Clinical trial NCT04934670
Conditions: Steroid-Refractory Acute Graft Versus Host Disease
Keywords: T-Guard Ruxolitinib Steroid-Refractory GVHD Acute GVHD aGVHD Grade III Grade IV Complete Response (CR) Transplant Hematopoietic Stem Cell Transplant (HSCT)
Sponsor: Xenikos
Start date: 2022-06-16; Completion date: 2023-01-19
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, randomized, Phase 3, multicenter trial, which has been designed to compare the efficacy and safety of T-Guard to ruxolitinib in patients with Grade III or IV Steroid-Refractory acute Graft-Versus-Host Disease (SR-aGVHD). The primary hypothesis is that T-Guard treatment will improve the Day 28 complete response (CR) rate in patients with Grades III and IV SR-aGVHD compared to ruxolitinib.

Detailed description:
Graft-vs-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. Acute GVHD (aGVHD) typically develops within the first three months after HSCT and is typically treated with steroid therapy. A significant fraction of the aGVHD population (10-50%) fail to respond to treatment and are deemed steroid-refractory (SR).

Participants that develop Grade III or IV SR aGVHD will be randomized to receive T-Guard or ruxolitinib and will be followed for approximately 180 days. Participants will be stratified by center region (US vs. Europe) and age group (at least 55 years vs. under 55). Participants randomized to the T-Guard arm will receive 4 doses administered intravenously as four 4-hour infusions, and participants randomized to the ruxolitinib arm will receive one dose administered orally twice a day. The primary analysis will include all participants that are randomized.

Arms: arm 1: Participants will be administered four doses of T-Guard intravenously for a 4-hour period every other day arm 2: Participants will take ruxolitinib twice daily for continuous daily dosing
Interventions: intervention 1: T-Guard intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: T-Guard will be administered intravenously inpatient over 4 hours every 2 calendar days on Days 0, 2, 4, and 6, at a dose of 4mg/m2 Body Surface Area (BSA). intervention 2: Ruxolitinib will be administered orally twice a day starting on Day 0 through Day 56, at a dose of 10mg. Ruxolitinib taper can be initiated starting on Day 56 for participants responding to treatment, tapering will be done according to institutional practices.

Protocol documents:
ICF_000.pdf: 
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Informed Consent to Participate in Research 
BMT CTN 2002 
A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY, TO 
COMPARE T-GUARD TO RUXOLITINIB FOR THE TREATMENT OF PATIENTS 
WITH GRADE III OR IV STEROID-REFRACTORY ACUTE GRAFT-VERSUS-
HOST DISEASE (SR-AGVHD) 
 
Your Name: 
__________________________ 
Principal Investigator: 
__________________________ 
[Insert local PI information] 
 
Sponsor:  
This study is sponsored by Xenikos, BV and the National Institutes of 
Health, through the Blood and Marrow Transplant Clinical Trials Network  
 
<US country specific language, please delete for other countries> 
The ethics of this study have been reviewed and approved by the NMDP IRB. 
<Europe country specific language, please delete for other countries> 
The ethics of this study have been reviewed and approved by the EC in your country.  
 
Your study doctor or nurse will review this Consent Form with you, including: 
 The purpose of the research 
 Possible risks and benefits 
 Other options available to you 
 Your rights if you join the study 
 
 


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1. 
Study Overview  
We invite you to join this clinical trial, also known as a research study. You are being asked to 
join because: 
• You have acute graft-versus-host disease (aGVHD)  
• Your aGVHD symptoms did not get better with steroids (steroid-refractory) 
We’re doing this study because we want to see how well a new medicine, T-Guard, works 
compared to another medicine called ruxolitinib.  
In a previous clinical trial, ruxolitinib improved aGVHD for about half of patients. However, 
most patients still had aGVHD symptoms after a month of treatment. Ruxolitinib also has side 
effects and doctors don’t know how long patients should take it. We are testing whether T-Guard 
works better and has fewer side effects. 
This study will include 246 people at about 75 hospitals across the USA and Europe and will last 
about 3 years. If you join, you will: 
• Be in the study for up to 180 days, and contacted for follow-up after that 
• Get either T-Guard or ruxolitinib to treat your aGVHD. If your doctor thinks it’s best for 
your health, you will also keep taking your steroid medicine. 
• Give blood and urine samples to see how your body responds to the treatment  
• Take surveys about your quality of life or ability to complete daily tasks 
Some possible risks and benefits of joining the study include: 
Possible Risks: T-Guard or ruxolitinib may not help your aGVHD. You may have side 
effects during the study. Specific side effects depend on which medicine you get and can 
range from mild to severe. The study team will watch you carefully for any side effects 
and will do everything they can to keep you safe and treat any side effects.  
Possible Benefits: T-Guard or ruxolitinib may help your aGVHD. Doctors may learn 
more about T-Guard and ruxolitinib to treat future patients with aGVHD that doesn’t get 
better with steroids. 
If you do not join the study, your doctor will talk to you about other treatment options.  
 
<US country specific language, please delete for other countries> 
Ruxolitinib is the only drug approved by the FDA for treating aGVHD that does not get better 


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with steroids. You may have the option to receive ruxolitinib without joining the study. 
 
<Europe country specific language, please delete for other countries> 
In Europe there is not an approved drug to treat aGVHD that does not get better with steroids. 
Your doctor will talk to you about the best options to treat you. 
 
Key points: 
• Being in this research study is your choice. 
• You may or may not benefit from being in the study. Knowledge gained from this study may 
help others. 
• If you join the study, you can leave the study at any time. If you decide to leave the study, it 
will not affect your care at [name of facility or institution]. 
• Ask the study staff questions about anything you do not understand, or if you would like 
more information. You can ask questions now or at any time. 
• Take time to talk about the study with your doctor, study staff, and your family and friends. It 
is your choice to be in the study. If you decide to join, please sign the end of this Consent 
Form. You’ll get a copy to keep.  
2. 
Study Purpose 
We’re doing this study to see how T-Guard works compared to ruxolitinib to treat aGVHD that 
doesn’t get better with steroids. We want to know if T-Guard and ruxolitinib therapy will make 
your aGVHD go away completely after 28 days.  
Even though doctors have learned a lot about how the immune system reacts to a blood or 
marrow transplant (BMT), aGVHD is a common and serious side effect. Doctors and researchers 
want to find a good treatment for aGVHD when it doesn’t get better with steroids.  
This study is designed to see the benefits and risks of T-Guard. T-Guard has not been approved 
by the FDA, European Medicines Agency (EMA), or other regulatory authorities. T-Guard, as of 
November 2020, has been given to 44 patients with aGVHD that did not respond to steroids. T-
Guard improved aGVHD in over half of those patients. 
This research study is registered with the FDA and EMA. Both will monitor the research study. 


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3. 
Study Treatment and Tests 
Once you agree to be in the study, you will need to have several tests to see if you meet the study 
requirements. Most of these check-ups and tests are already part of your regular care and will be 
done even if you do not join the study. The tests include: 
• Complete aGVHD and medical history evaluation 
• Draw blood (about 15 mL or 3 teaspoons [insert volume according to local standard]) to 
test: 
o The number of different blood cells you have (cell counts) 
o How well your liver and kidneys work 
o If there is any damage to your blood and vessels  
• Pregnancy test (if you could be pregnant) 
Before Your Treatment 
If you meet the study requirements, a computer will assign you to get either T-Guard or 
ruxolitinib. The computer assigns you by chance, like flipping a coin or drawing a name out of a 
hat. This is called randomization. Neither you nor your study doctor will have any control over 
which treatment group you’re assigned to. You’ll have an equal chance of being assigned to 
either group. 
Before you start your treatment, we will do several tests to check your health. These tests will 
include: 
• Physical exam, including a Performance Score. A Performance Score is when your doctor 
will see how well you can do certain activities like going to work and caring for yourself. 
• Complete aGVHD evaluation 
• Draw blood (about 15 mL or 3 teaspoons [insert volume according to local standard]) to 
test: 
o The number of different blood cells you have (cell counts) 
o How well your liver works 
o If you have cytomegalovirus (CMV) or Epstein-Barr virus (EBV). CMV and EBV 
may not cause symptoms before transplant but can be serious after getting a 
transplant. 
• Research blood samples to see: 
o How your immune cells respond to the treatment (about 5 mL or 1 teaspoon will 
be drawn) if you are randomized to receive T-Guard 
o How your blood cells respond to the treatment (about 30 mL or 2 tablespoons will 
be drawn) 


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o How your immune system recovers (about 10 mL or 2 teaspoons will be drawn) 
o Whether changes in your blood cells (biomarkers) show if the treatment works for 
you (about 5 mL or 1 teaspoon will be drawn) 
• Research urine sample to see whether changes in your urine (biomarkers) show if the 
treatment works for you (about 6 mL or 1 teaspoon will be collected) 
• A series of questionnaires to see how the disease and treatment has affected your quality 
of life. They will take about 20 to 30 minutes to complete. If you use reading glasses, 
bring them to your appointments. 
During the Study 
During the study, we will do regular tests to check your health during and after you get 
treatment. Many tests will be done once a week for about 8 weeks after you start study treatment. 
Some tests will happen less often. We’ll look at: 
• Your aGVHD  
• For signs of chronic graft-versus-host disease (cGVHD) 
• Your Performance Score 
• Your blood pressure 
• Draw blood (about 15 mL or 3 teaspoons [insert volume according to local standard]) to 
test: 
o How many different blood cells you have (cell counts) 
o How well your liver and kidneys work 
o If there is damage to your blood and vessels 
o If you have cytomegalovirus (CMV) or Epstein-Barr virus (EBV). 
• Research blood samples to see: 
o How your immune cells respond to the treatment (about 5 mL or 1 teaspoon will 
be drawn) if you are randomized to receive T-Guard 
o How your blood cells respond to the treatment (about 30 mL or 2 tablespoons will 
be drawn) 
o How your immune system recovers (about 10 mL or 2 teaspoons will be drawn) 
o Whether changes in your blood cells (biomarkers) show if the treatment works for 
you (about 5 mL or 1 teaspoon will be drawn) 
• Research urine sample to see whether changes in your urine (biomarkers) show if the 
treatment works for you (about 6 mL or 1 teaspoon will be collected) 
• Any side effects you may have and medications you may be taking 
• A series of questionnaires to see how the disease and treatment has affected your quality 
of life. They will take about 20 to 30 minutes to complete. If you use reading glasses, 


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bring them to your appointments. 
If you’re randomized to T-Guard, you can expect to: 
• Stay in the hospital for at least 1 week 
• Get T-Guard through an intravenous (IV) infusion every 2 days for a total of 4 doses. 
Each infusion takes 4 hours. 
• Get medicine to prevent allergic reactions before each dose 
• Have your temperature, heart rate, breathing rate, and blood pressure checked during and 
after each infusion 
• Draw blood before, right after, and the day after each dose of T-Guard (about 5 mL or 1 
teaspoon will be drawn each time; with a total maximum of 25 mL or 5 teaspoons on the 
day of infusion) to see: 
o How much T-Guard is in your blood 
o The amount of proteins in your blood that may change your immune response 
When you finish T-Guard treatment, you’ll visit the clinic at least 1 time each week for 7 weeks. 
Then, you’ll visit the clinic on days 70 and 90, and 180 after treatment. Your doctor may want to 
see you more often.  
If you’re randomized to ruxolitinib, you can expect: 
• You’ll take ruxolitinib, which is in pill form, 2 times each day by mouth for at least 56 
days.  
• You’ll visit the clinic at least 1 time each week for 8 weeks when you start treatment. 
Then, you’ll visit the clinic on days 70, 90, and 180 after treatment. Your doctor may 
want to see you more often. 
Tables 1 and 2 show all the tests you can expect to get for each treatment. The numbers for each 
column are the number of days after your first study treatment. 
 


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Table 1. Schedule of Study Tests for T-Guard 
Test 
Prior to 
Randomization 
Day of 
Randomization 
and Prior to 
Treatment 
First 
Infusion 
Second 
Infusion 
Third 
Infusion 
Fourth 
Infusion 
Follow-up (# days after randomization) 
0 
2 
4 
6 
14 
21 
28 
35 
42 
49 
56 
70 
90 
180 
Acute GVHD evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood tests to see:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Your protein levels 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
• How well your liver works 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• How well your kidneys work 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
• If there is damage to your blood and 
vessels 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
• How much enzyme is in your muscles 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• How many different cells are in your 
blood 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
• If you have EBV or CMV  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
• How well your immune cells work 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
• How many antibodies you have 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
• How your body is responding to the drug 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
• How the GVHD is responding to the 
drug 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
• How much T-Guard is in your blood 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Chronic GVHD evaluation 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Health history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Score (How well you can do 
daily activities) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Physical exam 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of life questions 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Urine sample for GVHD biomarkers 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 


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Table 2. Schedule of Study Tests for Ruxolitinib 
Test 
Prior to 
Randomization 
Day of 
Randomization and 
Prior to Treatment 
Treatment and Follow-up (# days after randomization) 
0 
6 
14 
21 
28 
35 
42 
49 
56 
70 
90 
180 
Acute GVHD evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood tests to see: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Your protein levels  
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
• 
How well your liver works 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
How well your kidneys work  
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
• 
If there is damage to your blood and vessels 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
• 
How much enzyme is in your muscles 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
How many different cells are in your blood 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
• 
If you have EBV or CMV 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
• 
How well your immune cells work 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
• 
How many antibodies you have 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
• 
How the GVHD is responding to the drug 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
Chronic GVHD evaluation 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Health history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Score (how well you can do daily activities) 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of life questions 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Urine sample for GVHD biomarkers 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 


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4. 
Risks and Benefits 
Possible Benefits 
T-Guard or ruxolitinib may help your aGVHD get better. Doctors may learn more about T-Guard 
and ruxolitinib to treat future patients with aGVHD that doesn’t get better with steroids. 
Possible Risks 
T-Guard or ruxolitinib may not help your aGVHD get better. You may have side effects that 
range from mild to severe (including death). Your health care team may give you medicine to 
help with certain side effects, like an upset stomach. 
Your doctor will watch you carefully for any side effects. The study team will do everything they 
can to keep you safe and to treat any side effects. Tell your doctor about any side effects you 
have. 
A. Risks of T-Guard 
As of November 13, 2020, 44 patients have received T-Guard through their participation in a 
clinical trial or special access program for the treatment of aGVHD that did not respond to steroids 
(43 patients) or for the treatment of Systemic Sclerosis (1 patient). The side effects, as seen in 
aGVHD patients that used T-Guard as 2nd line treatment, are shown in the table below. Several of 
these side effects are common in people with aGVHD. T-Guard might increase the likelihood that 
(some of) these side effects develop. Of the patients that received T-Guard, some died within 30 
days of getting their first dose of T-Guard. Although it is possible T-Guard contributed to these 
deaths, these patients were also very ill with other complications when they started treatment. The 
eligibility criteria to be allowed to be part of this study help to reduce the risks for patients. Your 
study doctor can provide more details on how we will be monitoring your safety. 
 
 


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Table 3. Risks and Side Effects of T-Guard 
Likely 
(Seen in more than 20% of patients) 
Less Likely 
(Seen in 10% to 20% of patients) 
• 
Fever 
• 
High blood sugar 
• 
High protein or enzyme levels in your 
blood, which could be a sign of liver 
damage 
• 
Infections, which could be mild to 
moderate (for instance in the lungs, 
mouth, eyes, skin, urinary tract) which 
may or may not require treatment or 
could be severe and lead to death 
• 
Low platelet counts, which may cause 
bruising or bleeding 
• 
Low protein, calcium, magnesium, or 
phosphate levels in your blood 
• 
Muscle weakness 
• 
Swollen arms, legs or other body parts 
• 
Blood vessels leaking fluid to your body 
tissues, which may result in swelling 
• 
Abdominal pain 
• 
Bleeding in your stomach or intestines  
• 
Changes to the acid level of your blood 
• 
Chronic GVHD 
• 
Confused thinking 
• 
Cough 
• 
Damaged red blood cells 
• 
Difficult breathing 
• 
Fatigue or tiredness 
• 
Headache 
• 
Hemorrhoids or piles 
• 
High heart rate and heart rhythm changes 
• 
High potassium or sodium levels in your blood  
• 
Indigestion (pain in the stomach after eating) 
• 
Kidney reduced functioning or failure 
• 
Low blood pressure 
• 
Low potassium or sodium levels in your blood 
• 
Low red blood cell counts 
• 
Low white blood cell count, which can raise 
your risk of infection 
• 
Nausea 
• 
Pain, bruising or swelling where you got the 
infusion 
• 
Pain in arms, hands, legs, or feet 
• 
Thrombotic Microangiopathy (TMA): 
Developing GVHD increases your risk for 
TMA. TMA can lead to low blood counts, 
organ failure, such as kidney failure, and even 
death. It is possible that T-Guard may further 
increase your risk of TMA. We will monitor 
you closely for signs of TMA and we will not 
continue treatment with T-Guard if you develop 
TMA. 


