in the brain and spinal cord 
x
Diabetes complications resulting in excess blood acids and diabetic coma 
x
Erythema multiforme: skin inflammatory reaction  
x
Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle 
weakness or paralysis  
x
Inflammation of blood vessels 
x
Inflammation of the brain, potentially life-threatening or fatal 
x
Lung infiltrates, associated with infection or inflammation 
x
Muscle inflammation 
x
Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) 
including myasthenia gravis, a nerve disease that may cause weakness of eye, face, 
breathing, and swallowing muscles. 
x
Polymyalgia rheumatica, an inflammatory disorder causing muscle pain and stiffness 
x
Rhabdomyolysis: muscle fiber released into the blood stream which could damage 
your kidneys 
x
Rosacea: acne-like skin condition resulting in redness of face 
x
Sarcoidosis, a disease involving abnormal collections of inflammatory cells 
(granulomas) in organs such as lungs, skin, and lymph nodes 
x
Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes, 
resulting in blistering and shedding of skin 
x
Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and 
peeling of the top layer of skin resembling a severe burn 
x
Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the 
lymph nodes which causes the lymph nodes to become enlarged, inflamed and 
painful, commonly affecting lymph nodes of the neck and possibly associated with 
fever or muscle and joint pains.  
Lung Inflammation (pneumonitis):  It is possible that nivolumab may cause inflammation of the 
tissues of the lung.  This adverse effect has been reported infrequently in patients treated with 
nivolumab.  While many patients with x-ray or CT abnormalities have not developed any 
symptoms, some patients have developed mild to severe symptoms and in rare cases, death has 
occurred as a result of their lung inflammation.  Signs and symptoms of lung inflammation may 
include difficulty breathing, pain or discomfort while breathing, chest pain, cough, shortness of 
breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.   
Potential Risk or Discomfort from Research Procedures 
Blood Draws 
The insertion of the needle to draw blood is painful; however, the discomfort is usually brief.  
For most people, needle punctures to get blood samples do not cause any serious problems; 
however, they may cause bleeding, bruising, discomfort, infections, dizziness, or fainting. 
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Biopsies 
Risks associated with biopsies include pain, redness, swelling, low blood pressure, 
excessive bleeding, bruising, or draining at the needle site, abnormal wound healing, fever, 
infection, and allergic reaction to the medication used to numb the skin over the biopsy site. Two 
to 3% of patients require hospitalization after a tumor biopsy. Rarely, an infection can occur. 
Your doctor will determine the safest way of the biopsy. The procedure will be done using local 
anesthesia or sedation to minimize discomfort from the biopsy. The specific risks of the biopsy 
depend on the location and the type of biopsy and will be discussed by the physician performing 
the procedure. 
Risks specifically associated with lung biopsy are pneumothorax (collapse of lung), air embolus 
(air in a blood vessel), hemopericardium (blood around the heart), and lung torsion (twisting that 
interrupts the blood supply to the lung). Sometimes you might cough up blood. 
Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
Reproductive risks:  
THU-Dec 
You should not get pregnant, breastfeed, or father a baby while in this study. The THU-Dec used 
in this study could be very damaging to an unborn baby.  Decitabine caused harmful effects to 
offspring of exposed pregnant animals, although, the effects of decitabine to human mothers and 
their babies during pregnancy or breast feeding have not been formally studied. Since decitabine 
may affect the behavior of DNA in actively dividing cells, including the developing fetus, birth-
control is necessary for the participants in this study and their partners. Taking decitabine may 
also involve unknown risks to a man or woman's ability to father a child or to become pregnant 
in the future. 
Female Participants 
Participating in this research may involve risks to pregnant women and/ or an unborn 
baby which are currently unforeseeable.  To protect against possible side effects of the 
study drug, if you are pregnant or nursing a child you may not take part in this study.  If 
you think that you have become pregnant during the study, you must tell the doctor 
immediately.  If you become pregnant, your participation will be stopped. 
If you are a female and you have child bearing potential, then you must agree to take 
important actions to avoid pregnancy during the study, from the time of agreeing to 
participate in this study by signing this informed consent form and during the duration of 
the study.  
These actions are either:  
x
Not having heterosexual sexual contact beginning at the screening visit and 
continuing until 4 weeks after the last dose of decitabine/THU OR  
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x
Using TWO (2) methods of birth control beginning at the screening visit and 
continuing until 4 weeks after the last dose of decitabine/THU: 
o
One birth control method must be highly effective, such as an Intrauterine 
Device (IUD), birth control pills, depo-provera (medroxyprogesterone acetate) 
injections, or tying of the fallopian tubes. 
o
The other additional effective birth control method can be use of a diaphragm 
or a condom by the male partner.   
These steps must be taken even if you have a history of infertility, unless you have had a 
hysterectomy or have not had periods for at least 24 months. 
Male Participants
Because decitabine has unknown effects to semen, you must agree to use a latex condom 
when engaging in any sexual contact with a woman of child-bearing age even if you have 
had a successful vasectomy. 
Nivolumab 
You must not be pregnant or breastfeeding, and you should not become pregnant or breastfeed 
while you are taking the study treatments. Females should not breastfeed while receiving 
nivolumab and up to 5 months from the last dose of nivolumab. You must use an adequate 
method to avoid pregnancy for the duration of this study and for up to 5 months after the last 
dose of study drug. Male subjects who are sexually active with a woman of child bearing 
potential should also use an adequate method of birth control to avoid pregnancy of their partner 
for up to 7 months after the last dose of nivolumab. You should immediately contact your study 
doctor if there is a change in your method to avoid pregnancy or if you start any prescription 
drug or other medication (including over-the-counter drugs and herbal supplements) not 
prescribed by the study doctor.  
If you become pregnant, your participation will be stopped. 
There may be unknown risks to you, your unborn baby or nursing infant if you are or become 
pregnant during this study or are breastfeeding during this study. 
The use of nivolumab in pregnant women has not been formally studied in clinical studies. 
One case has been identified of a nivolumab treated male patient with a female partner who 
became pregnant. The pregnancy was uneventful and at birth, the infant was slightly 
underweight. 
In case of a pregnancy, your pregnancy and its outcome will be reported to the 
investigator/Sponsor and to Bristol-Myers Squibb. 
You are asked to inform your study doctor if your partner becomes pregnant while you are 
enrolled in this clinical trial, and you and your partner will be asked to provide information about 
the pregnancy outcome.  
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What possible benefits can I expect from taking part in this study? 
We cannot know if you will have any benefit as a result of your participation in the study; it is 
possible the study treatment may improve your cancer, which may give you relief from some 
symptoms, improve your quality of life or prolong your survival. However, it is possible that 
your condition could worsen.  Your participation in this study will help to obtain information 
about treating subjects with NSCLC. 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
The study doctor may take you out of the study: 

If your health changes and the study is no longer in your best interest 

If new information becomes available 

If you do not follow the study requirements 

If the study is stopped by the sponsor, Institutional Review Board (IRB) or FDA. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights.  
What are the costs of taking part in this study? 
Your involvement in this research study is voluntary and you will not be paid for your 
participation. 
The study agent, THU-Dec, will be provided free of charge by the study sponsor while you are 
participating in this study.  Neither you nor your insurance provider will be responsible for the 
costs of any research-only tests or procedures.  The blood work for research purposes will not be 
charged to you.  It will be paid for by the research study.  Neither you nor your health care 
plan/insurance carrier will be billed for the collection of the tissue that will be used for this study. 
Nivolumab will be supplied by Bristol Myers-Squibb for this study at no cost to you. 
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study (i.e., medical history, review of medications, physical exams, 
performance status, routine blood tests, pregnancy test, x-rays and/or scans for tumor 
measurement). Some health plans will not pay these costs for people taking part in studies. 
Check with your health plan or insurance company to find out what they will pay for. Taking 
part in this study may or may not cost your insurance company more than the cost of getting 
regular cancer treatment.  
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019


CASE 3516 
Consent version date:  August 10, 2018 
14 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout.
What happens if I am injured or hurt because I took part in this study? 
If you believe that you are injured as a result of the research procedures being performed, please 
immediately contact the study doctor. 
If injury occurs as a result of your involvement in this research, medical treatment is available 
from Cleveland Clinic or another medical facility but you/your medical insurance will be 
responsible for the cost of this treatment.  A research injury is an injury that happens as a result 
of taking part in this research study.  If you are injured by a medical treatment or procedure that 
you would have received even if you weren’t in the study, that is not considered a “research 
injury”. There are no plans for payment of medical expenses or other payments, including lost 
wages, for any research related injury.  To help avoid injury, it is very important to follow all 
study directions. 
Further information about research-related injuries is available by contacting the Cleveland 
Clinic Institutional Review Board at (216) 444-2924. 
Optional Biopsy at Disease Progression  
If you choose to take part in this study and your disease progresses, you will be asked to have an 
additional, optional biopsy.  This biopsy will be done to look at the progressing cancer tumor 
tissue more closely.  Researchers hope this kind of procedure might one day be used to identify 
which patients are best suited for which cancer treatments by learning more about what happens 
to growing tumors after treatment with nivolumab with or without THU-Dec. The use of this 
tissue is still being tested and researchers do not know how accurate or useful it is. 
The results of the biopsy would only be used for research and not to guide your medical care. 
I agree to allow the biopsy at disease progression. 
Yes
No
Initials
HIPAA AUTHORIZATION 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a 
Research Study  
If you volunteer to participate in this research, your protected health information (PHI) that 
identifies you will be used or disclosed to Nathan Pennell, MD, PhD and the research study staff 
at Cleveland Clinic for the purposes of this research and to Case Western Reserve University for 
administration. 
The PHI that we may use or disclose (release) for this research may include your name, address, 
phone number, date of birth, Social Security number, information from your medical record, lab 
tests, or certain information relating to your health or condition.. 
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019


CASE 3516 
Consent version date:  August 10, 2018 
15 
Some of the tests and procedures done solely for this research study may also be placed in your 
medical record so other doctors know you are in this study.  Upon completion of the study, you 
may have access to the research information that is contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be looked at by 
other groups involved with the study such as the Cleveland Clinic Institutional Review Board, 
and the Case Comprehensive Cancer Center Protocol Review and Monitoring Committee.  Your 
PHI may also be used by and/or disclosed (released) to: 

Dr. Yogen Saunthararajah, study monitors and representatives 

Dr. Yogen Saunthararajah’s collaborators and licensees 

Case Comprehensive Cancer Center members and collaborators 

The Food and Drug Administration; 

The Department of Health and Human Services; 

The National Cancer Institute (NCI); 

Other Institutional Review Boards;  

Data Safety and Monitoring Boards

Bristol Myers-Squibb
Once your personal health information is released it may be re-disclosed and no longer protected 
by privacy laws. 
Your research information may be used and disclosed indefinitely, but you may stop these uses 
and disclosures at any time by writing to: 
Nathan Pennell, MD, PhD 
Case Comprehensive Cancer Center 
Cleveland Clinic 
9500 Euclid Ave. 
Cleveland, OH 44195 
Your participation in the research will stop, but any information previously recorded about you 
cannot be removed from the records and will continue to be used as part of this research.  Also, 
information already disclosed outside the Cleveland Clinic cannot be retrieved.  This will not 
affect your rights to treatment or benefits outside the research study.    
The Cleveland Clinic will not use your information collected in this study for another research 
purpose without your written permission; unless the Cleveland Clinic Institutional Review Board 
(IRB) assures your privacy and confidentiality is protected.  The IRB is a committee whose job it 
is to protect the safety and welfare of research subjects. 
By signing this informed consent form, you are authorizing such access to your research and 
medical record information.  If you choose not to sign this consent form, you will not be able to 
participate in this research study.  This Authorization does not have an expiration date. 
Voluntary Participation 
Your participation in this research study is voluntary. Choosing not to participate will not alter 
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019


CASE 3516 
Consent version date:  August 10, 2018 
16 
your usual health care or involve any penalty or loss of benefits to which you are otherwise 
entitled. If you decide to join the study, you may withdraw at any time and for any reason 
without penalty or loss of benefits. If information generated from this study is published or 
presented, your identity will not be revealed.   
In the event new information becomes available that may affect the risks or benefits associated 
with this study or your willingness to participate in it, you will be notified so that you can decide 
whether or not to continue participating.   
Questions about the Research 
If you have any questions, you can ask the Principal Investigator and/or research staff at (216) 
444-8665. 
Emergency or after-hours contact information  
If you are a Cleveland Clinic patient, you should contact the page operator at (216) 444-2200 or 
toll free at (800) 223-2273, and ask for the oncologist (cancer doctor) that is on call. 
Where Can I Get More Information? 
If the researchers cannot be reached, or if you would like to talk to someone other than the 
researcher(s) about: concerns regarding the study, research participant’s rights; research-related 
injury; or other human subjects issues, you may contact the Institutional Review Board (IRB) at 
Cleveland Clinic IRB 216-444-2924.  
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237)  
You may also visit the NCI Web site at http://cancer.gov/ 

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.   
US National Institutes of Health (NIH) Clinical Trial Database:
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, if 
applicable, as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019


CASE 3516 
Consent version date:  August 10, 2018 
17 
Signature 
Signing below indicates that you have been informed about the research study in which you 
voluntarily agree to participate; that you have asked any questions about the study that you may 
have; and that the information given to you has permitted you to make a fully informed and free 
decision about your participation in the study.  By signing this consent form, you do not waive 
any legal rights, and the investigator(s) or sponsor(s) are not relieved of any liability they may 
have.  A copy of this consent form will be provided to you. 
Signature of Participant 
 
 
Date 
 
 
Printed Name of Participant 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. 
Signature of Person Obtaining Consent 
 
Date 
 
 
 
Printed Name of Person Obtaining Consent 
CCF IRB #: 16-986
Approval Date: 8/29/2018
Expiration Date: 8/11/2019

Prot_SAP_002.pdf: 
CASE 3516  
 
Page 1  
 
 
Version date: 9/7/2018 
 
 
 
 
 
 
 
 
 
 
STUDY NUMBER: CASE 3516 
 
Protocol Date:  August 10, 2018  
 
OFFICIAL TITLE:  Phase II Evaluation of Nivolumab, an Immune Checkpoint Inhibitor, 
alone or in combination with Oral Decitabine/Tetrahydrouridine as Second Line 
Therapy for Non-Small Cell Lung Cancer 
 
Abbreviated Title: Pharmacologically Rational EpigenetiC Immunotherapy for SEcond 
line Therapy in patients with Non-Small Cell Lung Cancer: PRECISE trial 
 
NCI Number:  NCT02664181 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
Nathan Pennell, MD, PhD 
Case Comprehensive Cancer Center / Cleveland Clinic  
Taussig Cancer Institute 
 
9500 Euclid Avenue  
 
 
 
Cleveland, OH 44195 
 
  
 
PRINCIPAL INVESTIGATOR 
National Cancer Institute 
David S. Schrump, MD 
10 Center Drive 
Room 4-3942 
Bethesda, MD 20892-1202 
 
  
 
CO- INVESTIGATORS: 
 
 
James Stevenson, MD, Cleveland Clinic, Cleveland, OH 
Marc Shapiro, MD, Cleveland Clinic, Cleveland, OH 
 
Trial Pathologist: 
Sanjay Mukhopadhyay, MD, Cleveland Clinic, Cleveland, OH 


CASE 3516  
 
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Version date: 9/7/2018 
 
 
STATISTICIAN: 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
STUDY COORDINATOR: Ben Pannell 
 
SPONSOR:   
 
Case Comprehensive Cancer Center; 
Yogen Saunthararajah, MD, Cleveland Clinic, Cleveland, OH 
 
 
 
 
 
 
SUPPORT/FUNDING: 
Cleveland Clinic Taussig Cancer Institute, National Cancer 
Institute, American Society of Clinical Oncology 
 
SUPPLIED AGENT(S): 
Oral THU-decitabine, Nivolumab 
 
IND #:  
 
 
 
 
 
 
 
OTHER AGENT(S):  
NA 
 


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SUMMARY OF CHANGES 
 
 
Protocol Date 
Change 
Reason 
05/31/2016 
Removed option for 
crossover of patients in 
control arm 
Per request from NCI co-investigators and 
study sponsor 
05/31/2016 
Updated statistics section 
Incorporating comments from study sponsor 
and co-investigators 
05/31/2016 
Study calendars updated to 
reflect the correlative blood 
collections accurately 
For clarity on time points for blood collection 
05/31/2016 
Updated safety reporting 
section 
Administrative per Sponsor request 
05/31/2016 
Clarified WOCB age and 
requirements 
for 
contraception 
Administrative per Sponsor request  
05/31/2016 
Clarification on days of 
administration of THU-dec 
in treatment plan 
Minor clarification on treatment plan 
05/31/2016 
Adverse event definitions 
updated and clarified 
Per sponsor request 
05/31/2016 
Nivolumab (standard of 
care) product information 
included  
Per sponsor request 
05/31/2016 
Section 12.8, patients 
beyond cycle 8 continue to 
have CT scans every 2 
cycles i.e. 8 weeks; option 
of doing scans every 12 
weeks per investigator is 
now removed. 
Per 
recommendations 
from 
NCI 
co-
investigators 
 
 
 
08/25/2016 
Section 13.1, adding 
language regarding use of 
Overture 
Per sponsor request 
 
 
 
03/31/2017 
Including response 
information, clarifying 
safety parameters, 
updating calendar, 
updating treatment plan 
and other administrative 
changes throughout 
document 
Per recommendations from Taussig Cancer 
Center Quality Assurance 


CASE 3516  
 
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Version date: 9/7/2018 
 
03/31/2017 
Sections 6.1 and 9.3, 
Nivolumab will be given 
as a flat 240 mg dose 
Per recommendations from Taussig Cancer 
Center Quality Assurance; the flat dose is 
standard of care 
 
 
 
7/24/2017 
Sections 4.1 and 4.2, 
updating inclusion and 
exclusion criteria 
Clarification of inclusion criteria regarding 
pre-study biopsies and exclusion criteria 
regarding cardiac events, organ function, 
prior malignancy, and autoimmune disease 
7/24/2017 
Section 10.0, study 
calendar updated to clarify 
frequency of thyroid 
assessments 
Calendar updated to more clearly indicate that 
thyroid assessment only need to be performed 
on Day 1 of applicable cycles 
 
 
 
02/02/2018 
9.1.3 Method of 
Administration 
 
- Starting dose of oral THU and Dec is by 
weight (all subsequent doses are based on the 
Cycle 1 Day 1 dose with dose modifications 
based on toxicities and tumor response as 
described in the protocol): 
02/02/2018 
3.4 Expected Duration of 
Treatment and Subject 
Participation 
Clarified the duration of treatment and the 
assessment of response and treatment beyond 
progression based on clinical benefit. 
02/02/2018 
4.1 inclusion criteria 
Clarified “systemic therapy” criteria 
Clarified “biopsy requirement criteria and 
exception” 
Clarified brain met inclusion criteria 
02/02/2018 
4.2 Exclusion criteria 
Clarified language on additional malignancies 
 
02/02/2018 
6.0 Treatment plan 
Clarified dose reduction criteria and the 
weight based dosing.  
02/02/2018 
6.23 General Concomitant 
Medications 
Clarified the use of radiation on trial. 
02/02/2018 
6.34 Discontinuation of 
Subjects from treatment 
Clarified the disease progression and criteria 
for continuation of treatment for patients with 
clinical benefit. 
02/02/2018 
7.1 Dose reduction  
Criteria for dose reduction and use of growth 
factors clarified 
02/02/2018 
8.2.1 Adverse event 
AE reporting process clarified 
02/02/2018 
12.0 Measurement of 
Effect 
Clarified evaluation of response criteria 
 
 
 
9/7/2018 
Removing Dr. Vamsidhar 
Velcheti as PI. Adding Dr. 
Nathan Pennell as PI. 
Dr. Velcheti leaving CCF. 
9/7/2018 
Changing coordinator to 
Ben Pannell 
Study was transitioned to new coordinator 


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STUDY SCHEMA 
 
   
 
 


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 PROTOCOL SUMMARY  
 
Official Title: Phase II Evaluation of Nivolumab, an Immune Checkpoint Inhibitor, alone or 
in combination with Oral Decitabine/Tetrahydrouridine as Second Line Therapy for Non-
Small Cell Lung Cancer 
Number/Title: Case 3516 Pharmacologically Rational EpigenetiC Immunotherapy for 
SEcond  line Therapy in patients with Non-Small Cell Lung Cancer: PRECISE trial  
Study Phase: Phase II 
Principal Investigator:  Nathan Pennell, MD, PhD 
IND Holder:  Yogen Saunthararajah, MD; IND # 112,914 
Rationale/Hypothesis/Objective: Lung cancer is the world’s leading cause of cancer death. 1st-
line platinum-based cytotoxic (p53-dependent) chemotherapy for advanced non-small cell lung 
cancer (NSCLC) produces transient responses at best, possibly because p53-system 
mutation/deletion is universal in NSCLC and metastatic disease2-10. A recent landmark development 
has been approval of the immune checkpoint inhibitor (anti-PD-1) nivolumab in 2nd-line for 
NSCLC. Unfortunately, the objective response rate to nivolumab is only ~20%. A key factor 
underlying this limited response is use by cancer cells of altered epigenetics to suppress neo-antigen 
expression and avoid immune-recognition (reviewed in1). As such, we and several other groups 
have conducted clinical trials adding inhibitors of epigenetic repression to immunotherapy. The 
major class of epigenetic drugs in these trials are the DNA methyltransferase (DNMT1)-depletors 
(5-azacytidine, decitabine). DNMT1-depletion is appealing beyond immuno-modulatory effects 
because we and others have validated DNMT1 as a molecular target that cytoreduces NSCLC11-16 
and other cancers directly by p53-independent mechanisms (via upregulation of p27/CDKN1B)11-
13,15-22, offering a true alternative to cytotoxic chemotherapy.  
Unfortunately, 5-azacytidine and decitabine (Dec) have fundamental pharmacologic 
limitations that have impeded translation of the compelling pre-clinical science: although it is 
possible to separate DNMT1-depletion by Dec from anti-metabolite effects/cytotoxicity that would 
suppress immune-effectors, plasma t½ is <15 minutes and solid tissue distribution/oral 
bioavailability is negligible, because of rapid deamination/inactivation by the enzyme cytidine 
deaminase (CDA)23,24. This is a severe limitation because the DNMT1-depletion is S-phase, and 
hence exposure time, dependent. We recognized that this pharmacology was undermining clinical 
translation after conducting clinical trials with Dec alone21,25. Therefore, we combined very low 
doses of oral Dec with an inhibitor of CDA, tetrahydrouridine (THU) and showed in a Phase 1 
clinical trial (IND#112,914, NCT#01685515) that the combination solves the oral 
bioavailability/solid-tissue-distribution problems, producing Dec low Cmax/multi-hour Tmax (>1 log-
improvement) needed for non-cytotoxic DNMT1-depletion in solid tissues26-28. Thus, the 
hypothesis driving this clinical trial is: Oral THU-Dec overcomes pharmacologic limitations of Dec 
alone to deplete DNMT1 within solid tumors to the extent necessary to increase the proportion of 
patients who benefit from FDA-approved immunotherapy.  
Study Design: This is a randomized two arm phase II trial of nivolumab alone or in combination 
with THU-Dec, in previously treated patients with stage IV NSCLC. The primary goal of this trial 
is to compare the efficacy of THU-Dec as a way of enhancing the anti-tumor immune response to 
nivolumab to that of nivolumab alone. Patients will be randomized 2:1 favoring the treatment arm 
with THU-Dec.  
Sample Size: 60  patients  


CASE 3516  
 
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Version date: 9/7/2018 
 
Primary objective: To determine if non-cytotoxic oral THU-Dec when combined with 
nivolumab can improve objective response rates of nivolumab  
Secondary objectives: (i) To evaluate clinical efficacy end points and toxicity of oral THU-Dec 
when combined with nivolumab; (ii) evaluate the induction of a T-cell response in patients with 
metastatic NSCLC; (iii) To evaluate hypotheses regarding mechanisms of resistance and 
predictive biomarkers for response to nivolumab 
Criteria for Evaluation:  
-Primary end-point:  
1. Objective response by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)  
-Secondary endpoints/scientific correlates:  
1. To determine the progression-free and overall survival in patients with NSCLC receiving 
nivolumab with and without THU-Dec 
2. To determine the safety and toxicity of the combination of THU-Dec and Nivolumab 
3. To examine potential predictive biomarkers in tumor samples and peripheral blood  
4. To evaluate the induction of a T-cell response in patients with metastatic NSCLC treated with 
THU-Dec 
5. Molecular pharmacodynamics by immunohistochemical and flow cytometric assessment of 
DNMT1-protein in tumor tissue (where feasible) and peripheral blood buffy coat cells 
respectively, and by measurement of plasma CDA enzyme activity by HPLC enzyme assay 
6. QRT-PCR evaluation of DCK, UCK2, CDA and KI67 in baseline and post treatment tissue 
where feasible  
Study Population: Histologically confirmed metastatic NSCLC; progression of disease on one 
prior line of systemic therapy; measurable disease per RECIST v1.1; ECOG performance status 0-
2. 
Treatment: Patients will receive study drugs as follows:  
Nivolumab 240mg IV Q2 weeks until progression per RECIST v1.1; This is the standard of 
care for patients with NSCLC who have progressed on prior chemotherapy. 
With or without 
Oral tetrahydrouridine and decitabine: THU is supplied as 250 mg/capsule, Dec as 5 
mg/capsule. 
- Starting dose of oral THU-Dec is by weight (all subsequent doses are based on the Cycle 
1 Day 1 dose with dose modifications based on toxicities and tumor response as described 
in the protocol): 
Weight 40-60kg = 2 capsules of each drug. Dec capsules are ingested ~60 minutes after THU 
capsules. Weight 61-80kg = 3 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. Weight 81-100kg or higher = 4 capsules of each drug. Dec capsules are ingested 
~60 minutes after THU capsules. 
- Timing between THU and Dec: Oral THU capsules followed 60 minutes later by oral Dec 
capsules. . 
- Frequency of THU and Dec ingestion:  
- THU ~10 mg/kg is administered 60 minutes before oral decitabine ~0.2 mg/kg 2X/week on 
consecutive days if there is no ≥ grade 3 treatment-related non-hematologic toxicity and the 
ANC is >0.5x109/L (if ANC is <0.5x109/L, treatment is held until recovery above this threshold 
then resumed with a dose reduction as per Table 1). 
- G-CSF neutropenia prophylaxis is recommended 1X/week if the ANC is <1.5x109/L 


CASE 3516  
 
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Clinical Monitoring: History and examination, laboratory tests, and regular radiologic 
assessments. Patients will continue study treatment until disease progression by clinical and/or 
radiologic parameters (RECIST v1.1), or unacceptable toxicity. Efficacy will be determined by 
radiographic evaluation and other measures as described above. THU-Dec safety profile will 
be determined by incidence of treatment emergent adverse events captured from the first dose 
of THU. Each adverse event will be  summarized by grade, causality, expected/unexpected 
based on the current knowledge. Further, adverse events will be summarized by body system 
and at the patient level (worst grade for specified adverse event). 
 
 
 
 
 
 
 


CASE 3516  
 
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ABBREVIATIONS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC Protocol Review and Monitoring Committee 
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
BMS 
Bristol Myers Squib 
Dec 
Decitabine 
THU 
Tetrahydrouridine  
SAE 
Serious Adverse Event 


CASE 3516  
 
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Version date: 9/7/2018 
 
TABLE OF CONTENTS 
 
1.0 INTRODUCTION  
 
1.1    Background of Refractory Non-small cell lung cancer  
1.2    Rationale for the use of Tetrahydrouridine-Decitabine in lung cancer 
1.3    Mechanisms of immune-resistance in lung cancer 
1.4    Background on the study drugs 
1.5    Scientific Rationale for the study  
1.6    Background and the rationale for the correlatives proposed in the study  
 
2.0 OBJECTIVES 
2.1   Primary Objective 
 
2.2   Secondary Objective(s) 
 
3.0 STUDY DESIGN 
3.1  Study design 
3.2  Statistics and Sample size justification 
3.3  Replacement of Subjects 
3.4  Expected Duration of Treatment and Subject Participation 
 
 
4.0 SUBJECT SELECTION 
4.1 Inclusion Criteria 
4.2 Exclusion Criteria 
4.3 Inclusion of Women and Minorities 
 
5.0 REGISTRATION 
 
 
6.0 TREATMENT PLAN 
6.1 Nivolumab 
6.2 Oral Tetrahydrouridine and Decitabine  
6.3 General Concomitant Medications and Supportive Care Guidelines 
6.4 Discontinuation of Subjects from Treatment 
6.5 Stopping Rule 
6.6 Duration of Follow-Up 
6.7 Post Study Access to Therapy 
 
7.0 DOSE MODIFICATIONS 
 
8.0 ADVERSE EVENTS and POTENTIAL RISKS 
8.1 Known Investigational Drug Associated Adverse Events 
8.2 Definitions 
8.3 Serious Adverse Event Report Form 
8.4 Reporting Procedures for Serious Adverse Event  
8.5 Serious Adverse Events and OnCoreTM    
8.6 Data Safety Toxicity Committee 
8.7 Data and Safety Monitoring Plan 


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9.0 PHARMACEUTICAL INFORMATION 
9.1 Decitabine 
9.2 Tetrahydrouridine 
9.3 Nivolumab 
 
10.0    STUDY CALENDAR  
 
11.0 CORRELATIVE STUDIES  
 
12.0 MEASUREMENT OF EFFECT 
12.1 Primary End Point 
12.2 Secondary End Point 
 
13.0   DATA REPORTING / REGULATORY CONSIDERATIONS 
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
REFERENCES 
 
APPENDEX I: PERFORMANCE STATUS CRITERIA 
 
APPENDEX II: SUBJECT CAPSULE DIARY FOR TWICE WEEKLY DOSING 
 
APPENDEX III: MANAGEMENT GUIDELINE OF IMMUNE RELATED ADVERSE 
EVENTS 
 
APPENDEX IV: RESPONSE EVALUATION CRITERIA in SOLID TUMORS 
[RECIST]  
 
 
 
 
 
 
 
 
 
 
 
 
1.0 
INTRODUCTION  
 


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1.1 
Poor Prognosis of Metastatic Non-small Cell Lung Cancer (NSCLC)  
Lung cancer is the leading cause of cancer related mortality in the United States, with over 
two third of patients presenting at an advanced stage. 5-year survival for patients with 
advanced lung cancer is a dismal 15%.29 For decades treatments and research has been 
focused on inducing apoptosis using cytotoxic chemotherapy, but with little improvement 
in clinical outcomes. Conventional chemotherapies have varying proximal molecular 
targets but the final common pathway converges onto p53 and p16/CDKN2A which are 
the master regulators of apoptosis. A majority of lung cancers have inactivating genetic 
alterations in the p53 and p16/CDKN1A genes30,31 conferring natural resistance to 
conventional cytotoxic chemotherapy.2-10 Perhaps therefore, it is therefore no surprise that 
decades of work focused on cytotoxic chemotherapy in lung cancer have been largely 
disappointing.22 In this proposal, we evaluate a novel approach to terminate malignant 
proliferation that does not require master apoptosis regulators such as p53 and 
p16/CDKN2A and that moreover, can improve tumor antigenicity by re-expression of 
tumor specific antigens.32-35  Cancers including lung cancers overexpress un-mutated forms 
of master differentiation driving transcription factors (e.g., CEBPA, GATA1, FOXA1, 
PAX2, SOX2, HNF1, MITF), that is, the “Yamanaka” factors that usually drive lineage-
differentiation. 
Paradoxically, 
however, the terminal 
differentiation 
(epithelial 
differentiation) genes 
which are targets of 
these 
master 
transcription 
factors, 
and 
which 
usually 
antagonize 
MYC-
function to terminate 
proliferation, 
are 
epigenetically silenced (discussed in our review36). This epigenetic repression is caused by 
mutations in co-factors for the master transcription factors, including co-activators, such 
that there is unbalanced activity of corepressors that create epigenetic repression instead of 
activation of the terminal differentiation target genes. DNMT1 is a key member of the 
network of corepressor proteins. Hence, depleting DNMT1 rebalances towards the action 
of activating chromatin modifying enzymes, and because the cancer expresses very high 
levels of differentiation-driving transcription factors at baseline, physiologic, 
differentiation-related maturation genes are activated and MYC is physiologically 
antagonized to terminate proliferation. This approach has a good therapeutic-index, since 
normal stem cell express master stem cell transcription factors, and self-renew in response 
to the same treatments, whereas normal progenitors differentiate, their intended fate 
dictated by the baseline master transcription factor context.18 
 