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Potential serious risks in medicines like T-Guard 
T-Guard belongs to a family of drugs (antibodies that are connected to a toxin), and some of the 
drugs in this family have certain side effects. When these side effects occur, they may have 
serious consequences. These side effects are: 
• Swelling of the muscles causing muscle pain and weakness 
• Life-threatening allergic reactions (anaphylaxis) to the drug, which may cause trouble 
breathing and death 
• Cytokine release syndrome, which can cause fever, nausea, headache, rash, fast heartbeat, 
low blood pressure, and trouble breathing 
Reproductive and Breastfeeding Risks with T-Guard 
T-Guard may or may not affect your ability to have children. We also don’t know how it affects 
unborn babies. Because of this, it is important that you are not pregnant or breastfeeding and that 
you (or your partner) do not become pregnant while you’re in this study. 
If you are sexually active, you will need to use birth control. Talk with your doctor about ways to 
prevent pregnancy. If you can become pregnant, you must use birth control until 30 days after 
your last infusion of T-Guard. If your partner can become pregnant, you must use birth control 
from the start of your treatment until 65 days after your last infusion of T-Guard. 
Tell your doctor right away if you or your partner becomes pregnant during the study. 
Your doctor will talk with you about the risks to your unborn child and your options. If you are 
pregnant, you will be asked to stop study treatment. 
B. Risks of Ruxolitinib 
The table below shows side effects seen in people who have received ruxolitinib. 
 
 


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Table 4. Risks and Side Effects of Ruxolitinib 
Likely 
(Seen in more than 20% of 
patients) 
Less Likely 
(Seen in 10% to 20% of 
patients) 
Rare, but Serious 
(Expected to happen in 2% or 
fewer patients) 
• 
High cholesterol  
• 
Increased enzyme levels in 
your blood, which could be 
a sign of liver damage 
• 
Low platelet levels, which 
may cause bruising or 
bleeding 
• 
Low red blood cell counts 
• 
Diarrhea, constipation, 
nausea, passing gas 
• 
Dizziness 
• 
Headache 
• 
High blood pressure 
• 
High triglyceride levels in 
your blood 
• 
Infection, which may cause 
fever and chills 
• 
Low white blood cell count, 
which can raise your risk of 
infection 
• 
Muscle spasms 
• 
Problems sleeping 
• 
Trouble breathing 
• 
Weight gain 
• 
Allergic reaction which may 
cause rash, low blood 
pressure, wheezing, 
shortness of breath, swelling 
of the face or throat 
• 
Brain swelling that can 
cause confusion, weakness, 
trouble speaking, sadness or 
personality changes, trouble 
with memory, balance 
problems, and/or changes in 
vision 
• 
Skin cancers 
 
Reproductive and Breastfeeding Risks with Ruxolitinib 
Although the FDA allows for ruxolitinib to be used for someone who is pregnant if the potential 
benefits to the parent outweigh the potential risks to the unborn child, these risks are not fully 
known.  In animal studies, pregnant animals were given this medication and had some babies 
born with problems. It is important that you are not pregnant or breastfeeding and that you (or 
your partner) do not become pregnant while you’re in this study. 
If you are sexually active, you will need to use birth control. Talk with your doctor about ways to 
prevent pregnancy. If you can become pregnant, you must use birth control until 30 days after 
your last dose of ruxolitinib. If your partner can become pregnant, you must use birth control 
from the start of your treatment until 65 days after your last dose of ruxolitinib. 
Tell your doctor right away if you or your partner becomes pregnant during the study. 
Your doctor will talk with you about the risks to your unborn child and your options. If you are 
pregnant, you may be asked to stop study treatment. 


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C. Other Risks 
Infections  
Because your immune system will be weak, you have a higher risk for infections, which can be 
fatal. You’ll get medicines to help your body prevent infection, but you’ll still be watched 
carefully for any sign of infection. Tell your doctors right away if you get a fever, chills, cough 
or any other new symptoms. They may be a sign of an infection. 
Other Treatments or Medicines 
Some medicines react with each other, so it’s important to tell the study doctor or staff about any 
other drugs, treatments, or medicines you’re taking. This includes non-prescription or over-the-
counter medicines, vitamins, and herbal treatments.  
It’s also important that you tell the study staff about any changes to your medicines while you’re 
in the study. 
Blood Draws 
There are no major risks associated with drawing blood. Having your blood drawn can be 
uncomfortable and can sometimes cause a bruise. In rare cases, a blood draw can cause fainting. 
Only trained people will draw your blood.  
Surveys 
There are very few risks with taking the study surveys. Some of the questions or topics may 
upset you. If you are sad or upset, or if some of the survey questions or topics upset you, it is 
important to tell your doctor and care team. Your doctors can connect you with a counselor or 
trained support specialist if you want one. 
Unforeseen Risks 
There may be some unknown or unanticipated side effects from being in this study. Other new 
risks might come up at any time during the study. These risks might be different from what is 
listed in this Consent Form. 
For more information about risks and side effects, ask your study doctor. 
 
 


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5. 
Your Rights to Withdraw, Ask Questions, and Seek Other Treatment 
Being in this study is your choice. You can choose not to be in this study or leave this study at 
any time. If you choose to not join or leave this study, it won’t affect your regular medical care 
in any way. If the treatment does not work, you can still receive other treatment options 
available. 
You have the right to ask questions about the study at any time. If you have questions about your 
rights as a participant or you want to leave the study, please contact:  
[Insert contact details] 
If you want to talk with someone not directly involved in the study, or have any complaints or 
questions about your rights as a research participant, you may contact: 
[Insert contact details] 
If you choose not to join, other options are available. Your study doctor will talk with you about 
your options. If you decide not to join this study, your medical care will not be affected in any 
way. 
Every treatment option has benefits and risks. Talk with your doctor about your choices before 
you decide if you will be in this study. 
6. 
New Information Available During the Study 
During this study, the study doctors may learn new information about T-Guard, ruxolitinib or the 
risks and benefits of taking part in the study. If they learn new information, they’ll tell you as soon 
as it’s available. 
The new information may mean that you can no longer participate in the study, or you may not want 
to continue. If this happens, the study doctor will stop your participation and offer you all available 
care to meet your health care needs. 
7. 
Privacy, Confidentiality, and Use of Information 
 
<UK country specific language, please delete for other countries> 
Xenikos, BV (Xenikos) is the sponsor for this study taking place in the United Kingdom and 
elsewhere. Xenikos will be using information from you in order to undertake this study and will act 


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as the data controller for this study. This means that Xenikos will be responsible for looking after 
your information and using it properly. [<Optional if applicable> Xenikos has appointed [CRO] as 
its ‘representative’ to fulfil its obligations under this law.] Xenikos will keep identifiable 
information about you for 25 years after the study has finished. The information may be stored for 
longer, for example, when used in applications for approval to market a medicine. 
Your rights to access, change or move your information are limited, as we need to manage your 
information in specific ways in order for the research to be reliable and accurate. If you withdraw 
from the study, we will keep the information about you that we have already obtained. To safeguard 
your rights, we will use the minimum personally-identifiable information possible. 
Health and care research should serve the public interest, which means that we have to demonstrate 
that our research serves the interests of society as a whole. We do this by following the UK Policy 
Framework for Health and Social Care Research. 
We use personally-identifiable information to conduct research to improve health and care. As a 
pharmaceutical company we have a legitimate interest in using information relating to your health 
and care for research studies, when you agree to take part in a research study. This means that we 
will use your data, collected in the course of a research study, in the ways needed to conduct and 
analyse the research study. 
Your personal information may be shared with: 
• Xenikos and its present or future affiliates, 
• Research partners/service providers (such as laboratories conducting tests on behalf of 
Xenikos) and authorized representatives of Xenikos, 
• Study monitors appointed by Xenikos or Xenikos’ service providers to check how the study 
is going, 
• Auditors/inspectors appointed by Xenikos or Xenikos’ service providers or by health and 
regulatory authorities to check that the study is being run properly, 
• Relevant health and regulatory authorities such the Food and Drug Administration (FDA) in 
the United States of America and the European Medicines Agency (EMA). 
Recipients of your information may be in countries that do not provide the same standard of legal 
protection for your information as in the United Kingdom, raising the risk that you will not be able 
to enforce the above rights and recipient organisations may not be legally required to fully secure 
your data. Xenikos is taking appropriate safeguards to make sure that your personal information is 
protected. These include implementing special contract clauses, known as Standard Contractual 
Clauses, which protect transfers of personal information between companies in Xenikos, which can 
be provided on request. Xenikos is implementing similar appropriate safeguards with third party 
service providers and partners, and further details can be provided upon request. If you wish to 
obtain a copy of the Standard Data Protection Clauses, you should firstly contact your study doctor 


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who will be able to direct your query where appropriate to staff responsible for data protection at the 
[Sponsor] or site, including the site Data Protection Officer 
[NHS/other site] will keep your name, NHS number and contact details confidential and will not 
pass this information to Xenikos. [NHS/other site] will use this information as needed, to contact 
you about the research study, and make sure that relevant information about the study is recorded 
for your care, and to oversee the quality of the study. Certain individuals from Xenikos and 
regulatory organisations may look at your medical and research records to check the accuracy of the 
research study. Xenikos will only receive information without any identifying information. The 
people who analyse the information will not be able to identify you and will not be able to find out 
your name, NHS number or contact details. Xenikos may forward information about you (again, 
without any identifying information) to its service providers, for activities related to the study, such 
as laboratory analysis. 
[NHS/ other site] will keep identifiable information about you from this study [for x years after the 
study has finished/ until x]. 
Xenikos will collect information about you for this research study from your medical records. 
Identifying information about you that is included in your medical records will not be shared with 
Xenikos. We will use this information for the purpose of the research study. 
When you agree to take part in a research study, the information about your health and care may be 
provided to researchers running other research studies in this organisation and in other 
organisations. These organisations may be universities, NHS organisations or companies involved 
in health and care research in this country or abroad. Your information will only be used by 
organisations and researchers to conduct research in accordance with the UK Policy Framework for 
Health and Social Care Research. 
This information will not identify you and will not be combined with other information in a way 
that could identify you. The information will only be used for the purpose of health and care 
research, including future research, and cannot be used to contact you or to affect your care. It will 
not be used to make decisions about future services available to you, such as insurance. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 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. The trial may also 
be registered on national registries and a summary of the results may be posted on publicly 
accessible databases (such as https://www.clinicaltrialsregister.eu or other national databases), if 
required by local laws or regulations. 
 


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<All other countries specific language, please delete for UK> 
Your privacy is very important to us. The study doctors will do everything they can to protect it. 
The study doctors can protect your records if there is a court case. However, some of your medical 
information may be shared if required by law. If this happens, the study doctors will do their best to 
make sure that any information that goes out to others will not identify you. 
Your confidentiality is one of our main concerns. We will do our best to make sure that the 
personal information in your medical record is kept confidential (private). However, we cannot 
promise total privacy. 
To make sure the study is running ethically, some government agencies or other groups may need to 
access part of your medical records. For this study, those groups include: 
• [Institution] 
• The Center for International Blood and Marrow Transplant Research (CIBMTR) 
• The National Marrow Donor Program (NMDP) 
• The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI)  
•  Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN)   
• Data Safety and Monitoring Board (DSMB), not part of [Institution] 
• [Study investigators/ Study doctor(s) at this institution] 
• Food and Drug Administration (FDA) 
• Regulatory authorities, both local and from other countries 
• Xenikos, BV (Xenikos) (the study sponsor) 
• Other authorized study organizations that represent Xenikos 
• Study monitors 
Information from this study will be put in a public data repository when the study is over, but your 
name and other personal information will not be included. If information from this study is 
published or presented at scientific meetings, your name and other personal information will not be 
used. 
Study information may also be used for research in the future. These projects could be related to 
your disease or similar diseases, or development of the study drug. 
We might use information from this study to get approval from the government, like the Food 
and Drug Administration (FDA). 


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Blood taken during the study may be used for future research. If the study team does this, the blood 
or tissue will not be attached to you or your name in any way.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov/, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 
 
<US country specific language, please delete for other countries> 
You will not be able to access your study results before the study is done. This helps keep the 
study results accurate and trustworthy.  
When the study is complete, you can ask your study doctor for your health information from the 
study. By signing this Consent Form, you agree to ask for your results only after the study 
is done. You will still have access to your regular medical records. 
Data that was collected through the Center for International Blood and Marrow Transplant 
Research (CIBMTR) about your clinical situation, including follow-up after 180 days, may be 
shared with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) and the study 
sponsors. The CIBMTR collects information on all transplants done in the U.S. 
Most research samples will be sent to a repository for processing and storage. A repository is a 
place that protects, stores, and sends out samples for approved research studies. All research 
samples will have unique codes that do not identify you, however, a link to this code does exist. 
The link is stored at the BMT CTN Data and Coordinating Center (DCC). The staff at the 
repository where your sample is being stored do not have a link to this code. Your research 
samples will continue to be stored at the repository until they are used for this study to help us 
understand the two treatments for aGVHD. 
 
8. 
Stopping Treatment or Leaving the Study 
You can choose to stop treatment or to leave the study at any time. 
You may also be told to stop the study treatment if: 
• It has been 2 weeks since your first dose of T-Guard and you haven’t completed all 4 
doses 
• You don’t meet the study requirements  


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• You need a medical treatment not allowed in this study 
• The study doctor decides that it would be harmful for you to continue 
• You’re having serious side effects 
• You have a severe infection 
• You become pregnant 
• The disease you needed a transplant for comes back 
• You cannot keep appointments or take study drugs as directed 
• The study is stopped for any reason 
If you join this study and decide to stop your treatment early or are asked to leave by your doctor 
for medical reasons, we will ask you to still visit the clinic for your safety. We’ll also ask 
whether we can still collect information about how you are doing. Even if you leave the study, 
the information already collected from you will be included in the study evaluation. If you don’t 
want your information to be used, you must let your study doctor know. 
9. 
Cost and Reimbursement 
You will not be paid for joining this study. You will not be paid or reimbursed for any extra 
expenses (such as travel or meals) from your participation in this study. 
A new drug or product may be developed from this study. Xenikos (the study sponsor) will not 
pay you if a commercial product is developed from blood or tissue taken from you during this 
study.  
The cost of the T-Guard is covered by this study. The cost of ruxolitinib is covered through Day 
56 by this study. Your doctor will talk with you about taking ruxolitinib after Day 56. 
Most of the visits for this study are standard medical care for patients with SR-aGVHD and will 
be billed to your health insurance company. You and/or your health insurance company will 
need to pay for some or all of the costs of standard medical treatment in this study.   
Some health insurance plans will not pay for costs of care when you take part in a research study. 
Check with your health plan or insurance company to find out what they will pay. 
You or your health insurance company will not be charged for the extra tests or research costs 
for this study. The extra tests are done to see how the drug works in your body and how your 
body responds to the drug. 
For questions about your costs, financial responsibilities, and/or health insurance coverage for 
this study, please contact [Center/ Financial Counselor at /Number]. 


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<Additional information for US; please add country specific language or delete> 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
Physical Injury as a Result of Participation 
Tell your study doctor or staff if you think you’ve been hurt because of being in this study. You 
must contact [contact in case of research-related injury name, address and telephone number]. 
You’ll get medical treatment if you’re hurt as a result of this study. You and/or your health 
insurance company will be charged for this treatment, and you/your health insurance company will 
be responsible for payment of these charges.  
Xenikos will reimburse either you/your health insurance for emergency medical costs (including 
hospitalization) in the diagnosis and treatment of an injury that is a direct result of this study. This 
study will not pay for medical treatment as a result of unintended injury that is not a direct result of 
this study. 
In case of injury resulting from this study, you don’t lose any of your legal rights to seek payment by 
signing this form. 
 
<Europe country specific language; please delete for other countries> 
The Sponsor has affected insurance coverage in accordance to national legislative requirements 
of the country in which the clinical trial is performed. Such insurance coverage makes provisions 
for possible compensation to you in the event of injury to your health, which in the light of 
medical knowledge can reasonably be attributed to your participation in this clinical trial. 
Covered is all proven damage (being the financial consequences of the injury to health), with the 
provision that under certain national legislation, the liability of the Sponsor or the party 
conducting the clinical trial must be proven. 


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The insurance coverage applies, provided that: 
1. The injury or damage does not consist of temporary impairment of health, which is certain 
or expected; 
2. The injury or damage occurs and is reported within the fixed time limit (as per national 
legislative requirement) either during or after the termination of the clinical trial;  
3. You are to immediately report any injury to the clinical trial investigator; 
4. You observed the following regulations in case of injury or damage:  
• You are to put yourself under doctor's orders immediately and do everything in your 
power to further your recovery;  
• You are to inform the Sponsor at once of the situation by means of the clinical trial 
investigator or by means of contacting the insurer, of which the details are: [insert 
name of insurer, address, and phone number]; 
• If requested, and at the expense of insurer, you will be prepared to undergo a medical 
examination performed by a doctor of the insurer's choice at the venue where the 
doctor desires such an examination to be held as well as to supply the doctor with all 
information so desired by him/her; 
• If requested, at the expense of the insurer, you will have yourself admitted for 
examination at a hospital or other medical institution designated by the insurer; 
• You will authorize the insurer to see information from third parties; 
• You will provide or have provided to the insurer or its experts any information 
deemed necessary by the insurer and not withhold any information needed for a 
determination of the degree of damage, injury, or impairment. 
A copy of the insurance certificate may be obtained from the clinical trial investigator. 
During the period of the clinical trial, you are authorized to seek other medical treatment only 
after consultation with the clinical trial investigator. 
Notwithstanding the regulations, nothing contained in this ICF shall serve to alter the provisions 
of the insurance policy as taken out by the Sponsor. 
 