1.2 Rationale for Use of Tetrahydrouridine (THU) and Decitabine (Dec) in Lung 
Cancer  


CASE 3516  
 
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DNMT1 is a validated molecular target for treating lung cancer: Hypermethylation of key 
apoptosis and differentiation-related tumor suppressor genes including homeobox-
associated genes is nearly ubiquitous in NSCLC patients.30,31 DNMT1 has been validated 
as a molecular target for therapy of NSCLC in pre-clinical in vitro and in vivo models.11-16 
Also, CpG island methylator phenotype in lung cancer is strongly associated with increased 
expression of MYC, the master oncoprotein driver of cell growth and division.30,31 
Recently published comprehensive molecular profiling of of 230 lung adenocarcinomas 
revealed several mutations in chromatin-modifying genes that are components of 
coactivator complexes (e.g., SMARCA4, ARID1A and SETD2), that is, chromatin-
modifying enzymes that orthogonally oppose DNMT1 are genetically inactivated.31 
Epigenetic alterations are in many cases dynamic and reversible, thus are appealing targets 
for treatment. However, clinical translation of these scientific observations has been largely 
disappointing. Both Dec and 5-azacitidine (a prodrug for Dec) have been studied in several 
phase I/II trials in various solid tumors including lung. The objective response rates were 
very modest (<5%).37 In a trial combining 5-azacitidine and entinostat (a HDAC inhibitor), 
a modest OR (4%) was seen, although responses when they occurred were durable.38  
We propose that these disappointing clinical responses in lung cancer and other 
solid tumors are not because of erroneous pre-clinical observations, but instead, because of 
fundamental pharmacologic limitations of Dec and 5-azacytidine, the DNMT1-depleting 
drugs used for clinical translation. Impaired tissue bioavailability of Dec is a basic problem 
preventing effective clinical translation: Dec is very rapidly inactivated in solid organs: the 
half-life of Dec in buffer in vitro is over 10 hrs, however, in vivo, the plasma half-life is 
under 10 minutes, because of rapid metabolism by the enzyme cytidine deaminase (CDA), 
that deaminates Dec into its inactive uracil base moiety counterparts.39 This short in vivo 
half-life is especially a problem since the epigenetic therapeutic effect of Dec, depletion of 
DNMT-1, is exquisitely S phase dependent. Stated another way, exposure times to Dec 
must overlap with cancer cell S-phase entries, and thus a very brief exposure time 
fundamentally undermines the possibility of a meaningful clinical epigenetic therapeutic 
effect, regardless of exciting pre-clinical observations.  
This problem is not overcome by increasing Dec dose, since this produces off-target 
anti-metabolite and cytotoxic effects in more sensitive organs such as the bone marrow that 
have substantially lower CDA expression than other tissues such as the liver. Thus, to 
successfully use Dec to target DNMT1 in vivo to treat solid tissue cancers such as lung 
cancer, the pharmacologic barrier of CDA should be overcome. With the support from the 
National Institutes of Health Rapid Access to Interventional Development (NIH-RAID) 
Program, we have developed a combination therapy of oral Dec combined with an inhibitor 
of CDA (oral tetrahydrouridine, THU) and have an IND (#112, 914) for the novel 
combination therapy. Inhibiting CDA in this way produces the Dec pharmacology desired 
for a potent non-cytotoxic DNMT1-depleting effect: low Cmax that avoids off-target 
effects/cytotoxicity and extended Tmax with oral bioavailability and balanced distribution 
of Dec through the tissues of the body.27  
 
      The oral THU-Dec drug and trial concept are novel compared to Dec/5-azacytidine in 
lung cancer by overcoming the pharmacologic barriers as described above allowing (i) 
Substantially improved oral bioavailability26,40; (ii) Lower Cmax and log-fold increase in 
Tmax; (iii) Allowing meaningful distribution of Dec into solid tissues26; (iv) Noncytotoxic, 


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p53-independent mechanism of cell cycle exit that improves tolerability, safety and 
sustainability of therapy; (v) Preservation of immune-effectors and upregulation of neo-
antigens and antigen presentation by cancer cells, creating a logical platform for 
combination with FDA-approved immune checkpoint inhibitor drugs.  
 
1.3 Mechanisms of Immune-Escape in Lung Cancer that Limit the Response Rate to 
Newly Approved Immune Checkpoint Blockade  
Traditionally melanoma and renal cell cancer were considered “immunogenic” tumors 
while other solid tumors were considered “non-immunogenic”. Recently, however, a new 
class of immunotherapy agents, targeting the PD-L1/PD-1 immune-checkpoint axis, was 
approved in NSCLC (~20% overall response rate)41-44. The PD-L1/PD-1 axis (immune 
checkpoint) is used by self-tissue to suppress attack by adaptive immunity. Patients in 
whom these drugs have shown significant anti-tumor activity are those in whom the tumors 
appear to be “immune primed”, that is, enriched in lymphocytic infiltrates requiring that 
the tumor use immune checkpoints to survive. Conversely, patients who do not have 
responses to these agents appear to have tumors that have not triggered an immune 
response, despite the fact that primary and secondary lung cancer is genomically very 
deranged, suggesting it should be susceptible to host’s immune-recognition because of neo-
antigens.  
How then has most lung cancer evaded immune-recognition? Attack of a cancer by 
powerful adaptive immunity requires engagement of antigen-specific T-cell receptors 
(TCR) on CD8+ T lymphocytes by tumor-associated antigens presented on the cancer cell 
in 
the 
form 
of 
MHC 
class 
I 
molecule-bound 
peptides45, 
together 
with 
costimulatory/accessory molecules, e.g., CD80, CD86, and ICAM1 that engage their 
cognate counter-receptors on T cells. All these critical processes of antigen presentation, 
including MHC expression, are down-regulated in NSCLC by epigenetic changes, mainly 
DNA methylation (requiring DNMT1), but also histone post-translational modifications 
(e.g., by HDAC)45-531(Fig.1). Previously, we showed that such suppression is especially a 
characteristic of the most advanced or aggressive NSCLC54-56. 
Accordingly, we25,57-64 and many others have demonstrated that HDACi and 
DNMT1-depleting drugs 5Aza and Dec, can reverse this epigenetic silencing, promote 
antigen expression and induce anti-tumor immune responses in pre-clinical models65-67. In 
a Phase 1 clinical trial, we evaluated continuous infusions of Dec by a phase I dose-
escalation schema (n=35)25. Each full course of therapy consisted of two identical 35-day 
cycles. Immunohistochemical techniques were used to evaluate antigen presentation cancer 
tissue biopsies. Twenty-five subjects were evaluable for treatment response. No objective 
responses were observed. Improved antigen presentation was observed in 3 subjects. Our 
conclusion was that the pharmacology of Dec (or 5Aza), especially the severely 
abbreviated in vivo t½ and very poor solid tissue distribution23,24, and not flaws in the pre-
clinical science, were the cause of the limited efficacy, and that this pharmacology is likely 
to undermine the efficacy of several other ongoing clinical trials - in other clinical trials of 
Dec and 5Aza in various solid tumors including lung, objective response rates have been 
very modest (<5%)37,38. This pharmacology may similarly limit the ongoing phase 2 
clinical trial evaluating 5Aza and HDACi combination with nivolumab (NCT01928576), 
the recently concluded phase 2 trial evaluating 5Aza and HDACi vs. observation in 
resected stage I NSCLC (NCT01207726), and at least 9 other epigenetic immunotherapy 


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cancer clinical trials ongoing with Dec or the Dec analogue guadecitabine1. We expect 
immune-priming will be even more meaningful and significant with the pharmacology of 
oral THU-Dec that is optimized for non-cytotoxic DNMT1-depletion.  
 
 
1.4 Background on the Drugs 
 
1.4.1 Investigational Agent Oral THU-Dec. DNMT1-depletion requires cancer cell S-
phase entries to overlap with intra-cellular exposures, which in turn depends on extra-
cellular exposures. Plasma t½ is dictated by cytidine deaminase (CDA) - CDA drastically 
reduces plasma t½ to ~10 minutes from ~12 hours in vitro23,24. Moreover, we have 
demonstrated that CDA-enriched tissues (essentially all major solid tissue organs) provide 
sanctuary to malignant cells from Dec treatment-effects23. 
Figure 2.  Epigenetics and immune-evasion, and its pharmacologic editing to enable 
immune-recognition of cancer cells (figure from1). 


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This pharmacology is not solved by increasing Dec dose, since off-target effects 
from higher Cmax causes cytotoxicity that paradoxically decreases efficacy by restricting 
the feasible frequency of administration. Higher Cmax also destroys immune-effectors, 
subverting the rationale for epigenetic immunotherapy. Similarly, continuous infusion 
produces toxic increases of Dec in some tissues while inadequate exposure remains in 
others (CDA expression varies widely between tissues).    
 
Figure 3: Pharmacokinetics (PK) of Dec and oral THU-Dec. A) Dec PK after 
intravenous (IV), subcutaneous (SQ) and oral (PO) administration to baboons. B) Dec 
PK in human subjects from this clinical trial. Samples for PK analysis were obtained in 
12 of the 15 subjects who received study drug. Stated times are hours after administration 
of oral Dec, data-points are measured values while curves were fitted by a global fit model 
using the R package PKLMfit.R. The inset shows a close up for hours 0-4, to facilitate 
comparison to the 4 hour time-frame of the PK studies in baboons. Dec was quantified by 
a validated LC-MS/MS method. C) Dec AUC estimations in the baboons and in the 
different cohorts of the human clinical trial (model-dependent AUC estimates 
PKLMfit.R). The objectives with combination with THU were a wider concentration-time 
profile (that is low Cmax but extended Tmax or t½) and Dec distribution through CDA rich 
organs such as the intestines and liver.   


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To address this severe t½/distribution limitation, we combined lower dosages of Dec 
with the CDA-inhibitor THU, and have demonstrated in mice, non-human primates and in 
a Phase 1 clinical trial in sickle cell disease (in which the PK and pharmacodynamic 
objectives of non-cytotoxic DNMT1-depletion are the same as in this clinical trial), that 
this combination produces: (i) Low Cmax and log-fold increase in Tmax – High Cmax produces 
off-target anti-metabolite effects/cytotoxicity (undesired). High Tmax increases overlap 
between sufficient intracellular drug levels and S-phase entries of malignant cells, needed 
for DNMT1-depletion (desired). By inhibiting CDA, we have extended the plasma half-
life of Dec from ~10 minutes to >4 hours, with a Cmax ~50 nM26-28 (fig.3). (ii) Meaningful 
distribution of Dec into solid tissues – Marketed Dec is able to treat myeloid (liquid) 
cancers such as MDS (FDA-approval), but because of the high expression of CDA in 
organs such as the liver etc., Dec, like all cytidine analogues, is ineffective against cancers 
of or in these tissues (reviewed in23). Oral THU-Dec addresses this basic pharmacologic 
factor to rationally enable treatment of solid tissue malignancies and myeloid malignancies 
that infiltrate solid tissues, e.g., myeloproliferative neoplasms (fig.3). (iii) Oral 
bioavailability - CDA enrichment in the intestines and the liver is a substantial metabolic 
barrier to oral bioavailability of cytidine analogues such as Dec (no cytidine analogues are 
FDA-approved for this route of administration)27,28; although oral 5Aza is currently being 
investigated in clinical trials, there are major difficulties, including poor AUC, significant 
inter-individual variability and substantial GI toxicity from high dosages administered in 
an attempt to overcome the intestinal CDA-barrier. We have shown that combining THU 
and Dec improves oral bioavailability ~10-fold (fig.3)26-28. Thus, we administer Dec orally 
at a dose that is <10-25% of the FDA-approved intravenous dosages26-28. (iv) Decrease 
inter-individual variability - Pharmacogenetic differences in CDA expression and/or 
sequence between individuals causes clinically significant inter-individual variability in 
cytidine analogue pharmacokinetics (reviewed in39). Inhibiting CDA decreases this inter-
individual variability27,39. (v) Non-cytotoxic, normal stem cell sparing, p53-independent 
method of use - Dec was originally developed for the conventional oncotherapeutic 
objective of cytotoxicity (apoptosis), and FDA-regimens are pulse-cycled per anti-
metabolite therapy, can cause anti-metabolite effects and cytotoxicity, and require anti-
emetics. Underlying the proposed clinical trials are the observations that cytotoxicity is 
counter-productive in p53/p16-altered cancers, by selecting for the most apoptosis-resistant 
cancer sub-clones, by causing toxicity that limits frequency of drug administration, thereby 
decreasing the fraction of the malignant clone subject to S-phase dependent, p53-
independent epigenetic-therapeutic effects, and by destroying immune-effectors.  
 
When Dec is repositioned to avoid cytotoxicity and increase DNMT1-depletion as 
is the intent in this clinical trial, no significant clinical toxicities are anticipated. Non-
cytotoxic DNMT1 depletion whether by genetic means or by Dec has been demonstrated 
to shift hematopoietic differentiation towards megakaryopoiesis and erythropoiesis and 
away from granulopoiesis and monopoiesis). The major risk with therapy therefore is of 
neutropenia/neutropenic fever/sepsis associated with nadir. To reduce this risk, this clinical 
trial excludes patients with baseline neutrophil counts of <1.5 x 109/L. THU is not expected 
to cause any toxicities, based on a number of clinical trials, including trials with chronic 
administration at higher doses than are used in this study.   
 


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1.4.2  Background on Nivolumab 
 
For a complete review of non-clinical and clinical information, please refer to the BMS-
936558 Investigator Brochure (IB).68 
 
a) Non-clinical: Preclinical animal models of tumors have shown that blockade of 
Programmed death-1 (PD-1) by monoclonal antibodies (mAbs) can enhance the anti-
tumor immune response and result in tumor rejection. Antitumor activity by PD-1 
blockade functions in PD-L1+ tumors as well as for tumors that are negative for the 
expression of PD-L1.68-72 This suggests that host mechanisms (ie, expression of PD-
L1 in antigen-presenting cells) limit the antitumor response. Consequently, both PD-L1 
positive and negative tumors may be targeted using this approach. In humans, constitutive 
PD-L1 expression is normally limited to macrophage-lineage cells, although expression 
of PD-L1 can be induced on other hematologic cells as well, including activated T 
cells. However, aberrant expression of PD-L1 by tumor cells has been reported in a 
number of human malignancies.72 PD-L1 expressed by tumor cells has been shown to 
enhance apoptosis of activated tumor-specific T cells in vitro.68 Moreover, the expression 
of PD-L1 may protect the tumor cells from the induction of apoptosis by effector T 
cells. Retrospective analyses of several human tumor types suggest that tumor 
overexpression (as measured by IHC) of PD-L1 may permit immune evasion by tumors. 
PD-L1 expression had been shown to be consistently associated with tumors that 
are more inflamed and is a major mechanism of immune evasion. 55,73-75 
 
Reproductive and Developmental Toxicity: Preliminary new non-clinical safety findings 
of adverse pregnancy outcomes and infant losses in the absence of overt maternal toxicity 
have been reported. The findings of increased late stage pregnancy loss and early infant 
deaths/euthanasia in BMS-936558 (nivolumab) exposed pregnant monkeys  suggest  a 
potential risk to human pregnancy if there is continued treatment with BMS-936558 
during pregnancy.68 
 
b) Pharmacology: BMS-936558 (MDX-1106) is a fully human, IgG4 (kappa) isotype, 
mAb that binds PD-1. Blockade of the PD-1 pathway by BMS-936558 was studied using 
the mixed lymphocyte reaction (MLR). PD-1 blockade resulted in a reproducible 
enhancement of both proliferation and interferon release in the MLR. The effect of BMS-
936558 on antigen-specific recall response was investigated using a CMV-restimulation 
assay with human PBMC, and was evaluated by ELISA. These data indicated that BMS-
936558, versus an isotype-matched control antibody, augmented interferon secretion from 
CMV-specific memory T cells in a dose-dependent manner. PD-1 blockade by BMS-
936558 has therefore been pursued as a promising avenue for immunotherapy of tumors.68 
 
c) Clinical results: Two studies contributed to most of the clinical experience with BMS-
936558 in subjects with malignancies. MDX1106-01 was a Phase 1 single-dose 
escalation  study  in  subjects (N = 39) with previously treated advanced or metastatic 
cancer. Subjects received a single dose of BMS-936558 at 0.3, 1, 3, or 10 mg/kg with an 
option for re-treatment at 3 months. CA209003 (MDX1106-003) is an ongoing Phase 1 
multi-dose dose escalation study in subjects with previously treated advanced or metastatic 
melanoma, RCC, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or 
hormone-refractory prostate cancer (HRPC). 169 subjects have received at least one dose 


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of BMS-936558 intravenously every 2 weeks at doses of 0.1, 0.3, 1, 3, or 10 mg/kg. 
During the dose escalation portion of the study, subjects were treated at three dose levels: 
1, 3, and 10 mg/kg. Initial cohort expansions occurred in each tumor type at the highest 
tolerable dose evaluated (10 mg/kg) as well as in melanoma at 1 mg/kg and 3 mg/kg. 
The protocol was subsequently amended (Amendment 4), to include expansion cohorts 
in RCC at 1 mg/kg, melanoma at 0.1, 0.3, and 1 mg/kg, and NSCLC (squamous and 
non-squamous) at 1, 3, and 10 mg/kg.68 
 
d)  Safety Summary: No MTD was identified in CA209003. The maximum dose level 
evaluated was 10 mg/kg. The most frequent AEs were fatigue (49%), diarrhea (29%), 
decreased appetite (27%), nausea (26%), vomiting (22%), and rash (21%). There was no 
pattern in the incidence, severity or relationship of adverse events to the BMS-936558 
dose level. Any grade drug-related AEs were experienced by 57% of subjects. The most 
common drug related AEs were fatigue (22%), rash (15%), pruritus (11%), and diarrhea 
(9%). Most drug-related AEs were Grade 1 or Grade 2 in severity. Similar to the overall 
AE profile, there was no apparent relationship in the incidence or severity of drug-related 
AEs to BMS-936558 dose level. There were no apparent differences in the frequency 
of adverse events based on subjects’ tumor type. As of the clinical cut-off date (31-
May-2011), 18 deaths have been reported. Death was considered secondary to disease 
progression and unrelated to BMS-936558 in 16 subjects. One death was considered 
secondary to sepsis (Grade 5)/pneumonitis (Grade 4). The fatal sepsis was considered 
unrelated to study drug; however the preceding pneumonitis was considered related to 
BMS-936558. One death was considered secondary to ischemic cardiomyopathy and 
considered unrelated to BMS-936558. Subsequent to the clinical cut-off date, other 
cases of pneumonitis, including 2 fatal cases, have been reported. Additional details 
regarding these cases are provided in the Investigator Brochure, Section 5. 
 
1.5 Summary of Rationale for proposed study 
 
 A validated molecular target for therapy yet failure to translate: The epigenetic protein 
DNA methyltransferase 1 (DNMT1) has been extensively validated in pre-clinical studies 
as a molecular target for treatment of NSCLC11-16, since inhibition of DNMT1 produces 
cell cycle exits that do not require p16/p53, but instead utilize physiologic, cell maturation-
related MYC antagonists (e.g., p27/CDKN1B, reviewed in22). The extensively reproduced 
pre-clinical data prompted multiple clinical trials of the DNMT1-depleting drugs 
decitabine and 5-azacytidine to treat solid tumor malignancies, however, results have been 
disappointing (response rates typically <10%32,76-81), so Dec is not approved to treat any 
solid tumor malignancy, despite several clinical trials over decades. We hypothesize that 
this failure to translate from the lab into clinical benefit is not because of improperly 
executed pre-clinical science, but because of a failure to rigorously capitalize on basic 
pharmacologic properties of Dec.   
 
Bridging to delayed effect of immune therapy with non-cytotoxic tumor cytoreducing 
therapy: Delayed effects have been reported with immune therapies like nivolumab. Non-
cytotoxic, p53-independent therapy with oral THU-decitabine can potentially bridge this 


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gap while sparing the immune-system, thereby contrasting with traditional cytotoxic 
therapy. 
 
Immune priming effect of DNMT1 inhibition: The clinical trials with Dec and 5-azacytidine 
showed dismal responses. However patients on these trials had durable responses to their 
subsequent line of therapy, particularly immune-checkpoint inhibitors. Several of these 
patients had an unusually prolonged duration of responses.41,66,82-84 This raised the 
possibility of the epigenetic treatment “priming” the tumors for subsequent therapies.83 In 
trials evaluating DAC, an increase in the expression of tumor specific cancer testis antigens 
(NY-ESO-1 and MAGE-A3) were noted in the sequential biopsies Thus an “immune 
priming” effect of epigenetic therapy has been proposed.67 82 In in-vivo mice tumor models 
treatment with low dose Dec increased IFN-γ producing T lymphocytes in the tumors and 
resulting in an anti-tumor response.65 In addition, pre-clinical studies show that 5-
azacytidine can promote tumor infiltrating myeloid cells and promote differentiation into 
mature immune-stimulatory antigen presenting cells (APC) in addition to constitutively 
overexpressing HLA class I antigens and other co-stimulatory molecules.85-89 Increased 
APCs can orchestrate an immune cascade by activating cytotoxic T-Cells resulting in an 
anti-tumor effect. Furthermore the negative immune checkpoints, including PD1 on T-cells 
appear to be tightly regulated by methylation thus influencing cytotoxic T-cell 
differentiation.90 Recently, increased activation of immune evasive pathways mainly PD-
1/PDL1 and CTLA4 was demonstrated in leukemia cells with treatment of Dec.91 There is 
an ongoing phase II clinical trial evaluating Azacitidine and entinostat combination with 
nivolumab, an anti-programmed death-1, antibody (NCT01928576). In addition, there was 
a recently concluded phase II trial with the combination of 5azacytidine and entinostat vs. 
observation in resected stage I NSCLC (NCT01207726) the results of which are awaited. 
With the pharmacology of oral THU-Dec that is optimized for non-cytotoxic DNMT1-
depletion, we suspect that such immune-priming will be even more meaningful and 
significant. 
There are no other drugs available for clinical use that have been designed and 
optimized for non-cytotoxic epigenetic-differentiation therapeutic effects. Thus, this 
proposal constitutes a first pharmacologically rational attempt to translate extensive 
scientific data regarding the value of DNMT1 as a molecular target for therapy that can 
potentially be effective even in advanced NSCLC that is refractory to current therapies, 
including the latest alternative molecular targeted therapies. Moreover, by augmenting 
expression of neoantigens via epigenetic mechanisms, this non-cytotoxic therapy is a 
rational platform for increasing the response rate and effectiveness of immune-checkpoint 
inhibitors41 in NSCLC. 
       
Thus, our overall objective is to evaluate if oral THU-low dose Dec based on 
rational pharmacology can realize the potential for DNMT1 as a molecular target in 
NSCLC, with a distinctive p53/p16-independent pathway of action achieving efficacy in 
refractory disease with excellent safety profile and augment the efficacy of nivolumab by 
immune priming. 
 
1.6 
Background and rationale of correlative studies 
 
a)  
Correlatives in biopsy tissue  


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All the tissue based immunological correlatives PD-L1 expression and other exploratory 
correlatives will be performed in the Translational Immuno-oncology Laboratory lab at the 
Yale University. This laboratory is specialized in measurement of immune biomarkers and 
has access to CLIA-compliant facilities. 
i) Measurement of Tumor infiltrating immune cells on pre-treatment and post treatment 
biopsies: The automated quantitative spectral multiplexing platform for evaluation of 
immune biomarkers is highly novel. We have previously developed and validated ways to 
reproducibly measure and quantify TILs and immune biomarkers by QIF55,73,75. To 
understand the tumor immune landscape, we will characterize the immune infiltrates in the 
samples using a previously described and validated assay to objectively interrogate 
different lymphocyte subsets75. This assay comprises the simultaneous staining and 
measurement of tumor cells (cytokeratin), T cells (CD3), cytotoxic T cells (CD8) and B 
lymphocytes (CD20). The signal intensity and amount of cells will be measured using 
informatic tools as described for PD-L1. These will be done in collaboration with Tumor 
immunology lab at Yale to develop and validate several immune biomarker panels for 
potential use in the clinical setting. This collaboration will expand on our previous work. 
 
ii) Measurement of several immune biomarkers in the tumor and stromal compartments on 
pre-treatment and post treatment biopsies: PD-L1 expression will be determined for all 
patients on pre-treatment samples per standard of care using the DAKO PD-L1 assay in 
the Yale CLIA lab. Positivity will be determined by the presence of any (non-nuclear) PD-
L1 signal present in intact tumor and/or stromal cells within the tumor region of the tissue 
examined, as evaluated by a pathologist in preparations stained with chromogenic 
immunohistochemistry for PD-L1 and counterstained with hematoxylin. Operationally, a 
positivity threshold of signal present in >1% of cells will be used. An additional 3-tiered 
semi-quantitative categorical result will be rendered by the pathologist based in the 
estimation of the percentage of positive cells including 1+ (<30%), 2+ (30-<60%) and 3+ 
(60-100%). PD-L1 negative cases will be those with absence of any detectable signal in 
the sample tested and with appropriate tissue and staining controls.  
      In addition, to chromogenic PD-L1 IHC using novel platform we can increase specific 
staining of multiple tissue biomarkers (PD-L2, B7H4, TIM-3, VISTA, LAG-3, IDO-1 etc)  
and able to reach 6-plex and beyond in a single image retaining the morphologic context 
of the tumor. The incorporation of such novel approaches could positively impact the value 
of tissue biomarkers determination for anti-cancer immunotherapies. Finally, additional 
correlative studies using novel approaches with higher sensitivity and throughput such as 
the Luminex assay69 and CyTOF massspect based cytometry70 will be pursued once these 
platforms are appropriately standardized. 
 
iii) mRNA expression profiling: We will evaluate changes in mRNA expression profiles in 
FFPE tumor samples obtained before and after treatment with THU-Dec using the 
Nanostring and Counter Pancancer panel. Specifically, we will assess variations in 
immune-related transcripts and changes in MYC, as well as upregulation of the terminal 
differentiation markers and tumor specific antigen changes (Cancer testis antigens). We 
will also look at changes in DNMT1, DCK, UCK2 and CDA expression to study the 
intended pharmacodynamics of the THU-Dec combination 
 


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iv) Next Generation Sequencing for T-cell receptor clonality: TCR sequencing and 
clonality quantification on pre-and post-treatment samples will be performed using 
ImmunoSeq assay in a multiplexed PCR method using forward primers specific to TCR 
Vβ gene segments and reverse primers specific to TCR Jβ gene segments. In addition, using 
Immune Repertoire Capture™ (IRC™) technology we will evaluate immune response 
enabling the identification and generation of functional human antibodies and TCRs. This 
delivers an unparalleled quantitation of the adaptive immune response. This will be done 
in collaboration with Atreca Inc. 
 
v) Pharmacodynamic analyses: The intended molecular pharmacodynamic effect of oral 
THU-decitabine is depletion of DNMT1 in tumor tissue. This will be measured by QIF. 
DNMT1-depletion is expected to induce p53-independent cell cycle exits, with 
downregulation of MYC and upregulation of p27/CDKN1B. This will be measured by QIF 
also. Finally, the intracellular accumulation of decitabine to deplete DNMT1 depends on 
relative expression in the cancer cells of pyrimidine metabolism enzymes DCK, CDA and 
UCK2, and also the growth fraction of the malignancy, measured by surrogates such as 
KI67. These parameters will also be measured by QIF. 
 
b) 
Correlatives in blood:  
i) Phenotypic character of PBMC: To be performed by GenOptix. Multiplex T cell 
phenotyping flow cytometry panels: We will design a broad T-cell flow cytometry panel 
composed of multiple exhaustion markers, checkpoint receptors and activation markers. 
Non-biased automated algorithms will be used to determine T –cell signatures predictive 
of response and resistance to immunotherapies. The putative markers in the panel may 
include CD3, CD4, CD8, CD45RO, CD45RA, CCR7, CD95, CD27, CD25, CD57, CD107, 
CD69 CD11A, TIM3, HLA-DR, PD-1, LAG3, OX40, ICOS, CCR4, CXCR3, CCR6, BIM, 
EOMES, CTLA-4. In addition to T-cells, we will evaluate other immune cell subsets 
including DCs, monocyte populations, and NK cells. A whole blood immunophenotyping 
assay will quantify the absolute number and proportion of NK cells (CD56+CD3-), NKT 
cells (CD56+CD3+), B cells (CD19+), and monocytes (CD16+). In addition, both myeloid 
(CD45+HLADR+ CD11c+CD123-) and plasmacytoid (CD45+HLA-DR+CD11c-
CD123+) dendritic cell (DC) frequencies will be measured in this precision-validated 
multiparameter flow cytometric assay. In addition, PBMCs will be cryopreserved for future 
potential studies using platforms such as Mass cytometry (CyTOF), IRC™ and 
CIBERSORT, and will be correlated to the immunologic response, clinical response, and 
survival data.  
 
ii)  
Serum proteomic and ctDNA correlatives: Exploratory proteomic analysis using 
MALDI ToF mass-spectrometry and ProTS will be performed in collaboration with 
Biodesix and the Pandey lab at Johns Hopkins on baseline and on treatment plasma samples 
at time points defined in the protocol from patients in the study.  
 
PBMCs, Serum and plasma will be banked for other potential correlatives 
  
 
2.0  
OBJECTIVES & HYPOTHESES 


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Hypothesis:  We hypothesize that the combination of nivolumab with non-cytotoxic low 
dose oral Dec with THU achieves immune priming and improves clinical efficacy of 
nivolumab. 
 
Primary objective: To determine if non-cytotoxic oral THU-Dec when combined with 
nivolumab can improve objective response rates of nivolumab  
 
Secondary objectives:  
 
i) To evaluate clinical efficacy end points and toxicity of oral THU-Dec in combination 
with nivolumab;  
 
ii) To evaluate the Immune priming effect of THU-Dec combination therapy by functional 
and phenotypic circulating immune cell characterization and changes in the immune 
contexture in the tumor tissue 
 
iii) To evaluate hypotheses regarding mechanisms of resistance and predictive biomarkers 
for response to nivolumab 
 
3.0  
STUDY DESIGN 
 
3.1 Study design: This is a Phase 2 randomized two arm trial of nivolumab alone or in 
combination with THU-Dec, in previously treated patients with stage IV Non-Small Cell 
Lung Cancer (NSCLC). The primary goal of this trial is to compare the efficacy of oral 
THU-Dec as a way of enhancing the anti-tumor immune response to nivolumab to that of 
nivolumab alone. The primary efficacy endpoint is overall RECIST v1.1-defined response. 
To accomplish this goal 60 patients will be randomized 2:1 to THU-Dec plus nivolumab 
or nivolumab only respectively. 
 