 
 


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<US country specific language, please delete for other countries> 
10. 
Additional Study: Blood Samples for Future Research (Optional) 
Please note: This section of the Consent Form is about an additional study that will be done 
with people who are taking part in the main study. You may take part in this additional 
study if you want to. You can still be a part of the main study even if you say ‘no’ to this 
additional study. 
We ask for your permission to store any extra blood samples that are leftover from the main 
study. These samples will be used for future research. 
Your samples will be used only for research and will not be sold. The research done with your 
samples may help to develop new products in the future. You will not get paid for any samples 
or for any products that may be developed from current or future research. 
If you agree to allow us to store your extra blood samples, here’s what will happen: 
• These samples may be stored indefinitely for future research. 
• Your research samples will continue to be stored at the repository until they are used up 
for approved research. 
• Only research approved by an ethics board will be allowed to use your samples 
Changing your Mind 
If you agree to allow your leftover blood samples to be used for research, you can change your 
mind at any time. If you change your mind, please contact [the Principal Investigator at your 
transplant center] in writing to state that you are withdrawing permission for your leftover blood 
samples to be used for research. Their mailing address is on the first page of this Consent Form. 
Any unused samples will be destroyed if you withdraw your permission. If you choose not to 
participate in this additional research, there will be no change in your care. 
Benefits 
You will not benefit directly from providing blood samples for this study. Information gained 
from research on your blood may help doctors learn about, prevent, or treat GVHD, cancer, or 
other health problems. 
 
 


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Confidentiality and Your Medical Information 
The results of GVHD research using your blood will not be part of your medical record and will 
not be shared with you. If you agree to allow your blood samples to be used for research, your 
name will not be on the tubes. Only the study doctors or staff working with them will study the 
results from your blood samples. 
Research companies could make a profit (money) from what they learn using the blood samples. 
Making Your Choice 
Please read each sentence in the Statement of Consent and think about your choice to allow us to 
store your extra blood samples. After reading each sentence, make your selection by checking 
one of the boxes. If you have any questions, please talk to your doctor or nurse. 
You may also contact our research review board at [IRB's phone number]. 
No matter what you decide to do, it will not affect your care. 
 
 


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Statement of Consent for Blood Samples for Future Research (Optional) 
The purpose of storing blood samples, the procedures involved, and the risks and benefits have 
been explained to me. I have asked all the questions I have at this time and I have been told 
whom to contact if I have more questions. I have been told that I will be given a signed copy of 
this consent form to keep. I understand that I do not have to allow the use of my blood and for 
research. If I decide to not let you store research samples now or in the future, it will not affect 
my medical care in any way.  
I understand that I can still be a part of the main study even if I say ‘no’ to this additional study. 
I voluntarily agree that leftover blood samples and related information can be stored indefinitely 
by the BMT CTN Repository for research to learn about, prevent, or treat GVHD, cancer, or 
other health problems. 
 I agree to allow my leftover blood samples to be used for future research. 
 I do not agree to allow my leftover blood samples to be used for future research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Participant Name 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Signature (or Legally Authorized Representative) 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Legally Authorized Representative Name (if applicable) 
Date (MM/DD/YYYY) 
 
 
 


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<US country specific language, please delete for other countries> 
11. 
Health Insurance Portability and Accountability Act 1 (HIPAA) 
Authorization to use health information for research 
Your local study site will give you a separate form with information about the Health Insurance 
Portability and Accountability Act 1 (HIPAA).  You will need to sign this form as well before 
you are able to join this study. 
 
 
 


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12. 
Informed Consent Form 
TITLE: BMT CTN 2002: A Phase 3, Randomized, Open-Label, Multicenter Study, to 
Compare T-Guard to Ruxolitinib for the Treatment of Patients with Grade III or IV 
Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) 
• I have read and understood this Consent Form. The purpose and description of the 
research study has been explained to me. 
• I have had the chance to ask questions and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
• I freely agree to be a participant in the study. 
• I have had the chance to discuss my participation in this research study with a family 
member or friend if I choose. 
• I understand that… 
o I may not directly benefit from taking part in the study. 
o My name and personal information will not be identified even if information 
gained during the study is published. 
o I can leave this study at any time and doing so will not affect my current care or 
prevent me from receiving future treatment. 
o I will be given a copy of this signed consent form. 
o I do not give up any legal rights by signing this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Participant Name 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant (or Legally Authorized Representative) Signature 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Legally Authorized Representative Name (if applicable) 
Date (MM/DD/YYYY) 
 
 


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Physician certification 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Counseling Physician Name  
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Counseling Physician Signature 
 
 
 
 
Date (MM/DD/YYYY) 
 
Interpreter certification (if needed) 
I certify that I have provided an accurate interpretation of this consent form. I believe the 
participant has understood the information provided.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Interpreter Name 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interpreter Signature  
 
 
 
 
 
Date (MM/DD/YYYY) 

ICF_001.pdf: 
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Pregnancy Informed Consent to Participate in Research 
BMT CTN 2002 
A Phase 3, Randomized, Open-Label, Multicenter Study, to Compare T-Guard to 
Ruxolitinib for the Treatment of Patients with Grade III or IV Steroid-Refractory Acute 
Graft-Versus-Host Disease (SR-aGVHD) 
NCT04934670 
EudraCT No. 2021-000343-53 
 
Your Name: 
______________________________________________ 
Principal Investigator: 
______________________________________________ 
Study Site Address: 
______________________________________________ 
Study Site Telephone Number: 
______________________________________________ 
[Insert local PI information] 
Sponsor:  
This study is sponsored by Xenikos, BV and the National Institutes of 
Health, through the Blood and Marrow Transplant Clinical Trials Network 
 
<US country specific language, please delete for other countries> 
The ethics of this study have been reviewed and approved by the NMDP IRB. 
<European country specific language, please delete for other countries> 
The ethics of this study have been reviewed and approved by the EC in your country.  
Your study doctor or nurse will review this Consent Form with you, including: 
 The purpose of the research 
 Possible risks and benefits 
 Other options available to you 
 Your rights if you consent to the study 
 
 


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1. 
Study Overview 
We invite you to consent to provide information for this clinical trial, also known as a research 
study. We’re requesting this information to see if exposure to T-Guard or ruxolitinib affects an 
unborn baby. 
You’re being asked to provide information because you became pregnant while you or your 
partner was in a study of T-Guard or ruxolitinib. Researchers are studying T-Guard and 
ruxolitinib to see if it will help to treat acute graft-versus-host disease (aGVHD). aGVHD is a 
common and serious side effect of an allogeneic blood or marrow transplant (BMT). 
If you agree to provide information: 
• You’ll answer questions about your health and your pregnancy 
• We’ll collect information about your health, your pregnancy, and the result of your 
pregnancy, such as childbirth 
• We’ll collect information about the health of the newborn 
Some possible risks and benefits of consenting to provide information for the study include: 
Possible Risks: There is a small risk your confidentiality could be lost. The study team 
will do everything it can to keep your information confidential. 
Possible Benefits: Doctors may learn more about T-Guard and ruxolitinib to treat future 
patients. 
If you do not agree to provide information for the study, you can continue your usual health care. 
Key points: 
• Being in any research study is your choice 
• Knowledge gained from this study may help others 
• If you agree to provide information to the study, you can stop at any time. If you decide 
to stop providing information to the study, it will not affect your care at [name of facility 
or institution]. 
• Ask the study staff questions about anything you do not understand, or if you would like 
more information. You can ask questions now or at any time. 
• Take time to talk about the study with your doctor, study staff, and your family and 
friends. It is your choice to provide information to the study. If you agree to provide 


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information, please sign the end of this Consent Form. You’ll get a copy to keep. No one 
can force you to consent to this study. 
2. 
Study Purpose 
We are requesting this information to learn if exposure to T-Guard or ruxolitinib affects the 
pregnancy. You or your partner may have received either T-Guard or ruxolitinib. At this time, it 
is not known whether T-Guard or ruxolitinib has an effect on an unborn baby, sperm or egg, and 
it is not known if T-Guard or ruxolitinib is passed through sperm or human milk. There are 
animal reproduction studies using ruxolitinib that have shown some possible harm to the fetus, 
but the effects on human fetuses are not known. 
 
<US country specific language, please delete for other countries> 
Ruxolitinib has been approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of aGVHD. Ruxolitinib has an FDA pregnancy category of C. An FDA pregnancy 
category of C means that a drug should only be used in pregnancy if the potential benefit justifies 
the potential risk to the fetus. T-Guard has NOT been approved by the FDA for the treatment of 
aGVHD. This research study is registered with the FDA, and they will monitor it. 
 
<European country specific language, please delete for other countries> 
In Europe T-Guard and ruxolitinib have not been approved for the treatment of aGVHD. This 
research study is registered with the European Medicines Agency (EMA), and they will monitor 
it. 
 
3. 
Study Tests 
The study doctor will not do any examinations, tests, or procedures on you. 
You will answer questions about you and your pregnancy, and we will collect information from 
your medical records. We will also request information on the newborn until one year after birth. 
We will collect information about: 
• Your age, sex, and race/ethnicity 


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• Your physical or mental health 
• Any medicines that you take during your pregnancy 
• Any previous pregnancies, including any complications 
• Your current pregnancy 
• Your delivery 
• Your baby’s health 
If you have an abortion or a miscarriage, we’ll ask for health information from your doctor so we 
can learn if T-Guard or ruxolitinib affects pregnancy. 
4. 
Risks and Benefits  
Possible Benefits 
You will receive no benefits or payment for consenting to this study. The information we learn 
may help us care for people in the future who become pregnant while they or their partner is 
taking T-Guard or ruxolitinib. 
Possible Risks 
There are very few risks with sharing your medical information and answering questions about 
your pregnancy. The main risk is that your confidentiality could be lost. The study team will do 
everything it can to keep your answers confidential.  
5. 
Your Rights to Withdraw, Ask Questions, and Seek Other Treatment 
Being part of this study is your choice. You can choose not to be part of this study or leave this 
study at any time. If you choose to share information about your pregnancy, it won’t affect your 
or your partner’s regular medical care in any way. 
If you do not want to share information about your pregnancy, you may still contact the study 
doctor at any time to get updated information about the safety of T-Guard or ruxolitinib. 
You have the right to ask questions about the study at any time. If you have questions about the 
study, please contact: 
[Insert contact details] 
If you want to talk with someone not directly involved in the study, or have any complaints or 
questions about your rights as a research participant or about potential risks and injuries, you 


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may contact: 
[Insert contact details] 
You must tell [insert name of Principal Investigator] if you decide to leave the study. If you 
decide to leave this study, your medical care will not be affected in any way. 
6. 
New Information Available During the Study 
During this study, the study doctors may learn new information about T-Guard and ruxolitinib or 
the risks and benefits of taking part in the study. If they learn new information, they’ll tell you as 
soon as it’s available. 
7. 
Privacy, Confidentiality, and Use of Information 
 
<UK country specific language, please delete for other countries> 
Xenikos, BV (Xenikos) is the sponsor for this study taking place in the United Kingdom and 
elsewhere. Xenikos will be using information from you in order to undertake this study and will act 
as the data controller for this study. This means that Xenikos will be responsible for looking after 
your information and using it properly. [<Optional if applicable> Xenikos has appointed [CRO] as 
its ‘representative’ to fulfil its obligations under this law.] Xenikos will keep identifiable 
information about you for 25 years after the study has finished. The information may be stored for 
longer, for example, when used in applications for approval to market a medicine. 
Your rights to access, change or move your information are limited, as we need to manage your 
information in specific ways in order for the research to be reliable and accurate. If you withdraw 
from the study, we will keep the information about you that we have already obtained. To safeguard 
your rights, we will use the minimum personally-identifiable information possible. 
Health and care research should serve the public interest, which means that we have to demonstrate 
that our research serves the interests of society as a whole. We do this by following the UK Policy 
Framework for Health and Social Care Research. 
We use personally-identifiable information to conduct research to improve health and care. As a 
pharmaceutical company we have a legitimate interest in using information relating to your health 
and care for research studies, when you agree to take part in a research study. This means that we 
will use your data, collected in the course of a research study, in the ways needed to conduct and 
analyse the research study. 


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Your personal information may be shared with: 
• Xenikos and its present or future affiliates, 
• Research partners/service providers (such as laboratories conducting tests on behalf of 
Xenikos) and authorized representatives of Xenikos, 
• Study monitors appointed by Xenikos or Xenikos’ service providers to check how the study 
is going, 
• Auditors/inspectors appointed by Xenikos or Xenikos’ service providers or by health and 
regulatory authorities to check that the study is being run properly, 
• Relevant health and regulatory authorities such the Food and Drug Administration (FDA) in 
the United States of America and the European Medicines Agency (EMA). 
Recipients of your information may be in countries that do not provide the same standard of legal 
protection for your information as in the United Kingdom, raising the risk that you will not be able 
to enforce the above rights and recipient organisations may not be legally required to fully secure 
your data. Xenikos is taking appropriate safeguards to make sure that your personal information is 
protected. These include implementing special contract clauses, known as Standard Contractual 
Clauses, which protect transfers of personal information between companies in Xenikos, which can 
be provided on request. Xenikos is implementing similar appropriate safeguards with third party 
service providers and partners, and further details can be provided upon request. If you wish to 
obtain a copy of the Standard Data Protection Clauses, you should firstly contact your study doctor 
who will be able to direct your query where appropriate to staff responsible for data protection at the 
[Sponsor] or site, including the site Data Protection Officer. 
[NHS/other site] will keep your name, NHS number and contact details confidential and will not 
pass this information to Xenikos. [NHS/other site] will use this information as needed, to contact 
you about the research study, and make sure that relevant information about the study is recorded 
for your care, and to oversee the quality of the study. Certain individuals from Xenikos and 
regulatory organisations may look at your medical and research records to check the accuracy of the 
research study. Xenikos will only receive information without any identifying information. The 
people who analyse the information will not be able to identify you and will not be able to find out 
your name, NHS number or contact details. Xenikos may forward information about you (again, 
without any identifying information) to its service providers, for activities related to the study, such 
as laboratory analysis. 
[NHS/other site] will keep identifiable information about you from this study [for x years after the 
study has finished/until x]. 
Xenikos will collect information about you for this research study from your medical records. 
Identifying information about you that is included in your medical records will not be shared with 


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Xenikos. We will use this information for the purpose of the research study. 
When you agree to take part in a research study, the information about your health and care may be 
provided to researchers running other research studies in this organisation and in other 
organisations. These organisations may be universities, NHS organisations, or companies involved 
in health and care research in this country or abroad. Your information will only be used by 
organisations and researchers to conduct research in accordance with the UK Policy Framework for 
Health and Social Care Research. 
This information will not identify you and will not be combined with other information in a way 
that could identify you. The information will only be used for the purpose of health and care 
research, including future research, and cannot be used to contact you or to affect your care. It will 
not be used to make decisions about future services available to you, such as insurance. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 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. The trial may also 
be registered on national registries and a summary of the results may be posted on publicly 
accessible databases (such as https://www.clinicaltrialsregister.eu or other national databases), if 
required by local laws or regulations. 
 
<All other countries specific language, please delete for UK> 
Your privacy is very important to us. The study doctors will do everything they can to protect it. 
The study doctors can protect your records if there is a court case. However, some of your medical 
information may be shared if required by law. If this happens, the study doctors will do their best to 
make sure that any information that goes out to others will not identify you. 
Your confidentiality is one of our main concerns. We will do our best to make sure that the 
personal information in your medical record is kept confidential (private). However, we cannot 
promise total privacy. 
To make sure the study is running ethically, some government agencies or other groups may need to 
access part of your medical records. For this study, those groups include: 
• [Institution] 
• The Center for International Blood and Marrow Transplant Research (CIBMTR) 
• The National Marrow Donor Program (NMDP) 
• The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 


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Institute (NHLBI) and the National Cancer Institute (NCI)  
•  Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN)   
• Data Safety and Monitoring Board (DSMB), not part of [Institution] 
• [Study investigators/ Study doctor(s) at this institution] 
• Food and Drug Administration (FDA) in the United States of America and the European 
Medicines Agency (EMA) in Europe 
• Regulatory authorities, both local and from other countries 
• Xenikos, BV (Xenikos) (the study sponsor) 
• Other authorized study organizations that represent Xenikos 
• Study monitors 
If information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. Study information may also be used for research in the 
future. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov/, as required 
by U.S. Law, and under http://www.clinicaltrialsregister.eu. These websites will not include 
information that can identify you or your partner. At most, the websites will include a summary 
of the results. You can search the websites at any time. 
 