3.2 Statistics and Sample size justification: The primary goal of this trial is to compare 
the efficacy of immune priming with oral tetrahydrouridine (THU) plus decitabine (THU-
Dec) and immune check-point inhibitor nivolumab (THU-Dec+nivolumab) to that of 
nivolumab alone. The primary efficacy endpoint is overall response. To accomplish this 
goal 60 patients will be randomized 2:1 to THU-Dec+nivolumab versus nivolumab alone 
(standard of care) respectively. The purpose of the nivolumab alone arm is to support the 
notion that the population studied is typical of the general population for which nivolumab 
has an established response rate of 20%. If the THU-Dec+nivolumab arm has a response 
rate of 35% or higher, we will consider it worthy of further investigation in a phase III trial. 
Thus, using a two-stage design (http://www.swogstat.org/stat/public/twostage.htm), with 
alpha = 0.1 and beta = 0.2, we compute that 20 patients will be needed in each of two stages 
in the THU-Dec+nivolumab arm. If, after the 1st stage of 20 patients in the THU-
Dec+nivolumab arm, 2 or fewer respond, the trial will be stopped and the null hypothesis 
that THU-Dec+nivolumab is no better than nivolumab will be accepted, else the trial 
continues for an additional 20 patients, at the end of which if 13 or more respond of the 40 


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patients in the THU-Dec+nivolumab arm, the null hypothesis is rejected and experimental 
arm of THU-Dec+nivolumab is recommended for further study.  
 
As an additional exploratory analysis we will compare response rates between treatment 
groups. We expect a 20% response rate in our control arm of 20 patients.  The 95% 
confidence interval of the proportion 4/20 is 7% to 44%.  It thus includes our treatment 
arm expected response rate of 35%.  It is therefore very unlikely that our control arm will 
disprove our assumption that our sample population has a historical response rate of 20%. 
Thus, to increase the likelihood of gaining some information from our control arm, 
differences in proportions will be compared between arms. Using a calculator for two arm 
binomial studies we compute that the power to detect a difference in rates between our 
control arm and our treatment arm of 40 patients, assuming one-sided tests, alpha=0.10 and 
holding the treatment arm response rate at 35%, is, respectively, 89%, 70%, 50%, 32% and 
18% for control response rates of 5%, 10%, 15%, 20%, and 25%. Thus, if our control arm 
rates are <15%, we have >50% chance of detecting a difference in response. In addition, 
we will evaluate the PD-L1 expression in both the control and treatment arm after every 
20 patients. If there is >10% difference in the PD-L1 status between the groups, we will 
stratify randomization by PD-L1 status for additional patients to balance the PD-L1 status. 
Secondary endpoints include progression-free survival (progression is defined as 
progression by both RECIST v1.1), overall survival, and toxicity. Progression-free and 
overall survival will be summarized using the Kaplan-Meier method. Adverse events will 
be graded using CTCAE version 4.0 criteria, categorized by organ system, and summarized 
using frequency counts and percentages. With 20 patients treated with nivolumab only and 
40 with THU-Dec+nivolumab the probability of observing at least one toxicity of a 
particular type and/or grade on each arm is 64% and 87%, respectively, if the risk of such 
an event is 5%, i.e. 0.64 = (1-0.9520).   
Methods such as Fisher’s exact test, chi-square tests, logistic regression (categorical 
data), the log-rank test and proportional hazards models (time to event data) will be used 
to compare patient groups. These analyses are primarily exploratory and it is acknowledged 
that they will have relatively low statistical power. 
 
3.3 Replacement of Subjects  
      - If a subject is withdrawn from the study before week 8 for reasons not related to 
toxicity of study drug, the subject will be replaced. 
     - If a subject does not take at least 12 of the intended 16 doses in the first 8 weeks, the 
subject will be replaced because he/she has not taken enough THU-Dec that analysis of the 
primary end-point will be meaningful.  
 
3.4 Expected Duration of Treatment and Subject Participation 
Treatment on protocol monitoring continues until (i) disease progression (defined by 
RECIST v1.1 with the following caveat: since it is known that there can be initial 
progression by RECIST v1.1 criteria with immune checkpoint blockade followed by 
subsequent regression and clinical benefit, if the treating clinical team and the patient judge 
that they have benefitted from therapy, treatment continuation is allowed even if there is 
disease progression by RECIST v1.1 criteria. However, patients should have confirmed 
stable disease or better at the time of the following scheduled imaging time-point. If there 


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is progression at this following re-staging, patients should be discontinued from therapy); 
(ii) toxicity as defined in Section 7.1; or (iii) withdrawal of consent up to a maximum of 
24 months.  
At the end of the protocol-specified period of active study therapy, the sponsor will not 
continue to supply study drug to subjects/investigators unless the sponsor chooses to extend 
the study, which may include continuation of nivolumab. The investigator should ensure 
that the subject receives appropriate standard of care, which may include continued 
treatment with nivolumab. 
 
4.0 SUBJECT SELECTION 
 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility.  
 
4.1 Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment      
into the study:  
1. Histologically or cytologically-proven NSCLC 
 
2. Subjects must have received 1 or more prior systemic therapies for this disease, 
(this can include neo-adjuvant or adjuvant chemotherapy if administered <2years 
prior to study enrollment), should not have had prior treatment with immunotherapy 
(including immune checkpoint inhibitor drugs, or immunotherapy vaccines); 
Patients with EGFR or ALK alterations will need to have progressed on a TKI 
treatment. 
  
3. Measurable disease per RECIST v1.1 
 
4. Disease that can be accessed by a bronchoscopic, surgical or percutaneous biopsy, 
eligible for biopsy from safety perspective, and agrees to biopsy prior to study. 
The pre-study biopsy can be waived if (i) there is an archival biopsy specimen 
that was obtained after the most recent therapy or(ii) if the risks of biopsy are 
judged to be excessive by the study PI   
 
5. ECOG performance status 0 – 2 
 
6. Male or female, 18 years or older (Because no dosing or adverse event data are 
currently available on the use of oral THU-Dec in subjects ≤18 years of age, 
children are excluded from this study) 
 
7. Adequate organ function as defined by the following criteria: 
   
Adequate Organ Function Laboratory Values 
 System 
Laboratory Value 


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Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥8.5 g/dL or ≥5.6 mmol/L 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
 
≤1.5 X upper limit of normal (ULN) OR 
 
≥30 mL/min for subject with creatinine levels > 
1.5 X institutional ULN  
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2 mg/dL 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Patients with leptomeningeal disease are not eligible but patients with brain 
metastases are eligible – these patients should commence treatment on study > 
1 week after completion of gamma knife or whole brain radiotherapy or >4 
weeks after surgical resection of brain metastasis. Patients should ideally be off 
steroids at the start of study treatment, however patients on steroid taper and a 
dose of no more than 2mg/day of dexamethasone can begin study treatment; 
and steroids should be tapered off as quickly as clinically feasible.  
Repeat brain MRI after radiation is not required for eligibility but is strongly 
recommended, to establish the pre-treatment baseline status of any brain 
metastases, necessary to accurately assess for response or progression. 
 
Patients with untreated, asymptomatic brain metastasis not requiring steroids are 
also eligible, however, these patients need to be discussed with the study PI prior 
to being registered.  
 
9. Subjects must have the ability to understand and the willingness to sign a written 
informed consent document. 


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4.2 Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment: 
 
1. Within 6 months prior to study drug administration, clinically significant 
cardiovascular/cerebrovascular disease defined as follows: cerebral vascular 
accident/stroke, myocardial infarction, unstable angina, congestive heart failure 
(New York Heart Association Classification Class ≥ II), bleeding or pulmonary 
embolism or cardiac arrhythmias that was severe enough to cause hemodynamic 
compromise.  
  
2. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness (HIV-positive subjects on combination 
antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with oral THU-Dec. Appropriate studies will be undertaken in subjects 
receiving combination antiretroviral therapy when indicated.  
 
3. Pregnancy or breastfeeding (pregnant or breastfeeding women are excluded from 
this study because oral THU-Dec has the potential for teratogenic or abortifacient 
effects. Because there is an unknown, but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with oral THU-Dec, 
breastfeeding should be discontinued if the mother is treated with oral THU-Dec.  
 
4. Other severe acute or chronic medical or psychiatric conditions or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and in 
the judgment of the investigator would make the patient inappropriate for entry into 
this study. 
 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 2 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
6. Has had prior chemotherapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 2 or at baseline) from adverse events due to a previously 
administered agent and meeting the criteria for organ function described in section 
4.1.7 Patients who receive palliative radiation therapy within 1 week prior to day 1 
are allowed. Patients on treatment with targeted therapy (like EGFR or ALK TKIs) 
may start study treatment 5 days from last treatment.  
      Note:  Subjects with ≤ Grade 2 neuropathy or other clinically insignificant AEs as 
determined by the PI are an exception to this criterion and may qualify for the study 
following adequate pre-study documentation. 
      Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
 
7. Receiving other investigational agent concomitantly. 


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8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include superficial skin cancers that are surgically removed without 
need for systemic therapy, in situ cervical cancer, superficial bladder cancer or 
localized low grade prostate cancer not requiring active treatment. 
9. Has active or documented history of autoimmune disease that has required systemic 
treatment in the preceding 2 years (i.e. required use of disease modifying agents 
such as corticosteroids or other immunosuppressive drugs). Patients with psoriasis 
and rheumatoid arthritis with no evidence of disease flare off immunosuppression 
for >1year may be allowed after discussion with the study PI.  Replacement therapy 
(eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 217 days after the last dose of trial treatment.  Women of childbearing 
potential (WOCBP)* should agree to methods of contraception described in the 
protocol. 
* WOCBP is defined as any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal. Menopause is defined clinically 
as 12 months of amenorrhea in a woman over 45 in the absence of other 
biological or physiological causes. In addition, women under the age of 62 must 
have a documented serum follicle stimulating hormone (FSH) level >40 
mIU/mL.  
Women of childbearing potential (WOCBP) receiving nivolumab will be 
instructed to adhere to contraception for a period of 23 weeks after the last dose 
of investigational product. Men receiving nivolumab and who are sexually 
active with WOCBP will be instructed to adhere to contraception for a period 
of 31 weeks after the last dose of investigational product. These durations have 
been calculated using the upper limit of the half-life for nivolumab (25 days) 
and are based on the protocol requirement that WOCBP use contraception for 


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5 half-lives plus 30 days and men who are sexually active with WOCBP use 
contraception for 5 half-lives plus 90 days. 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
Male condoms with spermicide 
Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as 
Mirena® by WOCBP subject or male subject’s WOCBP partner Female 
partners of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they will 
not be receiving study drug 
Nonhormonal IUDs, such as ParaGard® 
Tubal ligation  
Vasectomy 
Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
Subjects who choose complete abstinence are not required to use a second 
method of contraception, but female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence. 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
Diaphragm with spermicide 
Cervical cap with spermicide 
Vaginal sponge 
Male Condom without spermicide  
Progestin only pills by WOCBP subject or male subject’s WOCBP partner  
Female Condom*. 
* A male and female condom must not be used together 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 


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4.3 Inclusion of Women and Minorities  
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0  
REGISTRATION 
 
All subjects who have been consented are to be registered in the OnCore™ Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. All 
subjects will be registered through Cleveland Clinic and will be provided a study number by 
contacting the study coordinator listed on the cover page.  
 
6.0  
TREATMENT PLAN 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
 
6.1 Nivolumab:  Nivolumab will be given every two weeks at a dose of 240mg IV to be 
administered as a 60 minute IV infusion. Subjects may be dosed no less than 12 days from 
the previous dose of drug. There are no pre-medications recommended for nivolumab on 
the first cycle. The dosing calculations should be based on the actual body weight at 
baseline. If the subject’s weight on the day of dosing differs by > 10% from the weight 
used to calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed. See section 
7 for dose delay guidelines.  
 
Treatment of Nivolumab Related Infusion Reactions:  
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according 
to NCI CTCAE (Version 4.0) guidelines.  
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; 
intervention not indicated): Remain at bedside and monitor subject until recovery from 
symptoms. The following prophylactic pre-medications are recommended for future 
infusions: diphenhydramine 50 mg  (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, iv fluids]; prophylactic 
medications indicated for 24 hours):  Stop the nivolumab infusion, begin an IV infusion 
of normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) 


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and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor 
subject until resolution of symptoms. 
 
Additional dose modifications (dose delays) of nivolumab are described in Section 7.0 
 
 
6.2 Oral Tetrahydrouridine (THU) and Decitabine (Dec):  
 
- 
THU is supplied as capsules containing 250 mg of THU per capsule, in bottles 
containing 8 capsules per bottle. See Section 9 for drug handling and storage 
recommendations. 
- 
Dec is supplied as capsules containing 5 mg of Dec per capsule, in bottles containing 
8 capsules per bottle.  
 
- Starting dose of oral THU and Dec is by weight (all subsequent doses are based on the 
Cycle 1 Day 1 dose with dose modifications based on toxicities and tumor response as 
described in the protocol): 
Weight 40-60kg = 2 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 61-80kg = 3 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 81-100kg or higher = 4 capsules of each drug. Dec capsules are ingested ~60 
minutes after THU capsules. 
 
Subsequent dose changes should be based on hematologic parameters, non-hematologic 
toxicities attributed to study drug or as specified in the protocol. 
 
- Timing between THU and Dec: Oral THU capsules followed ~60 minutes later by oral 
Dec capsules (oral Dec can be taken up to 6 hours after oral THU).  
  
- Frequency of THU and Dec ingestion:  
Oral THU ~10 mg/kg is administered 60 minutes before oral decitabine ~0.2 mg/kg 
2X/week on consecutive days if there is no ≥ grade 3 treatment-related non-hematologic 
toxicity and the ANC is >0.5x109/L (if ANC is <0.5x109/L, treatment is held until 
recovery above this threshold then resumed with a dose reduction as per Table 1). 
 
- Patients will be required to have the treatment on the same consecutive days every week. 
If patients miss a dose they need they can make up the dose the same week (±3 days) and 
the study team needs to be notified. 
 
- G-CSF neutropenia prophylaxis is recommended 1X/week if the ANC is <1.5x109/L 
 
If there is stable disease or partial response by RECIST v1.1 at the week 8 or 16 
staging CTs, and there are no treatment-related ≥grade 3 toxicities, and blood count 
trends (trends in the absolute neutrophil, absolute lymphocyte and platelet counts) 
suggest that such treatment-related toxicities are not imminent, the dose of THU and 
Dec can be increased by one capsule each. THU-Dec dose increases should not occur 


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more often than every 4 weeks and only to a maximum of 2 additional capsules of each 
drug from the starting dosage. 
 
-Pre-medications are not required, since nausea, vomiting and diarrhea are not anticipated 
with this non-cytotoxic mode of therapy. 
Dose modifications (dose reductions, dose escalations) of oral THU-Dec are described in 
Section 7.0 
 
Reported adverse events and potential risks of oral THU-Dec are described in Section 8.0 
 
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the subject's malignancy. 
 
6.3 
General Concomitant Medications  
    The following medications are prohibited during the study (unless utilized to treat a 
drug-related adverse event): 
a) Immunosuppressive agents 
b) Immunosuppressive doses of systemic corticosteroids  
 Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive radiation therapy, or standard or investigational 
agents for treatment of NSCLC Palliative and supportive care for disease related 
symptoms may be offered to all subjects on the trial. Palliative (limited-field) 
radiation therapy is permitted for subjects who have investigator assessed 
clinical benefit. However, radiation to target lesions is not permitted. For 
example patients with asymptomatic oligo-metastatic brain metastatic disease 
that would clinically be amenable to Gamma Knife Radiosurgeryis allowed on 
the protocol so long as they are not having systemic disease progression and per 
investigator are receiving clinical benefit from the trial. 
 Inter-current illness that prevents further administration of treatment 
 The investigator considers it, for safety reasons, to be in the best interest of the 
subject  
 Unacceptable treatment related toxicity, NCI CTC AE version 4.0 Grade 3 or 4 
that fails to recover to baseline or < Grade 3 in the absence of treatment within 
4 weeks See section 6.1.1, 6.1.2 and 6.1.3. 
 Subject decision to withdraw from treatment (partial consent) or from the study 
(full consent) 
 Pregnancy during the course of the study for a child-bearing participant 
 Death, or 
 Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study. 
 The date and reason for discontinuation must be documented. Every effort 
should be made to complete the appropriate assessments  
 
6.5 Stopping Rule 


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If 3 of the first 5 patients in the THU-Dec + nivolumab arm are removed from study for 
grade 3/4 non-hematologic toxicity or toxicities prior to cycle 2 that are likely attributable 
to THU-Dec, the study will be terminated.  
 
The study incorporates a two-stage design in the experimental THU-Dec + nivolumab 
arm. If after the 1st stage of 20 patients in the THU-Dec+nivolumab arm, 2 or fewer 
respond, the trial will be stopped and the null hypothesis that THU-Dec+nivolumab is no 
better than nivolumab will be accepted, else the trial continues for an additional 20 
patients.  
 
6.6 Duration of Follow Up 
Subjects will be followed for toxicity for 30 days after treatment has been discontinued, 
until start of new anti-cancer treatment or until death, whichever occurs first. The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause, unless the event 
exceeds 6 months in duration. Serious adverse events that are still ongoing at the end of 
the study period will necessitate follow-up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to 
the study treatment or study participation will be recorded and reported immediately. All 
randomized subjects who discontinue study treatment must continue to be followed for 
collection of outcome and/or survival follow-up data every 2 months until death or subjects 
withdraw consent from all study related activities. The survival and toxicity follow up of 
the patients could be by telephone or through review of medical records.  
 
6.7 Post Study Access to Therapy 
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will 
be eligible to receive study drug. Study drug will be provided via an extension of the study, 
a rollover study requiring approval by responsible health authority and ethics committee, 
or through another mechanism at the discretion of the sponsor. The sponsor reserves the 
right to terminate access to study drug if any of the following occur: a) the marketing 
application is rejected by responsible health authority; b) the study is terminated due to 
safety concerns; c) the subject can obtain medication from a government sponsored or 
private health program; or d) therapeutic alternatives become available in the local market.  
 
7.0  
DOSE MODIFICATION 
 
Potential dose modifications of oral THU-Dec include dose reductions and dose 
escalations, described in sections below. 
 
7.1 Dose Reduction of THU-Dec 
 
Table 1 lists standard laboratory values that should trigger dose reduction of the 
investigational drug oral THU-Dec. 
 
Table 1: Trigger Values that Result in Dose Reduction of oral THU-Dec 


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Measurement 
Trigger value for 
Dose Modification 
Dose Modification 
Absolute 
neutrophil 
count (ANC) 
<0.5 x 109/L 
(non-cytotoxic 
DNMT1-depletion 
shifts normal 
hematopoietic 
differentiation away 
from neutrophils 
towards platelets and 
hemoglobin) 
Hold treatment with THU-Dec until ANC≥0.5 x 
109/L, then restart with decrease in dose by 1 
capsule each of Dec and THU. If recurrent 
toxicity occurs, interrupt study drug 
administration until recovery from toxicity then 
resume with a reduction in treatment frequency of 
THU-Dec to 1X/week. If toxicity recurs at this 
dose, interrupt study drug until toxicity resolved 
then resume at same dose and frequency. The 
overall goal is to sustain regular administration, at 
a lower dose if necessary, rather than infrequent 
administration of a higher dose, however, a 
minimum dose is required to produce DNMT1 
depletion. Only continue treatment if it is judged 
to be in the best interests of the patient.  Only 
continue treatment if it is judged to be in the best 
interests of the patient. G-CSF growth factor 
support is recommended if ANC is <1.5 x 109/L. 
Absolute 
lymphocyte 
count 
<0.5 x 109/L 
 
Hold treatment with THU-Dec until absolute 
lymphocyte count ≥0.5 x 109/L, then restart with 
decrease in dose by 1 capsule each of Dec and 
THU. If recurrent toxicity occurs, interrupt study 
drug administration until recovery from toxicity 
then resume with a reduction in treatment 
frequency of THU-Dec to 1X/week. If toxicity 
recurs at this dose, interrupt study drug until 
toxicity resolved then resume at same dose and 
frequency. The overall goal is to sustain regular 
administration, at a lower dose if necessary, 
rather than infrequent administration of a higher 
dose, however, a minimum dose is required to 
produce DNMT1 depletion. Only continue 
treatment if it is judged to be in the best interests 
of the patient.  
Platelets 
>1,200 x 109/L  
(see above, 
differentiation shifts 
with non-cytotoxic 
DNMT1-depletion 
Withhold until platelets ≤1,200 x 109/L, then 
restart with decrease in dose by 1 capsule each of 
Dec and THU. If recurrent toxicity occurs, 
interrupt study drug administration until recovery 
from toxicity then resume with a reduction in 


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can increase platelet 
counts) 
THU-Dec frequency to 1X/week. If toxicity 
recurs at this dose, interrupt study drug until 
toxicity resolved then resume at same dose and 
frequency. The overall goal is to sustain regular 
administration, at a lower dose if necessary, 
rather than infrequent administration of a higher 
dose, however, a minimum dose is required to 
produce DNMT1 depletion. 
Hemoglobin 
Hemoglobin >17g/dl 
(differentiation shifts 
with non-cytotoxic 
DNMT1-depletion 
can increase 
hemoglobin) 
 
Withhold until hemoglobin ≤17 g/dl, then restart 
with decrease in dose by 1 capsule each of Dec 
and THU. If recurrent toxicity occurs, interrupt 
study drug administration until recovery from 
toxicity then resume with a reduction in THU-
Dec frequency to 1X/week. If toxicity recurs at 
this dose, interrupt study drug until toxicity 
resolved then resume at same dose and frequency. 
The overall goal is to sustain regular 
administration, at a lower dose if necessary, 
rather than infrequent administration of a higher 
dose, however, a minimum dose is required to 
produce DNMT1 depletion.   
Serum 
creatinine 
≥1.6 mg/dL (if pre-
treatment value 
<0.5mg/dL) 
≥1.7 mg/dL (if pre-
treatment value 0.6-
0.8 mg/dL) 
Doubling of creatinine 
(if pre-treatment value 
0.9-2.9 mg/dL) 
Neither Dec nor THU are known to be 
nephrotoxic. Consider other causes of worsening 
renal function. If no other causes are identified, 
hold THU-Dec until levels recover below 
threshold, then restart with decrease in dose by 1 
capsule each of Dec and THU. If recurrent 
toxicity occurs, interrupt study drug 
administration until recovery from toxicity then 
resume with a reduction in THU-Dec frequency 
to 1X/week. If toxicity recurs at this dose, 
interrupt study drug until toxicity resolved then 
resume at same dose and frequency. The overall 
goal is to sustain regular administration, at a 
lower dose if necessary, rather than infrequent 
administration of a higher dose, however, a 
minimum dose is required to produce DNMT1 
depletion.     
ALT 
ALT ≥ 2.5X the upper 
limit of normal 
Neither Dec nor THU are anticipated to be 
hepatotoxic. Consider other causes of worsening 
liver function (e.g., hepatitis). If no other causes 


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Non-Hematologic Toxicity ≥ Grade 3:  
 
Hold drug until recovery to grade 1 or baseline then resume with a reduction in dose by 1 
capsule each of Dec and THU. If recurrent toxicity occurs, interrupt drug administration 
and after recovery from the toxicity, resume therapy with a decrease in frequency of 
administration to 1X/week. The overall goal is to sustain regular administration at a lower 
dose if necessary, rather than infrequent administration of a higher dose. Only continue 
treatment if it is judged to be in the best interests of the patient.  
 
7.2  
Dose Escalation of THU-Dec 
Inter-individual differences in cytidine analogue metabolism (e.g., differences in CDA 
expression between individuals39) are anticipated to require the ability to increase dose if 
necessary in some individuals in order to better achieve the intended molecular 
pharmacodynamic 
effect 
of 
non-cytotoxic 
DNMT1-depletion. 
The 
following 
considerations guide the option of dose escalation: 
 
If there is stable disease or partial response by RECIST v1.1 at the week 8 or 16 
staging CTs, and there are no treatment-related ≥grade 3 toxicities (Table 1), and 
blood count trends (trends in the absolute neutrophil, absolute lymphocyte and 
platelet counts) suggest that such treatment-related toxicities are not imminent, then 
the dose of THU and Dec can be increased by one capsule each. THU-Dec dose 
increases should not occur more often than every 4 weeks and only to a maximum of 2 
additional capsules of each drug from the starting dosage. ALTERNATIVELY, if the 
patient is receiving oral THU-Dec 1X/week because of previous frequency reduction, the 
frequency of administration can be increased to 2X/week at the same dose of oral THU-
Dec.  
 
7.3  
Dose Modification or dose delay of Nivolumab 
No Dose modification for nivolumab is suggested. Because of the potential for clinically 
meaningful nivolumab-related AEs requiring early recognition and prompt intervention, 
are identified, hold THU-Dec until levels recover 
below threshold, then restart with decrease in 
dose by 1 capsule each of Dec and THU. If 
recurrent toxicity occurs, interrupt study drug 
administration until recovery from toxicity then 
resume with a reduction in THU-Dec frequency 
to 1X/week. If toxicity recurs at this dose, 
interrupt study drug until toxicity resolved then 
resume at same dose and frequency. The overall 
goal is to sustain regular administration, at a 
lower dose if necessary, rather than infrequent 
administration of a higher dose, however, a 
minimum dose is required to produce DNMT1 
depletion.     


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management algorithms have been developed for suspected AEs of selected categories. See 
Appendix III 
 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not 
the event is attributed to nivolumab). If AE is felt to be immune related and attributable to 
nivolumab, if the patient is on the study arm they can continue THU-Dec while nivolumab 
is held.  
 
Dose delay criteria apply for all drug-related AEs. Nivolumab must be delayed until 
treatment can resume  
 
Nivolumab administration should be delayed for the following: 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
 Any Grade 3 skin, drug-related AE 
 Any Grade 3 drug-related laboratory abnormality, with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase 
or lipase: 
 Grade 3 lymphopenia or leukopenia does not require dose delay. 
 If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade ≥ 2 toxicity. 
 If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity. 
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated closely as clinically 
indicated and resume nivolumab dosing when re-treatment criteria are met. 
 
Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR total bilirubin 
 Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 


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 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment. 
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the next 
scheduled timepoint per protocol, the next scheduled timepoint will be delayed until dosing 
resumes. 
 
If treatment is delayed or interrupted for > 6 weeks, the subject must be permanently 
discontinued from study therapy, except as specified in discontinuation section.  
 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS  
 
8.1 Decitabine 
Dec is manufactured by ScinoPharm (Taiwan) and formulated by KP Pharmaceutical 
Technologies (Bloomington, IN, USA) as per Federal Good Manufacturing Practice 
guidelines. Dec is supplied as capsules containing 5 mg of Dec per capsule, in bottles 
containing 8 capsules per bottle, together with a drying agent. Bottles should be tightly 
closed and stored at 2-8oC in the refrigerator. The label on the bottles includes the following 
information:  the (i) name of the drug; (ii) quantity of drug per capsule; (iii) date of 
packaging; (iv) recommended storage temperature; (v) lot number of bulk drug used to 
generate the capsules. 
 
Side-Effects of Dec: Dec is an intravenously-administered therapeutic which is FDA-
approved for the treatment of the blood cancer myelodysplastic syndrome (MDS) under 
the brand name Dacogen. As such, the toxicology, pharmacology and ADME profile of 
Dec has been reviewed by the FDA (NDA #21,790). 
There is substantial information regarding the toxicity of Dec in humans from clinical trials 
in patients with MDS and AML, including relapsed or poor prognosis cases. Some of this 
information is summarized in the package insert for this FDA approved drug. In almost all 
studies, the patients received doses much higher than the Dec doses planned in this study. 
Leukopoenia was a major toxicity and nausea, or vomiting were common non-hematologic 
toxicities. A better guide to anticipated side-effects in this clinical trial are observations 
from clinical studies of Dec repositioned for non-cytotoxic DNMT1-depletion for sickle 
cell disease (SCD), -thalassemia intermedia and MDS. In these clinical trials there were 
no episodes of non-hematologic NCI/CTEP grade 2 or higher toxicity from Dec. In the 
SCD and -thalassemia trials, consistent with a non-cytotoxic mechanism of action, the 
main side-effect was an increase in the platelet count (as opposed to the usual side-effect 
of thrombocytopenia seen with cytotoxic treatments). Cytotoxicity/DNA damage assays 
based on bone marrow morphological examination, bone marrow DNA content analysis, 
VDJ recombination assay, erythrocyte micronucleus assay and gamma-H2AX assay were 


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also negative. These assays did not reveal evidence of DNA damage or cytotoxicity. The 
increase in the platelet count was not associated with any clinical adverse events, and 
specifically, without evidence by correlative studies for an increase in thrombotic tendency.   
 
8.2 Tetrahydrouridine 
THU is a uridine analogue competitive inhibitor of CDA with a multi-decade track-record 
of safety in several clinical trials92-103. THU does not have therapeutic utility as a separate 
entity, instead, it has been used to increase the activity of co-administered cytidine 
analogues in these clinical trials92-103. In almost all these clinical studies, the intended 
pharmacodynamic effect of the co-administered cytidine analogue (e.g., cytarabine) was 
cytotoxicity, and toxicities were from the co-administered cytidine analogue and not from 
THU28,92-103. Therefore, this clinical protocol contrasts with these previous studies in that 
THU is being used to create a pharmacologic profile of Dec that avoids cytotoxicity while 
simultaneously increasing non-cytotoxic DNMT1-depletion. 
Currently, THU is being used in three NIH-sponsored clinical trials: at 350-500 
mg/m2 administered daily for 3-5 consecutive days in combination with 5-fluoro-2’-
deoxycytidine (e.g. NCT00077051), or daily for 7 or more days in combination with other 
oncotherapeutics (e.g. NCT00378807, NCT00521183).  
 
 Table 2:  Clinical trials with tetrahydrouridine (THU) (published data).   
 
THU dose 
THU 
Route 
Combination drug 
Number 
of 
patients 
Toxicity attributed 
to THU? 
350 mg/m2 Q12 
hours x 4 days 
IV 
IV Ara-C 100-200 
mg/m2 Q12 hours x 
4 days 
32 
None reported 
350 mg/m2 daily 
x 5 days 
IV 
IV 5-fluoro-2’-
deoxycytidine 5-80 
mg/m2 daily x 5 
days 
11 
None reported 
2,100 – 2,800 
mg/m2 total dose 
IV 
IV Ara-C 1,200 - 
1,600 mg/m2 and 
carboplatin 900 
mg/m2 total dose 
8 
Myelosuppression, 
unacceptable 
hepatoxicity, 
diarrhea.  No 
attribution to direct 
THU effect 
(attributed to Ara-C 
co-administered with 
THU) 
2 - 4 mg/kg 
(approx 75-150 
mg/m2) for 3 
oral 
Oral 5-azacytidine 
0.2mg/kg for 3 
2 
None reported 


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consecutive days 
every week 
consecutive days 
every week 
25 – 50 mg/kg 
(approx 900 – 
1800 mg/m2) 
daily x 5 days 
IV 
IV Ara-C 0.1 – 0.2 
mg/kg (approx 4 – 8 
mg/m2) daily x 5 
days 
 
None reported.  
Toxicities were as 
expected from Ara-C 
alone 
200 mg/m2 x 1 
IV, SQ 
and 
oral 
none 
5 
None reported 
          
Side-Effects of THU: The single dose toxicology of THU was evaluated in dogs and Rhesus 
monkeys at intravenous doses of up to 1000mg/kg104: with the exception of local 
inflammation at the injection site, no notable toxic effects were attributed to the 
administration of THU. Administration of THU to humans by the IV, SQ (SQ), and oral 
(PO) routes, in combination with various cytidine analogues, in studies spanning over 30 
years, suggest it has a benign toxicity profile, including with oral administration for more 
than 1 year92-98 (summarized in Table 2). In a study of THU alone administered by IV, SQ 
and PO routes at a single dose of 200 mg/m2 to 5 patients with malignant melanoma, there 
was no mention of toxicities.92 Similarly, THU administered at a daily dose of 
approximately 900-1800 mg/m2 for 5 consecutive days together with cytosine arabinoside 
did not produce toxicities other than those expected with cytosine arabinoside alone98. A 
similar experience is described when THU was administered at 700 mg/m2 daily for 4 
consecutive days together with cytosine arabinoside.96 Currently, THU is being used in 
three NIH-sponsored clinical trials: at 350-500 mg/m2 administered daily for 3-5 
consecutive days in combination with 5-fluoro-2’-deoxycytidine (e.g. NCT00077051), or 
daily for 7 or more days in combination with other oncotherapeutics (e.g. NCT00378807, 
NCT00521183).  
 