<US country specific language, please delete for other countries> 
You will not be able to access your study results before the study is done. This helps keep the 
study results accurate and trustworthy.  
When the study is complete, you can ask your study doctor for your health information from the 
study. By signing this Consent Form, you agree to ask for your results only after the study 
is done. You will still have access to your regular medical records. 
 
 
 


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8. 
Leaving the Study 
You may choose to leave the study at any time. 
If you leave the study, the information already collected from you will still be included in the 
study. If you don’t want your information to be used, you must let your study doctor know. 
9. 
Cost and Reimbursement 
You will receive no benefits or payment for taking part in this research. This research will not 
cover any costs related to your pregnancy, delivery, newborn care, abortion, or miscarriage. 
 
<US country specific language, please delete for other countries> 
10. 
Health Insurance Portability and Accountability Act 1 (HIPAA) 
Authorization to use health information for research 
Your local study site will give you a separate form with information about the Health Insurance 
Portability and Accountability Act 1 (HIPAA). You will need to sign this form as well before 
you are able to join this study. 
 
 
 


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11. 
Informed Consent Form 
TITLE: BMT CTN 2002: A Phase 3, Randomized, Open-Label, Multicenter Study, to 
Compare T-Guard to Ruxolitinib for the Treatment of Patients with Grade III or IV 
Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) 
• I have read and understood this Consent Form. The purpose and description of the 
research study has been explained to me. 
• I have had the chance to ask questions and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
• I freely agree to be a participant in the study. 
• I have had the chance to discuss my participation in this research study with a family 
member or friend if I chose to. 
• I understand that… 
o I may not directly benefit from taking part in the study. 
o My name and personal information will not be identified even if information 
gained during the study is published. 
o I can leave this study at any time and doing so will not affect my current care or 
prevent me from receiving future treatment. 
o I will be given a copy of this signed consent form. 
o I do not give up any legal rights by signing this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Participant Name 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant (or Legally Authorized Representative) Signature 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Legally Authorized Representative Name (if applicable) 
Date (MM/DD/YYYY) 
 
 


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Physician certification 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Counseling Physician Name  
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Counseling Physician Signature 
 
 
 
 
Date (MM/DD/YYYY) 
 
Interpreter certification (if needed) 
I certify that I have provided an accurate interpretation of this consent form. I believe the 
participant has understood the information provided.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Interpreter Name 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interpreter Signature  
 
 
 
 
 
Date (MM/DD/YYYY) 

Prot_SAP_002.pdf: 
CONFIDENTIAL 
A Phase 3, Randomized, Open-Label, Multicenter Study, to Compare 
T-Guard to Ruxolitinib for the Treatment of Patients with Grade III or IV
Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD)
(Posted on ClinicalTrials.gov as NCT04934670) 
BMT CTN PROTOCOL 2002 
Version 1.0 
Study Chairpersons 
John Levine, MD1, Gabrielle Meyers, MD2, and Gérard Socié, MD, PhD3 
Protocol Officer 
Mehdi Hamadani, MD4 
Haris Ali, MD5 
Hannah Choe, MD6 
Andrew Harris, MD7 
Ernst Holler, MD8 
Eric van Hooren9 
Denise King, MS10 
Willem Klaassen9 
Eric Leifer, PhD11 
Protocol Team 
Michael Martens, PhD4 
Ypke van Oosterhout, PhD9
Lia Perez, MD12 
Iskra Pusic, MD13 
Jenn Romeril, RN10 
Matthias Stelljes, MD14 
Walter Van der Velden, MD, PhD15 
Heather Wittsack, MPH10 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
Xenikos BV 
IND # 122098 
EudraCT # 2021-000343-53 
1Mount Sinai Medical Center 
9Xenikos BV 
2Oregon Health and Science University 
10The Emmes Company 
3AP-HP Hospital Saint Louis, Paris 
11National Heart, Lung, and Blood Institute 
4Medical College of Wisconsin 
12H. Lee Moffitt Cancer Center 
5City of Hope National Medical 
13Washington University School of Medicine 
6Ohio State University 
14Universitatsklinikum Munster 
7University of Utah 
15Radboud University 
8Universitatsklinikum Regensburg 
Approval Signature (Protocol Chair) 
Approval Signature (Protocol Chair) 
 
Approval Signature (Protocol Chair) 
Approval Signature (Protocol Officer) 
Approval Signature (Xenikos) 
John Levine
John  Levine
I am approving this document.
Gabrielle Meyers
Gabrielle  Meyers
Gerard  Socie
I am approving this document.
Gerard Socie
Mehdi  Hamadani
Mehdi Hamadani
07/01/2021 02:34
PM EDT
Ypke  van Oosterhout
Ypke van Oosterhout
06/30/2021
10:13 AM EDT
06/29/2021 02:23
PM EDT
06/30/2021 11:05
AM EDT
06/29/2021
07:37 PM EDT
I am approving this document.
I am approving this document.
Iamapproving thisdocu.


BMT CTN 2002/SR aGVHD 
 
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PROTOCOL SYNOPSIS – BMT CTN 2002 PROTOCOL 
 
 
A Phase 3, Randomized, Open-Label, Multicenter Study, to Compare  
T-Guard to Ruxolitinib for the Treatment of Patients with Grade III or IV Steroid-
Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) 
 
Co-Chairs: 
John Levine, MD, 
 
Gabrielle Meyers, MD, 
 
Gérard Socié, MD, PhD 
 
Study Design: 
The study is an open-label, randomized, Phase 3, multicenter 
trial, which has been designed to compare the efficacy and 
safety of T-Guard to ruxolitinib in patients with Grade III or IV 
Steroid-Refractory acute Graft-Versus-Host Disease (SR-
aGVHD). 
 
The primary analysis will include all participants that are 
randomized. 
 
Primary Objective: 
To assess the rate of complete response (CR) in Grades III 
and IV SR-aGVHD participants on Day 28 post-
randomization. 
 
Secondary Objectives: 
Secondary objectives are the following: 
1. Estimate the overall survival (OS) at Days 60, 90, and 180. 
2. Evaluate the duration of complete response (DoCR). 
3. Estimate the time to complete response (CR) from 
randomization. 
4. Estimate the overall response rate (CR or partial response 
(PR)) at Days 14, 28, and 56. 
5. Describe proportions of CR, PR, mixed response (MR), no 
response (NR), and progression of aGVHD at Days 6, 14, 
28, and 56. 
6. Estimate the cumulative incidence of non-relapse mortality 
(NRM) at Days 90 and 180. 
7. Estimate relapse-free survival at Day 180. 
8. Estimate GVHD-free survival at Days 90 and 180. 
9. Estimate the cumulative incidence of chronic GVHD 
(cGVHD) at Day 180. 
10. Estimate the cumulative incidence of underlying disease 
relapse/progression at Day 180. 
11. Describe the incidence of infections. 
12. Describe the incidence of toxicities. 
13. Assess the pharmacokinetics (PK) of T-Guard. 
14. Assess the immunogenicity of T-Guard. 
 
 


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Exploratory Objectives: 
Exploratory objectives are the following: 
1. Describe proportion of participants free of systemic 
steroids by Day 180 post-randomization. 
2. Estimate the incidence of Cytomegalovirus (CMV) 
reactivation requiring therapy by Day 180 post-
randomization. 
3. Estimate the incidence of Epstein-Barr Virus (EBV)- 
associate lymphoproliferative disorder or EBV reactivation 
requiring therapy with rituximab by Day 180 post-
randomization. 
4. Evaluate the evolution and characteristics of specific cell 
populations at randomization and Days 0, 14, 56, and 180. 
5. Evaluate aGVHD biomarkers at baseline and at Days 6, 14, 
and 28 post-randomization. 
6. Describe changes in patient-reported outcomes (PROs) 
from baseline to Days 28, 90, and 180 post-randomization. 
7. Estimate incidence of TMA at Days 6, 14, 21 and 28 post-
randomization. 
8. Describe EASIX score at screening. 
 
Correlatives: 
The pharmacokinetics and immunogenicity of T-Guard will be 
evaluated as referenced in the secondary and exploratory 
objectives. 
 
Eligibility Criteria: 
Inclusion Criteria: 
1. Patients must be at least 18.0 years of age at the time of 
consent. 
2. Patient has undergone first allo-HSCT from any donor 
source or graft source. 
3. Patients diagnosed with Grade III or IV SR-aGVHD after 
allo-HSCT. SR includes aGVHD initially treated at a lower 
steroid dose, but must meet one of the following criteria: 
• 
progressed or new organ involvement after 3 days of 
treatment with methylprednisolone (or equivalent) of 
greater than or equal to 2 mg/kg/day, 
• 
no improvement after 7 days of primary treatment 
with methylprednisolone (or equivalent) of greater 
than or equal to 2mg/kg/day 
• 
patients with visceral (GI and/or liver) plus skin 
aGVHD at methylprednisolone (or equivalent) 
initiation with improvement in skin GVHD without any 
improvement in visceral GVHD after 7 days of 
primary treatment with methylprednisolone (or 
equivalent) of greater than or equal to 2mg/kg/day 
• 
Patients who have skin GVHD alone and develop 
visceral aGVHD during treatment with 
methylprednisolone (or equivalent) of greater than or 
equal to 1mg/kg/day and do not improve after 3 days 


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of greater than or equal to 2mg/kg/day 
4. Patients must have evidence of myeloid engraftment (e.g., 
absolute neutrophil count greater than or equal to 0.5 × 
109/L for 3 consecutive days if ablative therapy was 
previously used). Use of growth factor supplementation is 
allowed. 
5. Patients or an impartial witness (in case the patient is 
capable to provide verbal consent but not capable to sign 
the informed consent) should have given written informed 
consent. 
 
Exclusion Criteria: 
1. Patients who have a creatinine greater than or equal to 
2mg/dL or estimated creatinine clearance less than 40 
mL/min or those requiring hemodialysis. 
2. Patients who have been diagnosed with active Thrombotic 
Microangiopathy (TMA), defined as meeting all the 
following criteria:  
• 
greater than 4% schistocytes in blood (or equivalent 
if semiquantitative scale is used e.g., 3+ or 4+ 
schistocytes on peripheral blood smear), 
• 
de novo, prolonged or progressive thrombocytopenia 
(platelet count less than 50 x 109/L or 50% or greater 
reduction from previous counts), 
• 
sudden and persistent increase in lactate 
dehydrogenase concentration greater than 2x ULN,  
• 
decrease in hemoglobin concentration or increased 
transfusion requirement attributed to Coombs-
negative hemolysis, AND  
• 
decrease in serum haptoglobin 
3. Patients who have previously received treatment with 
eculizumab. 
4. Patients who have previously received checkpoint 
inhibitors (either before or after allo-HCT). 
5. Patients who have been diagnosed with overlap syndrome, 
that is, with any concurrent features of cGVHD. 
6. Patients requiring mechanical ventilation or vasopressor 
support. 
7. Patients who have received any systemic treatment, 
besides steroids, as upfront treatment of aGVHD or as 
treatment for SR-aGVHD. Reinstitution of previously used 
GVHD prophylaxis agents (e.g., tacrolimus, cyclosporin, 
MTX, MMF) or substitutes in cases with previously 
documented intolerance will be permitted. Previous 
treatment with a JAK inhibitor as part of GVHD prophylaxis 
or treatment is not allowed. 
8. Patients who have severe hypoalbuminemia, with an 
albumin of less than or equal to 1 g/dl. 


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9. Patients who have a creatine kinase (CK) level of greater 
than 5 times the upper limit of normal. 
10. Patients with uncontrolled infections. Infections are 
considered controlled if appropriate therapy has been 
instituted and, at the time of enrollment, no signs of 
progression are present. Persisting fever without other 
signs or symptoms will not be interpreted as progressing 
infection. Progression of infection is defined as: 
• 
hemodynamic instability attributable to sepsis OR 
• 
new symptoms attributable to infection OR 
• 
worsening physical signs attributable to infection OR 
• 
worsening radiographic findings attributable to 
infection 
11. Patients with evidence of relapsed, progressing, or 
persistent malignancy, or who have been treated for 
relapse after transplant, or who may require rapid immune 
suppression withdrawal as pre-emergent treatment of early 
malignancy relapse. 
12. Patients with evidence of minimal residual disease 
requiring withdrawal of systemic immune suppression. 
13. Patients with unresolved serious toxicity or complications 
(other than acute GVHD) due to previous transplant. 
14. History of sinusoidal obstruction syndrome (SOS)/veno-
occlusive disease (VOD). 
15. Patients with known hypersensitivity to any of the 
components murine monoclonal antibodies (mAb) or 
recombinant Ricin Toxin A-chain (RTA). 
16. Patients who have had treatment with any other 
investigational agent, device, or procedure within 21 days 
(or 5 half-lives, whichever is greater) prior to enrollment. 
17. Patients who have received more than one allo-HSCT. 
18. Patients with known human immunodeficiency virus 
infection. 
19. Patients who have a BMI greater than or equal to 35 
kg/m2. 
20. Patients who are taking sirolimus must have it 
discontinued prior to starting study treatment. 
21. Female patients who are pregnant, breast feeding, or, if 
sexually active and of childbearing potential, unwilling to 
use effective birth control from start of treatment until 30 
days after the last treatment dose. 
22. Male patients who are, if sexually active and with a female 
partner of childbearing potential, unwilling to use effective 
birth control from start of treatment until 65 days after the 
last treatment dose. 
23. Patients with any condition that would, in the investigator's 
judgment, interfere with full participation in the study, 
including administration of study drug and attending 


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required study visits; pose a significant risk to the patient; 
or interfere with interpretation of study data. 
24. Patients whose decision to participate might be unduly 
influenced by perceived expectation of gain or harm by 
participation, such as patients in detention due to official or 
legal order. 
 
Interim Analysis: 
This trial will include one interim analysis for futility after 
23 participants on the T-Guard arm (~46 participants total) 
become evaluable for the primary endpoint. One interim 
analysis for efficacy will be performed once 150 participants on 
combined arms have reached Day 28 and 100 participants on 
the combined arms have reached Day 180. 
 
Treatment Description: 
Participants will be randomized to receive either T-Guard or 
ruxolitinib. Participants on the T-Guard arm will receive 4 doses 
of T-Guard treatment, administered intravenously as four 4-
hour infusions at least two calendar days apart. Each dose 
consists of 4 mg/m2 Body Surface Area (BSA). Participants on 
the ruxolitinib arm will receive 10mg orally of ruxolitinib twice 
daily for a planned minimal period of 56 days. 
 
Accrual Objective: 
The target accrual is 246 participants randomized 1:1 between 
the treatment arms from approximately 75 transplant centers 
in the US and Europe. 
 
Accrual Period: 
Approximately 34 months is expected for accrual. 
 
Study Duration: 
Participants will be followed for 180 days after randomization for 
a total study duration of approximately 40 months. 
 
Safety Monitoring: 
A safety run-in phase of 12 T-Guard participants (~24 on the 
combined treatment arms) will begin the trial, with two 
comprehensive safety reviews conducted by the DSMB after 6 
and 12 T-Guard treated participants reach Day 60. The rates 
of early overall mortality post randomization will be monitored 
using sequential probability ratio tests (SPRT) for binary data. 
Two SPRTs will be implemented: one contrasting a Day 30 
mortality rate of 15% vs. a 30% rate in the T-Guard arm 
specifically, and another evaluating whether excessive Day 60 
mortality risk is present in the T-Guard arm compared to 
ruxolitinib. 
 