 
Side-Effects of THU and decitabine in combination: In the Phase 1 clinical trial of oral 
THU and decitabine in combination administered 2X/week on consecutive days for 8 
weeks at the doses used in this clinical trial, the side-effects of the combination treatment 
were the side-effects expected with non-cytotoxic DNMT1-depletion by decitabine, that 
is, an increase in the platelet counts and total hemoglobin concurrent with a decrease in the 
absolute neutrophil counts.  
       
Astex Pharmaceuticals has evaluated the combination of an orally ingested THU 
analog (a fluorinated THU) in combination with oral decitabine 15-40 mg per day for 5 
consecutive days repeated every 28 days to treat patients with myeloid malignancies. The 
dose of decitabine evaluated in combination with the THU analog was thus ~2-3X higher 
than the doses of decitabine used in this clinical trial. There were no significant non-
hematologic adverse events attributed to the combination, with the main risks being related 
to myelosuppression as seen with similar doses of decitabine alone. 
 
Side-Effects of Nivolumab: See section 1.4.2 and Nivolumab Investigator Brochure for 
information on the Adverse events of nivolumab, the standard of care drug in this protocol.  
 


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8.2 
Definitions  
 
8.2.1 
Adverse Event   
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a preexisting medical condition in a clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of investigational product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.) 
 
 
NONSERIOUS ADVERSE EVENT 
 Nonserious Adverse Events are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement [e.g. 
IND US trial] as part of an annual reporting requirement.  
 Nonserious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status 
for the subjects.  
A nonserious adverse event is an AE not classified as serious.  
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 30days following 
the last dose of study treatment, unless they start other treatments for the cancer within that 
time, transition to hospice or expire within 30 days after treatment. AE evaluation can be 
done by chart review and/or telephone encounter. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for nonserious AEs that cause interruption 


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or discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
 any laboratory test result that is clinically significant or meets the definition of an 
SAE 
 any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
 any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
 
 
8.2.2   Serious Adverse Events  
 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
 Potential drug induced liver injury (DILI) is also considered an important medical 
event.  


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 Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE.  
 Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
 a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-threatening 
event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 
 Medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
       
Potential Drug Induced Liver Injury (DILI) 
     Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of 
potential DILIs, meeting the defined criteria, must be reported as SAEs Potential drug 
induced liver injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 


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exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for subject safety).  
The investigator must immediately notify Worldwide Safety at BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form which is provided upon request from BMS. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 
8.2.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur after 
the subject has signed the informed consent are fully recorded in the subject’s medical 
records. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, 


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dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received conmed or other intervention, etc. 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.3  
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 
Since there is an early stopping rule for this clinical trial (Section 6.4), all AEs related to 
toxicity that cause patients to withdraw from the study in the first 5 patients should be 
reported to the DSTC in “real-time”.  
 
For the purposes of safety reporting, all adverse events will be reported that occur on or 
after Cycle 1 Day 1, through 30 days after the final dose of study drug. Adverse events, 
both serious and non-serious, and deaths that occur during this period will be recorded in 
the source documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 


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Participating investigators (all sites) must report all serious adverse events to the 
Sponsorwithin 24 hours of discovery or notification of the event. The participating 
investigator must also provide follow-up information on the SAE until final resolution. 
Sponsor contact: 
 Yogen Saunthararajah, saunthy@ccf.org  and research coordinator, Sherry Fada, 
FADAS@ccf.org   
 
The Sponsor will review the SAE and report the event to the FDA, external collaborator(s), 
and IRB as applicable. 
 
It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL serious 
adverse events that occur on the study (e.g. ALL SAEs that occur at each enrolling 
institution) are reported to all participating sites. 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
 For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection in the protocol. 
 If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form. 
 If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) initially 
reported.) 
 If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS using the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization.  All SAEs should be 
followed to resolution or stabilization. 
 
Institutional Review Board Reporting Requirements: 
Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events.  
 


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8.5 
SAEs and OnCore 
All SAEs will be entered into OnCore.   
A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
 
9.0 
PHARMACEUTICAL INFORMATION  
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8. 
 
 
9.1 Decitabine (Dec) 
 
 
Decitabine (Dec), NSC127716 
5-aza-2’-dexocytidine 
9.1.1 Product Description 
Dec is manufactured by ScinoPharm (Tainan, Taiwan) and formulated by KP 
Pharmaceutical Technologies (Bloomington, IN, USA) as per current Federal Good 
Manufacturing Practice guidelines. Dec is supplied as capsules containing 5 mg of Dec per 
capsule, in bottles containing 8 capsules per bottle, together with a drying agent. Bottles 
should be tightly closed and stored in the refrigerator at 2-8oC. The label on the bottles 
includes the following information:  the (i) name of the drug; (ii) quantity of drug per 
capsule; (iii) date of packaging; (iv) recommended storage temperature; (v) lot number of 
bulk drug used to generate the capsules. 


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9.1.2 Therapeutic Classification: 
DNA methyl-transferase enzymes (DNMTs) recognize and methylate target 
deoxycytidines that precede deoxyguanines (CpG), and are components of larger multi-
protein complexes that mediate gene repression (silencing). Decitabine (Dec) is a 
deoxycytidine analogue with an unmodified deoxyribose and a single-base modification in 
the pyrimidine ring. This chemistry produces DNMT1-depletion without termination of 
DNA chain elongation or cytotoxicity within certain concentration ranges. The mechanism 
of action of Dec begins with uptake into cells, which involves membrane nucleoside 
transporters such as the human equilibrative nucleoside transporter (hENT1), followed by 
Dec phosphorylation, which is initiated by deoxycytidine kinase (DCK), then Dec 
nucleotide incorporation into the replicating genome. DNMT1 is covalently trapped, 
modified and depleted as it tries to methylate the 5-N position of the triazine ring of DNA-
incorporated Dec. Replacement of 0.3% of cytidine in genomic DNA with Dec is sufficient 
to deplete 95% of DNMT166. Unlike cytidine analogues such as cytarabine or gemcitabine, 
the sugar back-bone of Dec is physiologic. Therefore, at low concentrations, Dec does not 
terminate DNA chain synthesis67,68, and can deplete DNMT1 without causing significant 
DNA damage or cytotoxicity, both in vitro and in vivo67-72. Low doses of Dec sufficient to 
deplete DNMT1 and produce hypomethylation do not overwhelm the cellular DNA-repair 
machinery, and although temporary growth arrest (cytostatic effect) may occur, cell 
division ultimately continues but with depleted DNMT1, DNA hypomethylation and 
consequently altered gene expression66,70,73,74. At high Dec concentrations, hydrolytic 
cleavage at DNMT-CpG complexes overwhelms the cellular DNA-repair machinery, 
damaging the replicating genome to an extent that results in cell-death73. Within cells, and 
at mucosal barriers and in the plasma, cytidine deaminase (CDA) is the enzyme most 
important in the break-down of Dec.  
 
9.1.3 Method of Administration 
 
- Starting dose of oral THU and Dec is by weight (all subsequent doses are based on the 
Cycle 1 Day 1 dose with dose modifications based on toxicities and tumor response as 
described in the protocol): 
Weight 40-60kg = 2 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 61-80kg = 3 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 81-100kg or higher = 4 capsules of each drug. Dec capsules are ingested ~60 
minutes after THU capsules. 
 
Subsequent dose changes should be based on hematologic paramters, non-hematologic 
toxicities attributed to study drug or as specified in the protocol. 
 
- Timing between THU and Dec: Oral THU capsules followed ~60 minutes later by oral 
Dec capsules (oral Dec can be taken up to 6 hours after oral THU).  
  
- Frequency of THU and Dec ingestion:  


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Oral THU ~10 mg/kg is administered 60 minutes before oral decitabine ~0.2 mg/kg 
2X/week on consecutive days if there is no ≥ grade 3 treatment-related non-hematologic 
toxicity and the ANC is >0.5x109/L (if ANC is <0.5x109/L, treatment is held until 
recovery above this threshold then resumed with a dose reduction as per Table 1). 
 
- Patients will be required to have the treatment on the same consecutive days every week. 
If patients miss a dose they need they can make up the dose the same week (±3 days) and 
the study team needs to be notified. 
 
9.1.4 Storage requirements: Capsules should be stored in the original bottles in which 
they are supplied in the refrigerator at 2-8oC.  
 
9.1.5 Drug Accountability: The investigator or designated study personnel are responsible 
for maintaining accurate dispensing records of the study drug. All study drugs must be 
accounted for, including study drug accidentally or deliberately destroyed. Under no 
circumstances will the investigator allow the investigational drug to be used other than as 
directed by the protocol. If appropriate, drug storage, drug dispensing, and drug 
accountability may be delegated to the pharmacy section of the investigative site.  
 
9.1.6 Drug Destruction: At the completion of the study, there will be a final reconciliation 
of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged 
on the drug reconciliation form, signed and dated. Any discrepancies noted will be 
investigated, resolved, and documented prior to return of unused study drug. Unused drug 
is to be shipped back to source at completion of the study. Please contact Dr Yogen 
Saunthararajah, 9500 Euclid Avenue, R40, Cleveland, OH 44195, tel: 216 444 8170, email: 
saunthy@ccf.org regarding shipping arrangements.  
 
9.2 Tetrahydrouridine (THU) 
 
 
 
 
 
 
 
 
 
 
 
3,4,5,6-Tetrahydrouridine, NSC112907 
2(1H)-pyrimidinone, tetrahydro-4-hydroxy-1-beta-D-ribofuranosyl 
 
9.2.1 Product description: The THU is manufactured by ASH Stevens (Detroit, MI, USA) 
and formulated by KP Pharmaceutical Technologies (Bloomington, IN, USA) as per 
Federal Good Manufacturing Practice guidelines. THU is supplied as capsules containing 
250 mg of THU per capsule, in bottles containing 8 capsules per bottle, together with a 
drying agent. Bottles should be tightly closed and stored in the refrigerator at 2-8oC. The 


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label on the bottles includes the following information:  the (i) name of the drug; (ii) 
quantity of drug per capsule; (iii) date of packaging; (iv) recommended storage 
temperature; (v) lot number of bulk drug used to generate the capsules. 
 
9.2.2 Therapeutic Classification 
Tetrahydrouridine (THU) is a competitive inhibitor of the pyrimidine metabolism enzyme 
cytidine deaminase (CDA) with Ki values of 3-5x10-8M75,76. The very high affinity of THU 
for CDA may be due to its resemblance to a tetrahedral intermediate of cytidine formed by 
addition of water across the 3,4 double bond76. CDA binds THU approximately 4-orders 
of magnitude more tightly than uridine, the substrate for the reverse reaction catalyzed by 
CDA76. However, slow onset of inhibition suggests that structural reorganization precedes 
the formation of a stable enzyme-inhibitor complex76. 
 
9.2.3 Dosing Information: 
 
- Starting dose of oral THU and Dec is by weight (all subsequent doses are based on the 
Cycle 1 Day 1 dose with dose modifications based on toxicities and tumor response as 
described in the protocol): 
Weight 40-60kg = 2 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 61-80kg = 3 capsules of each drug. Dec capsules are ingested ~60 minutes after 
THU capsules. 
Weight 81-100kg or higher = 4 capsules of each drug. Dec capsules are ingested ~60 
minutes after THU capsules. 
 
Subsequent dose changes should be based on hematologic parameters, non-hematologic 
toxicities attributed to study drug or as specified in the protocol. 
 
- Timing between THU and Dec: Oral THU capsules followed ~60 minutes later by oral 
Dec capsules (oral Dec can be taken up to 6 hours after oral THU).  
  
- Frequency of THU and Dec ingestion:  
Oral THU ~10 mg/kg is administered 60 minutes before oral decitabine ~0.2 mg/kg 
2X/week on consecutive days if there is no ≥ grade 3 treatment-related non-hematologic 
toxicity and the ANC is >0.5x109/L (if ANC is <0.5x109/L, treatment is held until 
recovery above this threshold then resumed with a dose reduction as per Table 1). 
 
- Patients will be required to have the treatment on the same consecutive days every week. 
If patients miss a dose they need they can make up the dose the same week (±3 days) and 
the study team needs to be notified. 
 
9.2.4 Storage requirements: Capsules should be stored in the original bottles in which 
they are supplied in the refrigerator at 2-8oC.  
 
9.2.5 Drug Accountability: The investigator or designated study personnel are responsible 
for maintaining accurate dispensing records of the study drug. All study drugs must be 
accounted for, including study drug accidentally or deliberately destroyed. Under no 


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circumstances will the investigator allow the investigational drug to be used other than as 
directed by the protocol. If appropriate, drug storage, drug dispensing, and drug 
accountability may be delegated to the pharmacy section of the investigative site.  
 
9.2.6 Drug Destruction: At the completion of the study, there will be a final reconciliation 
of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged 
on the drug reconciliation form, signed and dated. Any discrepancies noted will be 
investigated, resolved, and documented prior to return of unused study drug. Unused drug 
is to be shipped back to source at completion of the study. Please contact Dr Yogen 
Saunthararajah, 9500 Euclid Avenue, R40, Cleveland, OH 44195, tel: 216 444 8170, email: 
saunthy@ccf.org regarding shipping arrangements.  
 
9.3 Nivolumab 
 
Nivolumab (OpdivoTM) is manufactured by Bristol Myers Squibb (New Jersey, USA) as 
per Federal Good Manufacturing Practice guidelines. It is FDA approved for use in 
metastatic NSCLC. The drug for the study will be provided by Bristol Myers. See section 
1.4 and 6.1 for details on the drug and dosing.  
 
PRODUCT INFORMATION TABLE: Please also see Drug Information in 
Investigators brochure 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab include laboratory coats and 
gloves. 


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For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) 
Investigator Brochure section for “Recommended Storage and Use Conditions”  
Handling and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product information and 
the Investigator Brochure and per local regulations. It is the responsibility of the 
investigator to ensure that investigational product is only dispensed to study subjects. The 
investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. If concerns regarding the quality or appearance 
of the study drug arise, the study drug should not be dispensed and contact BMS 
immediately. 
Please refer to the current version of the Investigator Brochure and/or shipment reference 
sheets for additional information on storage, handling, dispensing, and infusion 
information for nivolumab. 
Destruction  
Sponsor/Investigator drug destruction is allowed provided the following minimal 
standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the Sponsor SOPs and a copy provided to BMS upon request. 
• Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, ie, incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for BMS 
to review throughout the clinical trial period as per the study agreement.  
If conditions for destruction cannot be met, please contact BMS.  
It is the Sponsor Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established according 
to applicable federal, state, local, and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
Dose calculations and administration 
Describe timing of first dose from registration/randomization. For preparation and 
administration details please refer to the current Investigator Brochure. 
 