 
 


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Outline of Treatment Plan 
 
 
 
 
 
 
 
Age 18.0 years and older
Grade III/IV SR aGVHD
T-Guard IV 
4mg/m2 every 2 days 
Days 0, 2, 4, and 6 
Ruxolitinib PO 
10 mg twice daily  
Starting Day 0 


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TABLE OF CONTENTS 
CHAPTER 1  ................................................................................................................ 1 
1 BACKGROUND AND RATIONALE .......................................................................... 1 
1.1 
Introduction ............................................................................................................... 1 
1.2 
Therapies for Acute GVHD ....................................................................................... 2 
1.2.1 
First-line Therapy: Corticosteroids ............................................................... 2 
1.2.2 
Second-line Therapies Background ............................................................. 2 
1.2.3 
New Emerging Therapies ............................................................................ 2 
1.3 
Investigational medicinal products ............................................................................ 4 
1.3.1 
T-Guard ....................................................................................................... 4 
1.3.2 
Ruxolitinib ...................................................................................................12 
1.4 
Study Rationale .......................................................................................................17 
CHAPTER 2  .............................................................................................................. 21 
2 STUDY DESIGN ...................................................................................................... 21 
2.1 
Study Overview ........................................................................................................21 
2.2 
Hypothesis and Specific Objectives .........................................................................21 
2.2.1 
Primary Hypothesis .....................................................................................21 
2.3 
Study Objectives ......................................................................................................21 
2.3.1 
Primary Objective .......................................................................................21 
2.3.2 
Secondary Objectives .................................................................................21 
2.3.3 
Exploratory Objectives ................................................................................22 
2.4 
Patient Eligibility.......................................................................................................22 
2.4.1 
Inclusion Criteria .........................................................................................22 
2.4.2 
Exclusion Criteria ........................................................................................23 
2.5 
Treatment Plan ........................................................................................................24 
2.5.1 
T-Guard ......................................................................................................25 
2.5.2 
Ruxolitinib ...................................................................................................29 
2.5.3 
Supportive Care ..........................................................................................34 
2.5.4 
Follow-Up Post Treatment Discontinuation .................................................35 
2.6 
Study Conduct .........................................................................................................36 
2.7 
Study termination .....................................................................................................36 
CHAPTER 3  .............................................................................................................. 37 
3 STUDY ENDPOINTS ............................................................................................... 37 
3.1 
Acute GVHD Response Definitions ..........................................................................37 


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3.2 
Relapse Definition ....................................................................................................37 
3.3 
Primary Endpoint .....................................................................................................39 
3.4 
Secondary Endpoints ...............................................................................................39 
3.4.1 
Key Secondary Endpoints: ..........................................................................39 
3.4.2 
Other Secondary Endpoints: .......................................................................40 
3.5 
Exploratory Endpoints ..............................................................................................41 
3.6 
Endpoint Review Process ........................................................................................42 
CHAPTER 4  .............................................................................................................. 44 
4 PATIENT ENROLLMENT AND EVALUATION ....................................................... 44 
4.1 
Approaching Patients, Eligibility Screening, and Obtaining Consent ........................44 
4.2 
Enrollment ...............................................................................................................44 
4.2.1 
Treatment ..................................................................................................44 
4.3 
Study Monitoring ......................................................................................................44 
4.3.1 
Follow-up Schedule ...................................................................................44 
4.3.2 
Assessments .............................................................................................46 
4.4 
Adverse Event Reporting .........................................................................................49 
4.4.1 
Definitions ...................................................................................................49 
4.4.2 
Classification of Adverse Events by Severity...............................................50 
4.4.3 
Classification of Adverse Events by Relationship to Investigational Product51 
4.4.4 
Required Adverse Event Reporting .............................................................51 
4.4.5 
Procedure in Case of Pregnancy ................................................................52 
CHAPTER 5  .............................................................................................................. 54 
5 STATISTICAL CONSIDERATIONS ........................................................................ 54 
5.1 
Study Design and Objective .....................................................................................54 
5.1.1 
Accrual and Study Duration ........................................................................54 
5.1.2 
Randomization and Blinding .......................................................................54 
5.1.3 
Analysis Populations ...................................................................................54 
5.1.4 
Primary Hypothesis .....................................................................................55 
5.1.5 
Sample Size and Power Considerations .....................................................55 
5.2 
Study Analysis Schedule .........................................................................................56 
5.2.1 
Simon’s Two-Stage Design for Demonstrating Superiority of T-Guard to 
Historical Therapies for Grade III-IV SR-aGVHD ........................................57 
5.2.2 
Efficacy Analysis for Demonstrating Superiority of T-Guard to Ruxolitinib 
Toward EMA Approval ................................................................................59 
5.3 
Guidelines For Safety Monitoring And Run-In Phase ...............................................59 


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5.3.1 
Safety Run-in Phase ...................................................................................60 
5.3.2 
Safety Endpoint Monitoring .........................................................................60 
5.4 
Demographic and Baseline Characteristics ..............................................................64 
5.5 
Analysis of Primary Endpoint ...................................................................................64 
5.6 
Analysis of Secondary Endpoints .............................................................................65 
5.6.1 
Overall Survival (OS) ..................................................................................66 
5.6.2 
Duration of Complete Response (DoCR) ....................................................66 
5.6.3 
Time to Complete Response (CR) ..............................................................66 
5.6.4 
Overall Response Rate (ORR)....................................................................67 
5.6.5 
Proportion of Response ..............................................................................67 
5.6.6 
Non-relapse Mortality (NRM) ......................................................................67 
5.6.7 
Relapse-free Survival (RFS) .......................................................................67 
5.6.8 
GVHD-free Survival ....................................................................................67 
5.6.9 
Chronic GVHD (cGVHD) .............................................................................68 
5.6.10 Relapse/Progression of Underlying Malignancy ..........................................68 
5.6.11 Incidence of Infections ................................................................................68 
5.6.12 Incidence of Toxicities ................................................................................68 
5.6.13 Subgroup Analyses of Day 28 CR Rate ......................................................68 
5.7 
Analysis of Pharmacokinetic / Pharmacodynamic Endpoints (T-Guard only) ...........69 
5.7.1 
Pharmacokinetics .......................................................................................69 
5.7.2 
Immunogenicity ..........................................................................................69 
5.8 
Analysis of Exploratory Endpoints ............................................................................69 
5.8.1 
Discontinuation of Systemic Steroids ..........................................................69 
5.8.2 
CMV Reactivation .......................................................................................69 
5.8.3 
EBV-associated Lymphoproliferative Disorder ............................................70 
5.8.4 
Evolution of Cell Populations ......................................................................70 
5.8.5 
GVHD-related Biomarkers ..........................................................................70 
5.8.6 
Patient Reported Outcomes (PROs) ...........................................................70 
5.8.7 
Thrombotic Microangiopathy (TMA) ............................................................71 
5.8.8 
EASIX Score ...............................................................................................71 
APPENDIX A: HUMAN SUBJECTS ........................................................................... A-1 
APPENDIX B: LABORATORY PROCEDURES ......................................................... B-1 
APPENDIX C: STAGING AND GRADING OF ACUTE GVHD ................................... C-1 
APPENDIX D: GRADING OF CHRONIC GVHD (NIH CRITERIA) ............................. D-1 


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APPENDIX E: PATIENT REPORTED OUTCOMES.................................................... E-1 
APPENDIX F: DERIVATION OF A SEQUENTIAL TEST FOR COMPARING 
BINOMIAL PROPORTIONS BETWEEN TWO STUDY ARMS ........... F-1 
APPENDIX G: BMT CTN INFECTION GRADING TABLE AND RECURRENCE 
INTERVAL DEFINITIONS .................................................................. G-1 
APPENDIX H: LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............ H-1 
APPENDIX I: REFERENCES ....................................................................................... I-1 
APPENDIX J: INVESTIGATOR’S SIGNATURE PAGE .............................................. J-1 
APPENDIX K: SCHEDULE OF ASSESSMENTS....................................................... K-1 
 


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CHAPTER 1 
1 BACKGROUND AND RATIONALE 
1.1 
INTRODUCTION 
Allogeneic Hematopoietic Cell Transplantation (allo-HSCT) is a potent immunotherapy with 
curative potential for several hematological disorders (Magenau, Runaas et al. 2016). 
Improvements in survival following allo-HSCT have led to its increasing use, but the leading 
cause of non-relapse mortality (NRM) remains Graft-Versus-Host Disease (GVHD) (Alousi, 
Weisdorf et al. 2009, Major-Monfried, Renteria et al. 2018). Serious infections and impairment of 
generalized immune function are responsible for GVHD mortality. GVHD incidence and severity 
depends primarily on donor and recipient matching for human leukocyte antigens and the 
regimen used for post-grafting immune suppression. The National Institutes of Health (NIH) 
consensus development project working group recognized two main categories of GVHD, each 
with two subcategories. The acute GVHD (aGVHD) category is defined in the absence of 
diagnostic or distinctive features of chronic GVHD (cGVHD) and includes (1) classic aGVHD 
occurring within 100 days after transplantation and (2) persistent, recurrent, or late aGVHD 
(features of GVHD occurring beyond 100 days, often during withdrawal of immune 
suppression). The broad category of cGVHD includes (1) classic cGVHD (without features or 
characteristics of aGVHD) and (2) an overlap syndrome in which diagnostic or distinctive 
features of cGVHD and aGVHD appear together. (Filipovich, Weisdorf et al. 2005, Jagasia, 
Greinix et al. 2015). 
Despite recent advances in the understanding of transplantation immune pathology, aGVHD is a 
frequent and major complication of allo-HSCT involving activation of donor T-lymphocytes, which 
ultimately causes host tissue damage (Holtan SG 2014, Hill 2018, Zeiser and Blazar 2017). 
Serious infections, organ failure and impairment of generalized immune function are responsible 
for aGVHD mortality. The condition involves three target organs, the skin (presenting as 
inflammatory, maculopapular, erythematous rash), the liver (presenting as hyperbilirubinemia 
due to cholestatic jaundice) and the gastro-intestinal (GI) tract (presenting as upper and/or lower 
GI tract manifestations: anorexia with weight loss, nausea, vomiting, diarrhea, severe pain, GI 
bleeding and/or ileus) (Schoemans, Lee et al. 2018). The diagnosis must occur in absence of 
cGVHD symptoms (Filipovich, Weisdorf et al. 2005, Jagasia, Greinix et al. 2015). Despite 
immune suppression prophylaxis, up to 50% of hematopoietic cell transplantation (HCT) 
recipients will experience grade II-IV aGVHD (Zakias PD 2014, Zeiser, Socie et al. 2016). 
Complete responses (CR) to upfront treatment at day 28 of therapy have been reported in 25% 
to 41% of patients, as defined as the absence of skin rash, diarrhea and hyperbilirubinemia 
(Hings, Severson et al. 1994, MacMillan, Weisdorf et al. 2002, Deeg 2007). With regards to 
second-line treatment, data from the prospective ruxolitinib treatment trials (REACH1 and 
REACH2), as well as from a prospective natural history trial (MAGIC), found the expected CR 
rate at day 28 after second-line therapy therapy is in the range of 25%-30%. The likelihood of 
GVHD treatment response decreases with increasing severity of the disease. (Martin, Schoch et 
al. 1990, Weisdorf, Haake et al. 1990). The response, more particular: Complete Response, to 
therapy is of central importance, as responses correlate with post-HCT survival. 


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1.2 
THERAPIES FOR ACUTE GVHD 
1.2.1 First-line Therapy: Corticosteroids 
The mainstay of treatment of aGVHD for over three decades has been high-dose 
corticosteroids, typically dosed at the prednisone equivalent of 1-2 mg/kg per day (Weisdorf, 
Haake et al. 1990, Bolanos-Meade and Vogelsang 2004, Bacigalupo 2007, Deeg 2007). 
However, high-dose corticosteroid therapy has several shortcomings, including toxicity issues, 
such as infection, diabetes, hypertension, osteoporosis, myopathy and avascular necrosis, as 
well as less than optimal efficacy. This has led to interest for alternate first-line therapies e.g. the 
development of the BMT CTN 1501 clinical trial “A Randomized, Phase II, Multicenter, Open 
Label, Study Evaluating Sirolimus and Prednisone in Patients with Refined Minnesota Standard 
Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease”, comparing outcomes of a 
non-steroid first-line therapy (sirolimus) for aGVHD (Pidala, Hamadani et al 2020). While this 
and other trials are evaluating alternate first-line therapies, in the interim and near future, 
steroids are still expected to be the primary first-line therapy for aGVHD. While steroids are 
considered first-line therapy for aGVHD, a significant fraction of the aGVHD population (10-
50%) fail to have a clinical response, deeming them steroid-refractory (SR). (Deeg 2007, 
MacMillan, Robin et al. 2015). 
1.2.2 Second-line Therapies Background 
If the manifestations of GVHD in any organ worsen over 3 days of high-dose steroid treatment 
or if the involved organs do not improve by 7 days of high-dose steroids therapy, it is unlikely 
that a response will be achieved in a timely fashion, and secondary therapy should be 
considered (Deeg 2007). Patients meeting the above criteria are classified as having SR-
aGVHD, and increases in steroid dosing do not improve survival, (Bacigalupo, van Lint et al. 
1983), thus another therapeutic agent/intervention is added to the treatment regimen. 
Though substantial progress has been made in the field over the last decade due to a) 
advances in selection of patient and donor, b) selection of the most appropriate preparative 
regimen and c) earlier identification of subpopulations by using biomarkers (Paczesny 2013, 
Major- Monfried, Renteria et al. 2018), there are still a vast number of patients who end up with 
SR-aGVHD. The long-term prognosis for this population is unfortunately very poor, with a 
mortality rate of approximately 70-80% (Weisdorf, Haake et al. 1990, Levine, Logan et al. 2010), 
attributed to poor response rates with second-line treatment (Deeg 2007, Pidala, Kim et al. 
2010, Castilla-Llorente, Martin et al. 2014), and infectious complications due to profound 
immunosuppression. 
1.2.3 New Emerging Therapies 
Given the dismal overall outcomes in patients with SR-aGVHD many innovative therapies are 
currently under development (Hill, Alousi et al. 2018). We may conclude that more effective 
aGVHD immunosuppressive agents will improve remission rates and decrease toxicities, 
especially in the SR-aGVHD patients, which will result in better survival after allo-HSCT. Ideally, 
agents should be targeted (i.e., not broadly immunosuppressive), have a favorable side effect 
profile, be effective upfront to avoid severe and irreversible tissue damage, and provide 


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complete and durable responses without impacting graft versus tumor effects and/or infection 
risk. 
Ruxolitinib 
The dual Janus Kinases (JAKs) JAK1 and JAK2 inhibitor ruxolitinib has shown efficacy and 
tolerability in the upfront treatment of aGVHD and SR-aGVHD. The pivotal phase 2 study of 
ruxolitinib for SR-aGVHD and steroid-dependent aGVHD showed an overall response rate 
(ORR) at Day 28 of 57% and 31% CR rate (Jagasia, Zeiser et al. 2018), leading to the FDA 
approval of this agent on May 24, 2019. The main complications seen with this agent include 
hematologic toxicity and infections, with 31% of patients discontinuing this agent on trial due to 
adverse reactions. The REACH 2 randomized trial comparing Ruxolitinib versus best available 
treatment (BAT) has been published (Zeiser, Bubnoff et al. 2020.). This multicenter open-label 
phase 3 trial compared the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the 
investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 
years of age or older who had SR-aGVHD after allogeneic stem-cell transplantation. The 
primary end point was overall response (complete response or partial response) at day 28. The 
key secondary end point was durable overall response at day 56. 
A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib 
group and 155 to the control group. Ruxolitinib was superior to BAT by multiple measures of 
efficacy including overall response at day 28 (62% vs. 39%; P<0.001), maintenance of response 
to day 56 (40% vs. 22%; P<0.001), estimated cumulative incidence of loss of response at 6 
months (10% vs. 39%), and median failure-free survival (5.0 vs. 1.0 month; hazard ratio 0.46; 
95% CI, 0.35 to 0.60). The median overall survival (OS) was significantly longer for the 
ruxolitinib group (11.1 vs. 6.5 months; hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The 
most common adverse events up to day 28 were thrombocytopenia (ruxolitinib 33%; controls 
18%, anemia (ruxolitinib 30%; controls 28%), and cytomegalovirus (CMV) infection (ruxolitinib 
26%; controls 21%). 
Results of ruxolitinib in SR-aGVHD have been recently reviewed (Socie & Zeiser Blood 
advances 2020) and new criteria have been proposed for ruxolitinib-refractory aGVHD after this 
pivotal trial (Mohty, M., Holler, E., 2020). Thus, ruxolitinib is currently the sole treatment that has 
been reported to improve response rate over BAT in the setting of a randomized phase 3 trial. 
Monoclonal Antibodies (mAbs) 
Other treatments for SR-aGVHD have included mAbs, such as ABX-CBL or an anti-interleukin 
receptor antibody (Leukotac) but these have failed to improve outcomes [reviewed in; Martin et 
al; Biol Blood Marrow Transplant 2012;18: 1150-1163] (Macmillan; Blood 2007; 109: 2657-2662. 
Socie; Blood 2017; 129: 643-649). 
SUMMARY 
Treatment failure and treatment-related toxicities remain major problems for patients with 
aGVHD despite numerous prior studies and the recent approval of ruxolitinib. The need for 
better treatment is especially important for patients at the highest risk for treatment failure, those 
with grade III/IV SR-aGVHD. 