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Nivolumab will be given every two weeks at a dose of 240mg IV flat dose to be 
administered as a 60 minute IV infusion. 
Subjects may be dosed no less than 12 days from the previous dose of drug. There are no 
premedications recommended for nivolumab on the first cycle. 
The dosing calculations should be based on the actual body weight at baseline. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate 
the original dose, the dose must be recalculated. All doses should be rounded to the nearest 
milligram. There will be no dose modifications allowed. 
Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to Protocol Section 6.1.  Doses of nivolumab may be interrupted, delayed, or 
discontinued depending on how well the subject tolerates the treatment. 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/mL (10 mg/mL)   Nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore 
size, low-protein binding polyethersulfone membrane in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Nivolumab injection 
can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP to protein concentrations as low as 1 mg/mL. Care must be 
taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent.  
 
Dose Modifications 
Dose reductions or dose escalations are not permitted. 
 
Management Algorithms 
Guidelines for the management of immune related events can be found in the current 
Investigator Brochure AND in the approved USPI in the US. Investigators should decide 
the appropriate source of AE management for each protocol. 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. Management 
algorithms have been developed to assist investigators in assessing and managing the 
following groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 


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For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
algorithms. These algorithms are found in the Nivolumab IB [and in Appendix] of this 
protocol. The guidance provided in these algorithms should not replace the Investigator’s 
medical judgment but should complement it. 
 
Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment  
 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, and infusion reactions, and 
endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
 Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 
4 within 1 week of onset.  
 Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management within 72 hours of their onset 


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 Grade 4 lymphopenia or leucopenia 
 Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Investigator 
 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
 Dosing delays or interruptions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks, the 
Investigator must be consulted. Tumor assessments should continue as per 
protocol even if dosing is interrupted or delayed 
 Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-
related reasons may be allowed if approved by the Investigator. Prior to re-
initiating treatment in a subject with a dosing interruption lasting > 6 weks, 
the Investigator must be consulted. Tumor assessments should continue as 
per protocol even if dosing is interrupted 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
 
Treatment beyond radiographic progression is allowed if it is felt by the 
investigators that there is clinical benefit. If new or pre-existing asymptomatic brain 
lesions are noted on surveillance MRI. These patients need to be followed closely 
with follow up brain imaging on treatment and can receive gamma knife therapy 
while actively receiving therapy on study – study drugs do not require disruption 
while receiving gamma knife therapy unless clinically indicated to do so. Use of 
steroids after Gamma knife therapy should be minimized but can be used per 
clinical discretion of the treating radiation oncologist.  
 
Treatment of Nivolumab Related Infusion Reactions 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE Version 4.0 guidelines. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 


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50 mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor 
or ventilatory support indicated).  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, 
and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from 
symptoms.  
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids). 
 
 
 


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10.0 STUDY CALENDAR  
 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-screening 
(Visit 1) 
Main Study 
Screening (Visit 
2) 
1 
2  
3 
4 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follow-up 
Survival 
Follow Upb 
Every 12 weeks 
post discon 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
D1 
±4 
days 
D15 
±4 
days 
At time of 
Discon 
30 days post 
discon 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
THU-Dec 
 
 
2X/week 
 
 
 
 
G-CSF neutropenia 
prophylaxis 
 
 
G-CSF (e.g., Neupogen, Granix) Recommended 1X/week if ANC is <1.5 x 109/L 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical 
Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or 
Serum -HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Comprehensive Serum 
Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
 
Xc 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue Collection 
 
Xd 
 
Xd 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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a) Patients will receive Nivolumab every 2 weeks (± 4 days per protocol) (4 weeks i.e 
2 treatments=1 cycle) until progression (by RECIST v1.1) or unacceptable toxicity. 
A treatment break for upto 6 weeks for will be allowed upon discussion with study 
PI 
b) Patients will be monitored post study every 12 weeks (± 3 weeks) for post-study 
treatment status, clinical safety updates and survival; these could be done by review 
of patient’s medical records or contacting patient’s medical provider or the subject. 
c) Patients disease will be monitored with CT scans of the chest, abdomen and pelvis 
after every 2 cycles (i.e prior to every odd cycle +/- 7 days) or sooner if clinically 
indicated;  
d) Patients who have recent (<6 weeks from start of study treatment) tissue biopsy or 
patients who have had recurrence after surgery within 6 months of surgical 
resection may be eligible without a fresh biopsy; Rest of the patients will require a 
biopsy prior to study enrollment. Patients will require a repeat biopsy in 6-10 weeks 
post treatment prior to cycle 3 of nivolumab. If the biopsy is felt to be high risk by 
the treating physician or interventional radiologist, an exception may be made upon 
discussing with the PI. 
e) For Cycle 1 Day 1 (C1D1) labs, screening labs can be used if ≤1 week; pregnancy 
tests need to be done within 24hrs of first dose. 
 
11.0 
CORRELATIVE STUDIES 
 
Tumor Biopsies:   
Percutaneous US or CT-guided core-needle biopsy: Patients are ineligible if they refuse 
percutaneous biopsy or if in the judgement of interventional radiology or pulmonologist 
the risk of significant complications exceeds 2%105. If percutaneous biopsy is feasible, it is 
planned at protocol screening, between week 6-10, and at disease progression (biopsy at 
progression is mandatory if a subject wishes to cross-over). Where possible, FFPE tissue 
from the time of original diagnosis should also be obtained. 
 
Percutaneous, bronchoscopy or surgical biopsies could be considered; The objective is to 
obtain 0.5-1.5 cm cores. The tissue samples are processed according to specifications in 
the correlatives/lab manual;  
 
Peripheral blood collections for PK and correlative studies: Patients will have baseline 
and follow up on treatment pre-treatment blood sample for correlatives to evaluate markers 
described in section 1.6; Detailed blood collection procedures, processing, handling and 
shipping information are provided in the accompanying Laboratory Manual.  
 
12.0  MEASUREMENT OF EFFECT  
 
12.1 Primary End Point 
Objective response: Objective response (OR) is the primary endpoint of this trial, subjects 
with measurable disease will be assessed by standard criteria. For the purposes of this 
study, subjects should be re-evaluated with CT scan with contrast (if clinically indicated 


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non-contrast CT or PET/CT could be used in lieu of CT with contrast) every 8 of weeks i.e 
after every 2 cycles (4 treatments) of Nivolumab.  
 
Evaluation of response: Response and progression will be evaluated in this study using the 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)106.  For 
the purpose of this study treatment will be discontinued in patients who experience disease 
progression by RECIST v1.1 (see Appendix IVa) with the following caveat: since it is 
known that there can be initial progression by RECIST v1.1 criteria with immune 
checkpoint blockade followed by subsequent regression and clinical benefit, if the treating 
clinical team and the patient judge that they have benefitted from therapy, treatment 
continuation is allowed even if there is disease progression by RECIST v1.1 criteria. 
However, patients should have confirmed stable disease or better at the time of the 
following scheduled imaging time-point.ORR is defined as the proportion of all 
randomized subjects whose best overall response (BOR) from baseline is either a CR or 
PR per RECIST v1.1 criteria. BOR is determined by the best response designation recorded 
between the date of randomization and the date of objectively documented progression or 
the date of subsequent anti-cancer therapy, whichever occurs first. For subjects without 
documented progression or subsequent anticancer therapy, all available response 
designations will contribute to the BOR determination. For subjects who continue 
treatment beyond progression, the BOR should be determined based on response 
designations recorded at the time of the initial RECIST v1.1. 
 
12.2 Secondary End Point 
 
       a) Progression free survival: It is defined as the time from randomization to the 
date of the first documented tumor progression (per RECIST v1.1) or death due to 
anycause. Subjects who die without a reported prior progression will be considered to have 
progressed on the date of their death. Subjects who did not progress or die will be 
censored on the date of their last evaluable tumor assessment. Subjects who did not have 
any on study tumor assessments and did not die will be censored on the date they were 
randomized. Subjects who started any subsequent anti-cancer therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to 
initiation of the subsequent anti-cancer therapy. Progression will be assessed every 
6 weeks (from the first on-study radiographic assessment) until disease progression is 
noted.  
 
         b) Overall survival: It is defined as the time from randomization to the date of death. 
A subject who has not died will be censored at last known date alive. OS will be followed 
continuously while subjects are on the study drug and every 3 months via in-person or 
phone contact after subjects discontinue the study drug. 
 
         c) Safety and tolerability: Safety and tolerability objective will be measured by the 
incidence of adverse events, serious adverse events, deaths, and laboratory abnormalities. 
Adverse event assessments and laboratory tests are performed at baseline, and continuously 
throughout the study at the beginning of each subsequent cycle. The safety analysis will be 
performed in all treated subjects. Descriptive statistics of safety will be presented using 


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National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 by treatment arm. All treatment emergent AEs, drug-related AEs, 
SAEs and drug-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.0 
criteria by system organ class and preferred term. On-study lab parameters including 
hematology, coagulation, chemistry, liver function and renal function will be summarized 
using worst grade per NCI CTCAE v 4.0 criteria. 
 
         d) Exploratory analysis: Other exploratory endpoints for include mainly anti-tumor 
immune response evaluation (tumor adaptive and innate cell immune responses), tumor 
tissue biomarker analysis, imaging based biomarkers and molecular pharmacodynamics 
analysis (DNMT1-protein in peripheral blood buffy coat cells and by measurement of 
plasma CDA enzyme activity by HPLC enzyme assay). These are discussed in detail in 
section 1.6. 
 
All subjects who signed an informed consent form, randomized and registered for the study 
will be included in the primary dataset for analyses of baseline characteristics, efficacy and 
biomarker analysis. All treated subjects, i.e all randomized subjects who received at least 
one dose of nivolumab or 1 dose of THU-Dec combination will be evaluated for safety and 
tolerability.  
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1     Data Reporting  
The Overture and OnCore™ Databases will be utilized, as required by the Case 
Comprehensive Cancer Center, to provide data collection for both accrual entry and trial 
data management. Overture and OnCore™ are Clinical Trials Management Systems 
housed on secure servers maintained at Case Western Reserve University. Access to data 
through Overture and OnCore™ is restricted by user accounts and assigned roles. Once 
logged into the Overture or OnCore™ system with a user ID and password, Overture and 
OnCore™ define roles for each user which limits access to appropriate data. User 
information and password can be obtained by contacting the OnCore™ Administrator at 
OnCore-registration@case.edu. 
 
Overture and OnCore™ are designed with the capability for study setup, activation, 
tracking, reporting, data monitoring and review, and eligibility verification. This study will 
utilize electronic Case Report Form completion in the Overture database. A calendar of 
events and required forms are available in Overture and OnCore™. 
 
 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 


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13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study as well as the subject’s financial responsibility. Subjects must also be notified 
that they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and be allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart 
in conformance with the institution’s standard operating procedures. A copy of the signed 
written Informed Consent Form must be given to the subject. Additionally, documentation 
of the consenting process should be located in the research chart. 
 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including 
subjects’ medical history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements. For multi-center studies, participating sites must inform the 
sponsor-investigator of pending audits.  
 


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APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 


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ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to carry on all pre-
disease performance without restriction. 
 
100 
 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
 
1 
Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work.  
 
2 
bed < 50% of the time.  Ambulatory and capable of all 
self-care, but unable to carry out any work activities. 
Up and about more than 50% if waking hours. 
 
60 
Requires occasional assistance, but is able to 
care for most of his/her needs. 
 
50 
equires considerable assistance and frequent 
medical care. 
 
3 
In bed > 50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of 
waking hours. 
 
40 
 
sabled, requires special care and assistance. 
 
30 
 
Severely disabled, hospitalization indicated.  
Death not imminent. 
 
4 
00% bedridden.  Completely disabled.  Cannot carry on 
any self-care. Totally confined to bed or chair. 
 
20 
Very sick, hospitalization indicated. Death 
not imminent.  
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead 
 
 
 
 
 
 
 
 
 
APPENDIX II 
SUBJECT CAPSULE DIARY FOR TWICE WEEKLY DOSING 
 Add or delete columns and rows and revise the information in red as appropriate for the trial. 
Subject Name ______________________ Subject Study ID __________   Today’s date ___/___/___ 
Drug _____________________________ Cycle #:_______________________________      


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INSTRUCTIONS FOR THE SUBJECT: 
1. Complete one form every 4 weeks (one treatment cycle). 
2. You will take ___number of capsules of THU 60 minutes before ___number of capsules of Decitabine on ______day of week and 
_______day of week (twice a week). Take the capsules with or without food, as you wish.  
3. Record the date, the number of capsules of each drug that you took, and what time you took them.  
4. If you have any comments or notice any side effects, please record them in the “Comments” column. 
5. Please bring this form and your bottles of THU and Decitabine to your physician when you return for each appointment.   
6. Please sign your name at the bottom of the diary. 
Day 
Date 
Time of 
THU 
dose 
# of capsules taken 
Time of 
Decitabine 
dose 
# of capsules 
taken 
 
Comments 
___ mg ___ mg 
 
___ 
mg 
___ 
mg 
 
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 
 
 
 
 
 
 
 
 
 
Add/remove days as needed 
Subject’s Signature: ____________________________________________ Date: _____________ 
 
 
 


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Appendix III 
 
Immune related adverse event management algorithms 
 
     These general guidelines constitute guidance to the Investigator. The guidance applies to all 
immuno-oncology (I-O) agents and regimens.  A general principle is that differential diagnoses 
should be diligently evaluated according to standard medical practice. Non-inflammatory 
etiologies should be considered and appropriately treated. Corticosteroids are a primary therapy 
for immuno-oncology drug-related adverse events. The oral equivalent of the recommended IV 
doses may be considered for ambulatory patients with low-grade toxicity. The lower 
bioavailability of oral corticosteroids should be taken into account when switching to the 
equivalent dose of oral corticosteroids. Consultation with a medical or surgical specialist, 
especially prior to an invasive diagnostic or therapeutic procedure, is recommended. The 
frequency and severity of the related adverse events covered by these algorithms will depend on 
the immuno-oncology agent or regimen being used. 
 
 
 
 
 


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Appendix IV 
 
A) RECIST Criteria: 
 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, CNS metastases, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
 
Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions.  
Measurements of these lesions are not required but the presence or absence of each should be 
noted throughout follow-up.  
 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 


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Clinical lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI 
These techniques should be performed with cuts of 10 mm or less in slice thickness contiguously.  
Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  This applies 
to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those of extremities 
usually require specific protocols. 
 
Ultrasound (US) 
When the primary endpoint of the study is objective response evaluation, US should not be used 
to measure tumor lesions.  It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might also be 
useful to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
Endoscopy and Laparoscopy 
The utilization of these techniques for objective tumor evaluation has not yet been fully and widely 
validated.  Their uses in this specific context require sophisticated equipment and a high level of 
expertise that may only be available in some centers.  Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in reference centers.  
However, such techniques can be useful to confirm complete pathological response when biopsies 
are obtained. 
 
Tumor markers 
n/a 
 
Cytology and Histology 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). 
 
Response Criteria 
 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 


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Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded from the time treatment was started or from the 
time treatment was held or the appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment was started or held. 
 
Evaluation of Non-target Lesions 
Complete Response (CR): Disappearance of all non-target lesions 
 
Incomplete Response/ 
Stable Disease (SD): Persistence of one or more non-target 
lesion(s) or/and maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the progression status 
should be confirmed at a later time by the review panel (or study chair). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
 
 
 
 


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CR 
CR 
No 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.”  Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
 
Confirmatory Measurement/Duration of Response 
 
Confirmation 
n/a 
 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR or PR (whichever is first recorded) until the first date that progression of disease 
is objectively documented while on study drugs (taking as reference for progressive 


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disease the smallest measurements recorded since the treatment was started or since 
treatment was last initiated). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met while on study drugs, taking as reference the smallest measurements recorded 
since the treatment started or since treatment was last initiated.  
 
Time to Disease Progression 
Time to disease progression will be recorded from the first day of protocol therapy until 
the criteria for disease progression are met while on sunitinib treatment, patient death from 
any cause or removal of the patient from study for any reason, whichever comes first.