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In this proposed study, a new immunotoxin will be investigated in patients with Grade III/IV SR-
aGVHD and compared to ruxolitinib. This agent is attractive to study based on 
immunosuppressive profile and response rates reported on 20 patients in a Phase 1/2 clinical 
trial (Groth, van Groningen et al. 2017). Anti-CD3/anti-CD7 antibody treatment in patients with 
severe SR-aGVHD resulted in high day 28 CR rate of 50%, which compares favorably with 
historical controls (20-30%), and a high Day 180 OS. In addition, the short treatment course (4 
treatments given every 48 hours) allows for a rapid response and fast restoration of the immune 
system due to the lack of ongoing exposure to immunosuppressive agents. 
1.3 
INVESTIGATIONAL MEDICINAL PRODUCTS 
In this study T-Guard will be compared to ruxolitinib. Both products will be supplied by the 
sponsor including protocol-specific dosing instructions (see sections 2.5.1.4 and 2.5.2.3). 
1.3.1 T-Guard 
T-Guard is an immunotoxin-combination, consisting of two equal amounts (w/w) of the murine 
mAbs SPV-T3a (anti-CD3, IgG2b) and WT1 (anti-CD7, IgG2a), each conjugated to the Ricin 
Toxic A (RTA) chain: SPV-T3a-RTA and WT1-RTA. This particular immunotoxin-combination 
harbors multiple mechanisms of action (see Figure 1-1). 
Both the anti-CD3 and anti-CD7 mAbs act as chaperones that bring the toxic RTA payload into 
the target cells after binding to the surface antigens on T cells (CD3+ and CD7+) and Natural 
Killer (NK) cells (CD7+ and CD3-). Once inside the cell, the bond between these mAbs and RTA 
toxin is broken, thereby releasing free RTA into the cytoplasm. The RTA toxin then irreversibly 
inhibits protein synthesis by means of a catalytic reaction culminating in programmed cell death 
(apoptosis) of T cells, with a preference for the recently activated ones, and NK cells (see section 
1.3.1.1). RTA toxin does not enter the cell autonomously. Because the RTA toxin is unable to 
bind or enter the cell autonomously, immunotoxins are only hazardous to cells capable of 
binding and internalizing the mAbs (Wayne, Fitzgerald et al. 2014), therefore mitigating toxicity 
to bystander cells (van Oosterhout, van Emst et al. 2000). 
Additionally, two other anti-T-cell immunotoxins have been clinically tested as a single-agent for 
the in vivo prevention/treatment of aGVHD: anti-CD5 immunotoxin H65-RTA (Xomazyme CD5), 
which was constructed with RTA chain, and anti-CD25 directed denileukin diftitox (Ontak), a 
recombinant fusion protein linking cytokine interleukin (IL)-2 to truncated diphtheria toxin. 
Although these single-agent immunotoxins showed promising initial results, when tested as 
second-line treatment for SR-aGVHD, they appeared not to be superior to available aGVHD 
treatments. (Byers, Henslee et al. 1990, Krance, Heslop et al. 1993, Hings, Severson et al. 
1994, Phillips, Nevill et al. 1995, Martin, Nelson et al. 1996, Ho, Zahrieh et al. 2004, 
Shaughnessy, Bachier et al. 2005). 
One of the reasons T-Guard might be more successful is that the simultaneous targeting of two 
or more antigens on the same target cell may result in a synergistic toxicity (see section 1.3.1.1). 
Moreover, CD3 antibody binding to the CD3/T cell receptor (CD3/TCR) complex results in 
competitive inhibition and internalization of the antibody-receptor complex, thus blocking T cell 
activation directly and may trigger activation-induced cell death of activated T cells. 


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Figure 1-1: T-Guard Mechanism of Action 
1.3.1.1 
Pre-Clinical Data 
We hypothesize that T-Guard might have a role in treatment and/or prevention of GVHD based 
on the pre-clinical immunological profile. 
1.3.1.1.1 Synergistic Apoptosis of a Combination of Anti-T-Cell Immunotoxins  
Several anti-T cell mAbs were conjugated to RTA and evaluated for their efficacy, alone and in 
combination, to eliminate or neutralize activated T cells in vitro. These experiments led to the 
selection of an immunotoxin-combination consisting of SVP-T3a-RTA (anti-CD3) and WT1-RTA 
(anti-CD7). This particular combination, having the working name ‘T-Guard’, was more effective 
at inducing T cell apoptosis than each of the individually tested immunotoxins. Figure 1-2 shows 
percent cell viability of Jurkat cells treated with either SPV-T3a-RTA and WT1- RTA or in 
combination (half a dose each). 
1.3.1.1.2 Cytokine Modulation by T-Guard 
Both SPV-T3a and WT1 deliver the toxic RTA-payload inside the T cells, and the SPV-T3a 
modulates the CD3/TCR complex (see above). Notably, SPV-T3a is particularly well suited for 
in vivo use, as this anti-CD3 mAb does not stimulate T cells (Land, Hillebrand et al. 1988, 
Smely, Weschka et al. 1990, Frenken, Koene et al. 1991, Woodle, Thistlethwaite et al. 1991, 
Anasetti, Martin et al. 1992, Knight, Kurrle et al. 1994). This strongly reduces the occurrence of 
cytokine release syndrome (CRS), a potentially life-threatening complication frequently 
associated with the clinical use of non-conjugated immunosuppressive anti-CD3 mAbs or Anti- 
Thymocyte Globulin (ATG). 


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Figure 1-2: Synergistic cell kill by the T-Guard combination 
 
1.3.1.1.3 Preferential Targeting of Activated T Cells over Non-Activated and Anti-
Viral T Cells 
The SPV-T3a-RTA and WT1-RTA immunotoxin-combination preferentially kills recently 
activated T cells (van Oosterhout, van Emst et al. 2000). Figure 1-3 depicts the outcome of an 
ex vivo experiment, in which non-activated and phytohemagglutinin (PHA)-activated Peripheral 
Blood Mononuclear Cells s were incubated with various concentrations of T-Guard. Incubation 
with clinically relevant T-Guard concentrations (10-9 M – 10-8 M) results in a reduction of the 
number of activated T cells to less than 1%, while 35% of their non-activated counterparts 
survived. Flow cytometric analysis revealed that the higher vulnerability of recently activated T 
cells could most likely be attributed to a strong increase in CD7 membrane expression. This 
upregulation of CD7 expression upon recent T cell activation with either PHA, anti-CD3 mAbs or 
in a Mixed Lymphocyte Reaction has been described by others as well (Heinrich, Gram et al. 
1989, Akbar, Amlot et al. 1990, Amlot, Tahami et al. 1996). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1-3: Preferential targeting of activated T Cells (ex vivo experiment) 
 
It is also noteworthy that, apart from recent T cell activation, CD7 expression also seems to be 
regulated by differentiation stage, with lower CD7 expression on mature effector memory T cells 
(Reinhold, Abken et al. 1993, Amlot, Tahami et al. 1996, Aandahl, Sandberg et al. 2003, Appay, 
van Lier et al. 2008). This may portend clinical benefit given that virus-specific T cells reside 
primarily in the effector memory compartments (Gamadia, Rentenaar et al. 2001, Aandahl, 
Quigley et al. 2004, Appay, van Lier et al. 2008, Shindo, Kim et al. 2013), and may therefore be 
relatively spared by T-Guard treatment. 
1.3.1.1.4 NK Cells Apoptosis 
Aside from T cells, the immunotoxin-antibody combination WT1-RTA also targets NK cells 
(CD3-/CD7+). In the Phase 1/2 clinical study using T-Guard, NK cells demonstrated the same 
depletion pattern as T cells, an early and quick depletion during the seven-day treatment period, 
followed by a rapid repopulation of the NK cell compartment (Groth, van Groningen et al. 2018). 
The NK cell depletion is thought to contribute to controlling established aGVHD disease, as NK 
cells may aggravate the severity of aGVHD through production of cytokines such as Interferon 
(IFN)-gamma (Gill, Olson et al. 2009). 
1.3.1.2 
Clinical Data 
T-Guard has been evaluated in three clinical trials: as third-line therapy in an investigator-
initiated dose escalation-study in seven patients suffering from SR-aGVHD (van Oosterhout, 
van Emst et al. 2000, van Oosterhout, van Emst et al. 2001) and as second-line therapy in a 
Phase 1/2 study in 20 patients with SR-aGVHD (Groth, van Groningen et al. 2017). T-Guard 
was also investigated in a single-arm Phase 3 trial (BMT CTN1802), although this study was 
closed early. Results from these studies are summarized below. 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1.2.1 T-Guard Dose Escalation Study as Third Line for SR-aGVHD Patients 
The main purpose of the investigator-initiated dose escalation study was to test the safety and 
PK of T-Guard. A total of seven male Caucasian patients, with a median age of 47 with SR-
aGVHD that had failed second-line therapy were included. Three of these patients (43%) had 
aGVHD Grade IV, 3 patients (43%) Grade III and 1 patient Grade II (14%). Six patients (86%) 
had visceral organ involvement, including four patients (57%) with liver involvement and two 
patients (29%) with GI involvement. One patient (14%) had grade IV aGVHD of the skin. Before 
T-Guard treatment, all patients received an initial course of steroids at 1-2mg/kg/day for at least 7 
days, followed by 1 gram of methylprednisolone equivalent per day for at least 3 days to treat 
SR-aGVHD. The first two patients started with T-Guard 2mg/m2 infused every 48 hours x 2 
doses, followed by 4mg/m2 every 48 hours x 2 doses. There were no toxicities associated with 
the T-Guard treatment, and therefore the next five patients were scheduled to receive 4mg/m2 
every 48 hours x 4 doses. 
The infusions were well tolerated, and biologic and clinical responses, as further described 
below, were achieved. Given the activity and tolerance of the 4mg/m2 every 48 hours x 4 doses 
schema, no further dose escalation was completed. The study team was concerned for capillary 
leak syndrome (CLS), which is a known complication of ricin-based immunotoxins. However, 
none of the patients had any severe toxic side effects (grade 3 or higher Common Terminology 
Criteria for Adverse Events (CTCAE) 4.3) associated with RTA-based immunotoxins, like severe 
CLS and rhabdomyolysis. Regarding Treatment Emerging Adverse Events (TEAE), the most 
frequent reported adverse events (AE) were: pyrexia (43%) and headache (29%) followed by 
pain, edema, aphasia, dizziness, epilepsia, diarrhea, hemorrhoids, paralytic ileus and protein 
losing gastroenteropathy (all 14%). 
PK analysis showed that the 4mg/m2 every 48 hours x 4 doses schedule resulted in T-Guard in 
vivo serum peak concentration (Cmax) of around 1.5 µg/ml (~10-8M). On the basis of in vitro 
experiments, the Cmax attained results in a 60-80% occupation of the target antigens CD3 and 
CD7 and corresponds with the optimal in vitro concentration for a specific elimination of antigen-
positive target cells (see Figure 1-3). 
Four patients were evaluated for biologic response with flow cytometric quantitation of NK and T 
cell levels. All of these patients showed a rapid and profound reduction in circulating T cells and 
NK cells, with additional doses leading to further reduction (less than 10-20%) of initial levels of 
circulating NK and T cells. With this prompt and marked decline in NK and T cells there was 
clinical improvement in GVHD, with four of the seven patients having clinically meaningful and 
rapid reduction in their GVHD. Five out of 7 patients (71%) responded. One patient (14%) was in 
complete remission, 4 patients (57%) had a PR. To date 6 patients died, two during the first 
eight days of treatment with T-Guard. All patient deaths were related to multisystem organ 
failure and opportunistic infections. 
Since the dose level of T-Guard at 4 mg/m2 x 4 doses generated biologically relevant serum 
concentrations (Cmax of 1.36 ± 0.27 µg/mL) which resulted in clear biological and clinical 
responses without inducing severe acute toxicities, the dosage was not further increased to 
prevent potentially dangerous dose limiting toxicities (DLTs). 


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1.3.1.2.2 T-Guard Single-arm, Phase 1/2 Clinical trial in second-line SR-aGVHD 
Patients 
Following the promising results of T-Guard for the indication SR-aGVHD in the investigator- 
initiated dose escalation study, a Phase 1/2 study XEN/TG-001 was conducted (Groth, van 
Groningen et al. 2018). The study was designed to evaluate the safety and efficacy of T- Guard 
in treating SR-aGVHD patients who were refractory to first-line therapy. In total 20 patients were 
treated with T-Guard with a dose of 4 mg/m2 every other day x 4 doses. All patients had grade II 
to IV SR-aGVHD. Seventeen of these patients (85%) had grade III-IV SR-aGVHD, and all 20 
patients had visceral involvement; 18 with GI (90%) and 5 with liver (25%) involvement. Sixteen 
patients (80%) had 2 or more organs involved. A validated two biomarker algorithm classified 
the majority of patients (11/20) as high-risk. 
The Day 28 ORR (primary endpoint), defined as having a CR or PR without the need for 
initiation of other treatments due to insufficient response, was 60%. Day 28 CR was 50% and PR 
10%. The Day 180 OS was 60%. The outcomes achieved were very favorable compared with 
the historical standard of care (SoC) data at the participating centers (Day 28 CR less than 20% 
and Day 180 OS 29%). 
1.3.1.2.3 Safety 
The most common side-effects described for RTA-based immunotoxins are vascular leakage 
and myalgia, the latter being often associated with an increase in serum creatine kinase (CK). 
Moreover, the systemic administration of anti-CD3 antibodies may result in the activation of T- 
cells leading to CRS. In both trials T-Guard was overall well-tolerated. Mild infusion related 
reactions, such as mild chills, were documented. However, no acute toxicity reactions seen 
were greater than Grade 1. The most commonly reported AEs considered to be related to T- 
Guard administration were hypoalbuminemia and thrombocytopenia. 
The potentially drug-associated side effects occurring in more than one patient consisted of 
(further) decrease in platelet count (thrombocytopenia), hypoalbuminemia and thrombotic 
microangiopathy. Regarding thrombocytopenia and hypoalbuminemia, the patients in the study 
already had a low platelet count and albumin level due to aGVHD and medications. 
Nevertheless, in several patients, a further decrease was observed during the treatment period. 
According to the Principal Investigators (PIs), thrombocytopenia and hypoalbuminemia were well-
manageable. TEAEs from the overall study are outlined in Table 1-1 from the Phase 1/2 Trial. 
 
 


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Table 1-1:MostFrequentlyReportedSystemOrganClass(≥10PatientsinTotal)and 
PreferredTerm(≥5PatientsinTotal)forTEAEs,OverallStudy 
System organ class/ Preferred term 
Total (N=20) n (%)
Any adverse event
20 (100.0%)
Infections and infestations 
19 (95.0%) 
Upper respiratory tract infection 
5 (25.0%) 
Metabolism and nutrition disorders 
17 (85.0%) 
Hypoalbuminemia 
8 (40.0%) 
Hyperglycemia 
7 (35.0%) 
Hypokalemia 
5 (25.0%) 
Hypophosphatasemia 
5 (25.0%) 
General disorders and administration site conditions 
16 (80.0%) 
Edema peripheral 
8 (40.0%) 
Pyrexia 
8 (40.0%) 
Fatigue 
6 (30.0%) 
Gastrointestinal disorders 
15 (75.0%) 
Nausea 
5 (25.0%) 
Investigations 
13 (65.0%) 
Blood bilirubin increased 
6 (30.0%) 
White blood cell count decreased 
5 (25.0%) 
Musculoskeletal and connective tissue disorders 
13 (65.0%) 
Muscular weakness 
5 (25.0%) 
Myopathy 
5 (25.0%) 
Vascular disorders 
12 (60.0%) 
Capillary leak syndrome 
8 (40.0%) 
Blood and lymphatic system disorders 
11 (55.0%) 
Anemia 
6 (30.0%) 
Thrombocytopenia 
6 (30.0%) 
Nervous system disorders 
11 (55.0%) 
 
In total 29 Serious Adverse Events (SAE) were reported in 14 patients (Table 1-2). Of those 
SAEs, 23 were reported as severe, 4 as moderate and 2 as mild. Eight (8) patients died during 
the course of the trial. The causes of death were determined to be refractory aGVHD, infections 
or the combination of the two. All deaths were reported as not related to T-Guard. No deaths 
occurred before 6 months (Day 180) due to relapse of the underlying disease. 
 
 


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Table 1-2: Summary of Adverse Events Potentially Related to Treatment (Groth, van 
Groningen et al. 2018) 
Grade 2a 
Grade 3 
Grade 4 
Anemia (1)b 
Thrombocytopenia (3) 
Thrombocytopenia (5) 
Abdominal pain (1) 
Neutropenia (1) 
Thrombocytopenia (1) 
Elevated bilirubin (2) 
Neutropenia (1) 
Myopathy (1) 
Microangiopathy (1) 
Microangiopathy (1) 
Chills (2) 
Hypoalbuminemia (1) 
Capillary leak syndrome (1)  
Hypoalbuminemia (1) 
 
 
Grading of each AE is based on Version 4.0 of the CTCAE, with the exception of CLS, which 
was graded using the system described by Messmann et al. (Messmann, Vitetta et al. 2000). 
The numbers in parentheses refer to the number of patients who experienced the indicated 
adverse event. 
The overall conclusion of the Phase 1/2 study is that T-Guard was well tolerated and can be 
safely administered in patients with SR-aGVHD. Additionally, the response rates, in particular 
CR rates, at Day 28 were markedly superior (CR 50%) to historical controls and the results of 
emerging therapies (CR 20-35%). 
1.3.1.2.4 BMT CTN 1802 T-Guard open-label, single-arm Phase 3 clinical trial in 
SR-aGVHD 
A Phase 3 single arm, open-label, multicenter clinical trial to evaluate the safety and efficacy of 
T-Guard was opened to accrual in November 2018 but was closed after the first three 
participants died within 30 days due to infection/sepsis. Careful review identified significant risk 
factors and features prognostic of early death at the start of T-Guard treatment in these 3 
patients, including findings concerning for progressive infection, renal dysfunction, prior 
sirolimus, prior checkpoint inhibitor use, high body mass index, and active or suspected 
thrombotic microangiopathy (TMA).  
A subsequent in-depth analysis compared the nine patients (3 in BMT CTN 1802 and 6 in the 
prior studies) who died within 30 days of enrollment to the 26 patients who survived more than 
30 days in both trials. An important factor identified is the LDH at enrollment being equal or 
higher than 290 (median 308 vs. 222) with 67% of patients with early death vs. 27% if lower 
than 289 (p=0.05). An elevated LDH in this setting may be a marker of severe microvascular 
injury/tissue damage and may thus represent transplant-associated TMA which carries a high 
risk for imminent death. Therefore, TMA screening with LDH criteria is mandated at screening 
for proposed trial to mitigate risks to patients on study. 
Further, the Body Mass Index (BMI) of the 9 patients with early death is higher (median 28.6 vs. 
22.8, p=0.03) than the BMI of those who survived beyond Day 30. While no correlation between 
the early deaths and BMI or T-Guard exposure could be found, for future trials patients with a 


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BMI greater than or equal to 35 are excluded and the Body Surface Area (BSA)-dose 
calculation will be optimized for patients exceeding 125% of their ideal body weight (IBW) as is 
usual practice for IV treatment (e.g., chemotherapy). More details can be found in section 
2.5.1.4 Dose and Administration of T-Guard and in the current version of the Investigators 
Brochure. 
Further analysis of all T-Guard patient outcomes as combined across all studies including 
Phase 1/2/3 trials and the Expanded Access Program, and inclusive of the three deaths on the 
BMT CTN 1802 protocol, suggests that T-Guard could provide a new and more effective 
therapeutic option for patients that currently have very few approved options. The efficacy 
evaluation now includes 35 SR-aGVHD patients, of whom 15 (42.8%) had a Complete 
Response (CR) and 6 (17.1%) a Partial Response, yielding an Overall Response Rate (ORR) of 
60.0%, with a 6-month OS of 60% (including the BMT CTN 1802 participants). These results 
compared favorably with higher Day 28 CR rate (historical control of 34.4%), similar to the ORR 
of 62.3%, and higher than the 6-month OS as reported in the REACH2 trial of 48.7% (Zeiser, 
NEJM 2020). The high D28 CR rate with T-Guard appears to be especially (or particularly) 
promising as CR at D28 is the strongest correlate with long term survival. Thus, in consultation 
with the FDA, BMT CTN 1802 was closed to pursue the randomized clinical trial design with 
ruxolitinib in Grade III-IV SR-aGVHD to be studied in current trial. The experience from BMT 
CTN 1802 has helped clarify inclusion/exclusion criteria and safety monitoring for this 
randomized trial. The randomization may also help determine if the toxicities observed in the 
single arm study may have been associated with T-Guard administration or if they are inherent 
to the very high-risk population eligible for SR-aGVHD trials.  
1.3.2 Ruxolitinib 
Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 which mediate the signaling of a number 
of cytokines and growth factors that are important for hematopoiesis and immune function. JAK 
signaling involves recruitment of STATs (signal transducers and activators of transcription) to 
cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to 
modulation of gene expression.  
1.3.2.1 
Clinical Data 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice.  
The safety of ruxolitinib was assessed in 617 patients in six clinical studies with a median 
duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 
studies.  
In these myelofibrosis studies, patients had a median duration of exposure to ruxolitinib of 9.5 
months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 
24.6% treated for more than 12 months. One hundred and eleven (111) patients started 
treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting 
treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 x 109/L) and 20 mg 
twice daily (pretreatment platelet counts greater than 200 x 109/L), 65% and 25% of patients, 


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respectively, required a dose reduction below the starting dose within the first 8 weeks of 
therapy.  
In the SR-aGVHD setting, a multicenter, randomized, open-label Phase 3 study of ruxolitinib 
versus BAT was performed (REACH2). Of the 154 patients assigned to the ruxolitinib arm, 152 
were treated with ruxolitinib, of the 155 patients assigned to the control arm, 150 patients 
received BAT. 
The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients 
[33%] receiving ruxolitinib and 27 of 150 [18%] patients receiving the control), anemia (in 46 
[30%] and 42 [28%], respectively), and CMV infection (in 39 [26%] and 31 [21%]) (Zeiser, 
Bubnoff et al. 2020). 
Treatment discontinuation occurred in 111 of 154 patients (72%) assigned to ruxolitinib and in 
132 of 155 (85%) assigned to the control; the most common reason was lack of efficacy (in 32 
[21%] and 68 [44%], respectively). The median duration of exposure to therapy was 63 days 
(range, 6 to 396) in the ruxolitinib group and 29 days (range, 1 to 188) in the control group. The 
median dose intensity of ruxolitinib was 16.8 mg per day (interquartile range, 11.9 to 19.6). 
Table 1-3 presents the most common adverse reactions occurring in the 152 patients who 
received ruxolitinib and the 150 patients treated with the control in the randomized REACH2 
study. 
 
 


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Table 1-3: Most Frequent Adverse Events up to Day 28 (Safety Population)* 
Most Frequent Adverse Events up to Day 28 (Safety Population)* 
Event 
Ruxolitinib (N= 152) 
Control (N=150) 
 
Any Grade
Grade≥3
Any Grade
Grade≥3
 
 
number of patients (percent) 
 
Any adverse event 
145 (95) 
118 (78) 
140 (93) 
117 (78) 
Thrombocytopenia 
50 (33) 
41 (27) 
27 (18) 
23 (15) 
Anemia 
46 (30) 
33 (22) 
42 (28) 
28 (19) 
Cytomegalovirus infection† 
39 (26) 
11 (7) 
31 (21) 
12 (8) 
Peripheral edema 
28 (18) 
2 (1) 
26 (17) 
1 (1) 
Platelet count decreased 
26 (17) 
22 (14) 
21 (14) 
20 (13) 
Neutropenia 
24 (16) 
20 (13) 
19 (13) 
14 (9) 
Hypokalemia 
20 (13) 
9 (6) 
25 (17) 
9 (6) 
Hypertension
16 (11)
9 (6)
14 (9)
6 (4)
Hypoalbuminemia 
16 (11) 
6 (4) 
15 (10) 
10 (7) 
Pyrexia 
16 (11)
2 (1)
17 (11)
2 (1)
Hypomagnesemia 
15 (10) 
0 
20 (13) 
1 (1) 
Diarrhea
14 (9)
7 (5)
15 (10)
5 (3)
White-cell count decreased 
14 (9) 
11 (7) 
13 (9) 
11 (7) 
Nausea 
13 (9)
0
9 (6)
0
Hypocalcemia 
12 (8) 
3 (2) 
10 (7) 
4 (3) 
Hypophosphatemia
12 (8)
5 (3)
14 (9)
7 (5)
Abdominal pain 
11 (7) 
4 (3) 
7 (5) 
2 (1) 
Sepsis 
11 (7)
10 (7)
6 (4)
5 (3)
Acute kidney injury 
10 (7) 
1 (1) 
3 (2) 
3 (2) 
Alanine aminotransferase increased
10 (7)
3 (2)
10 (7)
4 (3)
Neutrophil count decreased 
10 (7) 
10 (7) 
14 (9) 
11 (7) 
Vomiting 
10 (7) 
1 (1) 
6 (4) 
0 
Epstein-Barr virus infection 
9 (6) 
0 
8 (5) 
3 (2) 
Hyperglycemia 
9 (6) 
5 (3) 
14 (9) 
8 (5) 
Hypogammaglobulinemia 
9 (6) 
2 (1) 
5 (3) 
0 
Fall 
8 (5) 
1 (1) 
1 (1) 
0 
Hyperkalemia 
8 (5) 
3 (2) 
6 (4) 
2 (1) 
Hypotension 
8 (5) 
4 (3) 
9 (6) 
3 (2) 
Leukopenia 
8 (5) 
7 (5) 
2 (1) 
2 (1) 
Pancytopenia 
8 (5)
7 (5)
6 (4)
5 (3)
Urinary tract infection 
8 (5) 
3 (2) 
6 (4) 
4 (3) 
Gamma-glutamyltransferase increased
7 (5)
3 (2)
10 (7)
7 (5)
Pneumonia 
6 (4) 
5 (3) 
8 (5) 
7 (5) 
Blood bilirubin increased 
5 (3)
3 (2)
12 (8)
7 (5)
Pain in extremity 
4 (3) 
2 (1) 
8 (5) 
1 (1) 
*Shown are the adverse events that had an incidence of at least 5% in either group. The safety population included all patients 
who received at least on dose of trial therapy. 
†A distinction between cytomegalovirus infection and reactivation was not made in this trial. 
 


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1.3.2.1.1 Thorough QT Study 
The effect of single dose ruxolitinib 25 mg and 200 mg on QTc interval was evaluated in a 
randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover 
thorough QT study in 47 healthy subjects. In a study with demonstrated ability to detect small 
effects, the upper bound of the one-sided 95% confidence interval for the largest placebo 
adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 
10ms, the threshold for regulatory concern. The dose of 200 mg is adequate to represent the 
high exposure clinical scenario. 
1.3.2.1.2 Drug Interactions - CYP3A4 inhibitors 
Strong CYP3A4 inhibitors: In a trial of 16 healthy volunteers, a single dose of 10 mg of 
ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of ruxolitinib was 
administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 inhibitor, 
given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and AUC by 33% and 
91%, respectively. Ketoconazole also prolonged ruxolitinib half-life from 3.7 to 6.0 hours.  
Fluconazole: Simulations using physiologically-based pharmacokinetic (PBPK) models 
suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady state 
ruxolitinib AUC by approximately 100% to 300% following concomitant administration of 10 mg 
of Jakafi twice daily with 100 mg to 400 mg of fluconazole once daily, respectively.  
Mild or moderate CYP3A4 inhibitors: In a trial of 15 healthy volunteers, a single dose of 10 
mg of ruxolitinib was administered alone on Day 1 and a single dose of 10 mg of Jakafi was 
administered on Day 5 in combination with 500 mg of erythromycin (a moderate CYP3A4 
inhibitor, given twice daily on Days 2 to 5). Erythromycin increased ruxolitinib Cmax and AUC by 
8% and 27%, respectively.  
1.3.2.1.3 Drug Interactions - CYP3A4 inducers 
In a trial of 12 healthy volunteers, a single dose of 50 mg of Jakafi was administered alone on 
Day 1 and a single dose of 50 mg of Jakafi was administered on Day 13 in combination with 600 
mg of rifampin (a strong CYP3A4 inducer, given once daily on Days 3 to 13). Rifampin 
decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. In addition, the relative 
exposure to ruxolitinib’s active metabolites increased approximately 100%.  
1.3.2.1.4 Pharmacodynamics  
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy 
subjects and MF patients. Jakafi administration resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both 
healthy subjects and myelofibrosis patients.  
1.3.2.1.5 Pharmacokinetics  
Absorption: In clinical studies, ruxolitinib is rapidly absorbed after oral Jakafi administration with 
maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass 
balance study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean 
ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 


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to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon 
administration of Jakafi with a high-fat meal, with the mean Cmax moderately decreased (24%) 
and the mean AUC nearly unchanged (4% increase). PK data in transplant patients showed 
lower absorption (decreased Cmax and AUC) but similar elimination half-life compared to 
published data from healthy volunteers. (Ali, H., Snyder, D., Stiller, T., et al 2019) 
Distribution: The apparent volume of distribution of ruxolitinib at steady state is 53 to 65 L in 
myelofibrosis patients. Binding to plasma proteins in vitro is approximately 97%, mostly to 
albumin.  
Metabolism: In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser 
extent by CYP2C9.  
Elimination: Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, 
elimination was predominately through metabolism with 74% of radioactivity excreted in urine 
and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total 
radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean 
half-life of ruxolitinib + metabolites is approximately 5.8 hours.  
Effects of Age, Gender, or Race: In healthy subjects, no significant differences in ruxolitinib 
pharmacokinetics were observed with regard to gender and race. In a population 
pharmacokinetic evaluation in myelofibrosis 16 patients, no relationship was apparent between 
oral clearance and patient age or race, and in women, clearance was 17.7 L/h and in men, 22.1 
L/h with 39% inter-subject variability. 
1.3.2.2 
Toxicology 
Ruxolitinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model or in a 2-
year carcinogenicity study in the rat. 
Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in 
vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in vivo in 
a rat bone marrow micronucleus assay. 
In a fertility study, ruxolitinib was administered to male rats prior to and throughout mating and 
to female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib had 
no effect on fertility or reproductive function in male or female rats at doses of 10, 30 or 60 
mg/kg/day. However, in female rats’ doses of greater than or equal to 30 mg/kg/day resulted in 
increased post-implantation loss. The exposure (AUC) at the dose of 30 mg/kg/day is 
approximately 34% the clinical exposure at the maximum recommended dose of 25 mg twice 
daily. 
1.3.2.3 
In vitro studies 
In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 
at clinically relevant concentrations.  
In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, 
OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. Ruxolitinib 
is not a substrate for the P-gp transporter.  


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1.4 
STUDY RATIONALE 
T-Guard has a rapid onset, preferential killing of activated T cells, and short half-life, leading to 
depletion of allo-reactive T cells and quick post-treatment reconstitution of the immune system. 
In the Phase 1/2 trial with T-Guard, peripheral blood samples were analyzed before and after 
treatment. As expected, treatment with T-Guard led to profound depletion of T cells and NK 
cells, with rapid recovery starting as early as 14 days following treatment (see Figure 1-4). No 
specific treatment-induced changes in the relative proportions of naïve, memory, effector and 
effector memory type of T-cells were found before and after treatment, and regulatory T cells 
showed normal variation throughout the study. The study of T cell diversity found low T-cell 
diversity before T-Guard treatment, which further declined by month one post- treatment, likely 
due to reduction in T cell numbers. This was followed, at months two through six, with a steady 
rebound in the T-cell diversity. By 180 days post-treatment the T-cell repertoire was both 
diverse and expanded, with several new polyclonal T cell populations found. 
The proposed model is that immunodepleting the vast majority of alloreactive T cells will shift 
the immune balance to a more tolerogenic state in SR-aGVHD patients, resulting in better 
disease control and an improved survival. We hypothesize depleting NK cells will contribute to 
the tolerogenic state by suppressing cytokine release and inflammation. 
 
 


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Figure 1-4: T-Guard Observed Immune Reconstitution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T-Guard induces rapid immune reconstitution with a diverse T cell repertoire. (A-C) Time course of the median T cell 
count (A), median NK cell count (B), and median B cell count (C) for all patients. In each plot, the blue line represents 
the median value, and the lower and upper gray dotted lines represent the 25th and 75th percentiles, respectively. (D) 
Summary of the absolute number of unique T cell clones before administration of T-Guard (Pre) and at 30, 90, and 
180 days after treatment. The number of unique T cell clones was measured using the total number of unique CDR3 
sequences. The P values are based on the Wilcoxon matched-pairs signed-rank test. The significant increase in 
unique T cell clones at Day 180 after T-Guard treatment reflects an increase in the diversity of expanded T cells. (E-H) 
Representative histograms showing the T cell repertoires in a single patient before T-Guard treatment (E) and at 30 
days (F), 90 days (G), and 180 days (H) after therapy. 


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In this study, ruxolitinib will be the comparator drug since ruxolitinib is the only currently FDA 
approved drug for this indication, and in the EU, it is broadly used based on the REACH2 study 
demonstrating superiority over BAT. It is important to note that the ORR and benefits of 
ruxolitinib therapy are primarily driven by responses in patients with Grade II SR-aGVHD. 
Patients treated with ruxolitinib for grade III-IV SR-GVHD have significantly worse survival 
(Figure 1-5). An ad-hoc analysis of available data, of treatment outcomes for patients with 
Grade III-IV SR-aGVHD showed that patients treated with T-Guard had the highest Day 28 CR 
(43.3%) followed by patients treated with ruxolitinib on REACH2 (25.7%). The CR rates for 
patients with Grade III-IV SR-GVHD treated with ruxolitinib on REACH1 or BAT on the MAGIC 
natural history trial are also shown for comparison (Figure 1-6). The higher CR rate seen with T-
Guard is consistent with a higher OS observed in patients treated with T-Guard (Figure 1-7). 
Taken together the preliminary data and ad hoc analyses suggest that T-Guard may be 
efficacious for Grade III-IV SR-aGVHD and compares favorably to existing treatments. In this 
Phase 3 randomized, open-label, multicenter study we will directly compare T-Guard to 
ruxolitinib as treatment for Grade III-IV SR-aGVHD, the group at highest risk for treatment 
failure and death. 
 
Figure 1-5: Overall Survival Grade II vs. Grade III-IV SR-aGVHD Ruxolitinib 
 
OS by aGVHD grade at enrollment. aGVHD grade at enrollment was significantly associated with OS by 
log-rank test in the Kaplan-Meier analysis (P = .021). In model-based analysis of OS by Cox regression, 
aGVHD grade III/IV was again significantly associated with reduced OS (aGVHD grade III/IV vs. grade II; 
HR, 0.334; 95% CI, 0.150-0.747; P = .0076) (Jagasia et al. 2020). 
 
 
     Grade II aGVHD 
 
           Grade III-IV aGVHD 
   Grade III-IV aGVHD 
   Grade II aGVHD 


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Figure 1-6: Day 28 CR rates Grade III-IV SR-aGVHD patients T-Guard compared to data 
from ruxolitinib and MAGIC controls
 
Phase 1/2 study (n=17; (Groth et al. 2019)), expanded access program (n=11; 
(Groningen et al. 2019)) and BMT CNT 1802 (n=2)). 
 
Figure 1-7: Overall survival Grade III-IV SR-aGVHD patients T-Guard vs. ruxolitinib 
 
T-Guard integrated survival curve of Grade III-IV patients (n=30; data on file) vs. REACH1 (Jagasia 
et al. 2020) 
 
    Ruxolitinib Grade III-IV aGVHD 
    T-Guard Grade III-IV aGVHD 


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CHAPTER 2 
2 STUDY DESIGN 
2.1 
STUDY OVERVIEW 
This is a Phase 3, open-label, randomized, international multicenter trial designed to compare 
T-Guard to ruxolitinib for the treatment of patients with Grade III or IV SR-aGVHD. 
2.2 
HYPOTHESIS AND SPECIFIC OBJECTIVES 
2.2.1 Primary Hypothesis 
The primary hypothesis is that T-Guard treatment will improve the Day 28 complete response 
(CR) rate in patients with Grades III and IV SR-aGVHD compared to ruxolitinib. 
2.3 
STUDY OBJECTIVES 
2.3.1 Primary Objective 
The primary objective of this trial is to assess the rate of CR on Day 28 post-randomization in 
Grades III and IV SR-aGVHD patients treated with T-Guard treatment in comparison to 
ruxolitinib. 
2.3.2 Secondary Objectives 
1. Estimate overall survival (OS) at Days 60, 90 and 180 post-randomization. 
2. Evaluate the duration of complete response (DoCR). 
3. Estimate the time to CR from randomization. 
4. Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56 
post-randomization. 
5. Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression 
of aGVHD at Days 6, 14, 28, and 56 post-randomization. 
6. Estimate the cumulative incidence of NRM at Days 100 and 180 post-randomization. 
7. Estimate relapse-free survival at Day 180 post-randomization. 
8. Estimate GVHD-free survival at Days 90 and 180 post-randomization. 
9. Estimate the cumulative incidence of cGVHD at Day 180 post-randomization. 
10. Estimate the cumulative incidence of underlying disease relapse/progression at Day 180 
post-randomization. 
11. Describe the incidence of infections. 
12. Describe the incidence of toxicities. 
13. Assess the pharmacokinetics of T-Guard. 
14. Assess the immunogenicity of T-Guard. 
 
 


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2.3.3 Exploratory Objectives 
1. Describe the proportion of participant free of systemic steroids by Day 180 post-
randomization. 
2. Estimate the incidence of CMV reactivation requiring treatment by Day 180 post-
randomization. 
3. Estimate the incidence of EBV-associated lymphoproliferative disorder or EBV reactivation 
requiring treatment with rituximab by Day 180 post randomization. 
4. Evaluate the evolution and characteristics of specific cell populations at randomization and 
at Days 0, 14, 28, 56 and 180. 
5. Evaluate aGVHD Biomarkers at baseline and at Days 6, 14 and 28 post-randomization. 
6. Describe changes in patient-reported outcomes (PROs) from baseline to Days 28, 90 and 
180 post-randomization. 
7. Estimate incidence of TMA at Days 6, 14, 21 and 28 post-randomization. 
8. Describe the EASIX score at screening. 
2.4 
PATIENT ELIGIBILITY 
2.4.1 Inclusion Criteria 
To be eligible to participate in this study, patients must meet the following eligibility criteria: 
1. Patients must be at least 18.0 years of age at the time of consent. 
2. Patient has undergone first allo-HSCT from any donor source or graft source. Recipients of 
nonmyeloablative, reduced intensity, and myeloablative conditioning regimens are eligible. 
3. Patients diagnosed with Grade III/IV SR-aGVHD after allo-HSCT. SR includes aGVHD 
initially treated at a lower steroid dose, but must meet one of the following criteria: 
• 
Progressed or new organ involvement after 3 days of treatment with methylprednisolone 
(or equivalent) of greater than or equal to 2 mg/kg/day 
• 
No improvement after 7 days of primary treatment with methylprednisolone (or 
equivalent) of greater than or equal to 2mg/kg/day 
• 
Patients with visceral (GI and/or liver) plus skin aGVHD at methylprednisolone (or 
equivalent) initiation with improvement in skin GVHD without any improvement in 
visceral GVHD after 7 days of primary treatment with methylprednisolone (or equivalent) 
of greater than or equal to 2mg/kg/day 
• 
Patients who have skin GVHD alone and develop visceral aGVHD during treatment with 
methylprednisolone (or equivalent) of greater than or equal to 1mg/kg/day and do not 
improve after 3 days of greater than or equal to 2mg/kg/day 
Progression and no improvement are defined in Section 3.1. Improvement or progression in 
organs is determined by comparing current organ staging to staging at initiation of 
methylprednisolone (or equivalent) treatment. Staging is performed per MAGIC criteria (see 
APPENDIX C). 
4. Patients must have evidence of myeloid engraftment (e.g., absolute neutrophil count greater 
than or equal to 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). 
Use of growth factor supplementation is allowed. 
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but not capable of signing the informed consent form (ICF)) should have given written 
informed consent. 
2.4.2 Exclusion Criteria 
Patients will be excluded from study entry if they meet any of the following exclusion criteria: 
1. Patients who have a creatinine greater than or equal to 2mg/dL or estimated creatinine 
clearance less than 40 mL/min or those requiring hemodialysis. 
2. Patients who have been diagnosed with active TMA, defined as meeting all the following 
criteria: 
• 
Greater than 4% schistocytes in blood (or equivalent if semiquantitative scale is used 
e.g., 3+ or 4+ schistocytes on peripheral blood smear) 
• 
De novo, prolonged or progressive thrombocytopenia (platelet count less than 50 x 109/L 
or 50% or greater reduction from previous counts) 
• 
Sudden and persistent increase in lactate dehydrogenase concentration greater than 2x 
ULN 
• 
Decrease in hemoglobin concentration or increased transfusion requirement attributed to 
Coombs-negative hemolysis 
• 
Decrease in serum haptoglobin 
3. Patients who have previously received treatment with eculizumab. 
4. Patients who have previously received checkpoint inhibitors (either before or after allo-HCT). 
5. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent 
features of cGVHD. 
6. Patients requiring mechanical ventilation or vasopressor support. 
7. Patients who have received any systemic treatment, besides steroids, as upfront treatment 
of aGVHD or as treatment for SR-aGVHD. Reinstitution of previously used GVHD 
prophylaxis agents (e.g., tacrolimus, cyclosporin, MTX, MMF) or substitutes in cases with 
previously documented intolerance will be permitted. Previous treatment with a JAK inhibitor 
as part of GVHD prophylaxis or treatment is not allowed. 
8. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl. 
9. Patients who have a creatine kinase (CK) level of greater than 5 times the upper limit of 
normal. 
10. Patients with uncontrolled infections. Infections are considered controlled if appropriate 
therapy has been instituted and, at the time of enrollment, no signs of progression are 
present. Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection. Progression of infection is defined as: 
• 
hemodynamic instability attributable to sepsis OR 
• 
new symptoms attributable to infection OR 
• 
worsening physical signs attributable to infection OR 
• 
worsening radiographic findings attributable to infection 
Patients with radiographic findings attributable to infection within 4 weeks prior to enrollment 
must have a repeat radiographic exam within one week of enrollment that documents 
absence of worsening. 
11. Patients with evidence of relapsed, progressing, or persistent malignancy, or who have been 


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treated for relapse after transplant, or who may require rapid immune suppression 
withdrawal as pre-emergent treatment of early malignancy relapse. 
12. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune 
suppression. 
13. Patients with unresolved serious toxicity or complications (other than aGVHD) due to 
previous transplant. 
14. History of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD). 
15. Patients with known hypersensitivity to any of the components murine mAb or Recombinant 
Ricin Toxin A-chain (RTA). 
16. Patients who have had treatment with any other investigational agent, device, or procedure 
within 21 days (or 5 half-lives, whichever is greater) prior to enrollment. An investigational 
agent is defined as medications without any known FDA or EMA approved indications. 
17. Patients who have received more than one allo-HSCT. 
18. Patients with known human immunodeficiency virus infection. 
19. Patients who have a BMI greater than or equal to 35 kg/m2. 
20. Patients who are taking sirolimus must discontinue prior to starting study treatment. 
The sirolimus blood level must be less than 2 ng/mL prior to starting study treatment. 
21. Female patients who are pregnant, breast feeding, or, if sexually active and of childbearing 
potential, unwilling to use effective birth control from start of treatment until 30 days after the 
last study treatment. 
22. Male patients who are, if sexually active and with a female partner of childbearing potential, 
unwilling to use effective birth control from start of treatment until 65 days after the last study 
treatment. 
23. Patients with any condition that would, in the investigator's judgment, interfere with full 
participation in the study, including administration of study drug and attending required study 
visits; pose a significant risk to the patient; or interfere with interpretation of study data. 
24. Patients whose decision to participate might be unduly influenced by perceived expectation 
of gain or harm by participation, such as patients in detention due to official or legal order. 
2.5 
TREATMENT PLAN 
Participants should start treatment as close to the time of randomization as possible but no later 
than 72 hours after randomization. 
 
 


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Figure 2-1: Treatment Schema 
 
 
2.5.1 T-Guard 
2.5.1.1 
Drug Information for T-Guard 
T-Guard is a fixed dose combination of two active ingredients, SPV-T3a-RTA and WT1-RTA. It 
will be supplied as a single, frozen liquid for infusion and needs to be stored at -20°C (± 5°C) 
under controlled conditions.  
T-Guard is delivered as a pack containing two 50 RDIN vials of type-I glass with a rubber 
stopper and an aluminum flip-off cap. Each vial contains a fixed dose combination of 2.5 mg 
purified SPV-T3a-RTA and 2.5 mg purified WT1-RTA in a fill volume of 25 mL/vial at a 
concentration of 0.2 mg protein/mL. 
Stability testing of the infusion concentrate is ongoing, and no definite shelf life can be proposed 
yet. The clinical batches will continue to be validated to justify the retest dates by means of real 
time stability data according to a pre-defined stability protocol. 
All medication used in this study will be prepared and labeled according to the rules of Good 
Manufacturing Practice, International Conference on Harmonization (ICH)-Good Clinical 
Practice (GCP) and local regulatory requirements. Since this is an open-label trial, blinding 
procedures are not applicable. 
2.5.1.2 
Storage, Handling, and Dispensing of T-Guard 
T-Guard vials are to be stored at -20°C (± 5°C) until use. T-Guard will be prepared for infusion 
by the pharmacy of the participating centers. 
A certificate of analysis will be provided indicating the expiry date. 
Before administration to the participant, the medication is brought to room temperature for 1.5 
hours, mixed and transferred to a syringe. Before the start of administration, the prepared 


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infusion syringe can be stored for up to 4 hours, at room temperature (20°C ± 5°C), in a 
controlled environment. 
Detailed directions for use can be found in the Pharmacy Manual. 
2.5.1.3 
Drug Accountability for T-Guard 
T-Guard will be delivered at the Investigational Pharmacy per the Pharmacy Manual. The 
Investigational Pharmacist at each site will be responsible for receiving, storing, distributing and 
accounting of the study drug. All study drug supplied for the study should be kept in a locked 
secure place with appropriate pharmaceutical precautions. 
A “Drug Accountability” record for T-Guard should be maintained by the person responsible for 
dispensing the trial medication to the participant. This record should contain which supplies are 
issued to which participant, including the times of dosing, and any drugs returned unused. 
Details of any supplies that are inadvertently damaged should be reported on this record. Further 
information on study drug accountability is provided in the Pharmacy Manual. Study drug 
accountability logs will be monitored per the clinical monitoring plan. 
All unused study drug should be kept and added to the drug accountability record. All study drug 
in these categories will be inventoried by the Clinical Research Associate (CRA) during and at 
the conclusion of the study. The CRA will arrange for their secure disposal at the end of the 
study. 
The drugs supplied for this study are only intended for use by participants enrolled in this study. 
They must not be diverted for use by others. 
2.5.1.4 
Dose and Administration of T-Guard 
It is strongly recommended all doses of T-Guard be received while the participant is 
hospitalized. T-Guard will be administered over 4 hours every 2 calendar days on Days 0, 2, 4, 
and 6, at a dose of 4mg/m2 BSA (not to exceed a dose of 10mg). Dosing should be per the 
following steps: 
• 
Measure the participant’s actual body weight (ABW) 
• 
Determine the ideal bodyweight  
o Males IBW = 50kg + 2.3kg for each inch over 5 feet (or for each 2.5cm over 1.52m) 
o Females IBW = 45.5kg + 2.3kg for each inch over 5 feet (or for each 2.5cm over 
1.52m) 
• 
When the participant’s body weight is more than 125% of their IBW, the BSA calculation 
is based on the adjusted ideal body weight (AIBW; formula 2) as is usual practice for IV 
treatment (e.g. chemotherapy). 
For participants weighing more than 125% of their Ideal Body Weight, calculate the 
Adjusted Ideal Body Weight: AIBW = IBW + [(0.25) x (ABW - IBW)] 
 
 


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• 
Use the (adjusted ideal) body weight to determine BSA per the Mosteller calculation 
 
• 
Multiply BSA with 4mg/m2 as the T-Guard dose. If the participant’s BSA is more than 
2.5m2, the dose calculation should use 2.5m2. This dose will be maintained for all infusions 
(dose adjustments for changes in weight during the treatment period will not be made). 
Premedication with antihistaminica (e.g., diphenhydramine 50mg by mouth or 25mg IV, 
clemastine 2mg IV) is strongly recommended,20-60 minutes prior to each dose. Premedication 
with acetaminophen is permitted. 
It is recommended that T-Guard be infused via a central catheter using a dedicated line or can be 
administered via a peripheral line, if needed. If a multi-lumen central venous catheter is used, T-
Guard and crystalloid or total parenteral nutrition should be administered through different 
lumens of the catheter. PK samples should be drawn from the central catheter using a different 
lumen than the lumen used for infusion. 
Before the infusion, connect the syringe with the in-line filter and luer-lock extension tube to a 
central venous catheter (recommended) or peripheral line. The contents of the syringe will then 
be administered by means of an automated infusion device, over a period of 4 hours. Once the 
infusion syringe is empty, the administration tubes should be flushed. 
Vital signs (temperature, pulse, respiratory rate, blood pressure), should be checked at the 
following timepoints with each infusion: just before starting the infusion, 15 minutes after the 
start of the infusion, 30 minutes after the start of the infusion, then every 30 minutes during the 
infusion, and at 1-hour post-infusion. Deviation of +/- 5 minutes may occur for all vital sign 
collection timepoints. 
Infusion-related reactions are a potential risk with this medication. If the participant experiences 
a grade 3 or 4 infusion related reaction, the infusion should be held, and the reaction managed 
per institutional standards. Once the reaction has resolved the infusion can be restarted at half 
the rate. Subsequent infusions should be managed with an escalation in premedication based 
on type of reaction and initiated at the half rate. After 15 minutes, if no reactions are noted, then 
the infusion rate can be escalated to the full rate as tolerated. 
Participants should receive a maximum of 4 doses. The minimal interval between doses is 2 days 
(the start of infusion should be no less than 40 hours from the start of the previous infusion). If 
toxicity occurs, then dosing should be delayed until toxicity improves, but all dosing must be 
completed within 14 days. Infusions of T-Guard that exceed 4 hours are not considered 
deviations. Pauses in the infusion due to a participant reaction need to be documented. 
2.5.1.5 
T-Guard Infusion Delays 
In the event dosing must be delayed due to occurrence of toxicity, the protocol allows up to 14 
days to receive all four infusions. If the infusion visits are delayed, then the assessments for 
each infusion should still be done.  


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If an infusion is delayed to Day 11-13, the Day 14 visit can be combined as appropriate 
respecting the 3-day window for the Day 14 visits. However, it’s ideal for the assessments to be 
completed on Day 14. If an infusion is delayed and occurs on Day 14, then the infusion day 
assessments must be done while the Day 14 assessments can either be done on the same day 
or on another day within window, per investigator discretion. If all assessments for the infusion 
(Day 4 or 6) and Day 14 are combined to be completed on the same day, Peripheral blood for 
anti-drug-antibodies (ADA), Peripheral blood for GVHD biomarkers, and a urine sample for 
GVHD biomarkers are to be collected prior to infusion. If the samples can’t be drawn pre-
infusion, they may be collected the day after. 
Centers are to be mindful of the max blood draw volumes per day for participants and to 
combine sample collection to avoid unnecessary needle sticks. 
There should be at least 4 but preferably 7 days between the biomarker samples. 
2.5.1.6 
Toxicities and Guidelines for Withholding T-Guard 
A physician must be available for all infusions in order to treat anaphylaxis or CRS, should it 
occur. The following are expected toxicities that may impact administration of T-Guard. 
Allergic reactions: 
Each of the following well-recognized allergic reactions to foreign protein may follow the 
administration of a mAb including urticaria, bronchospasm, anaphylaxis, Arthurs reaction, 
vasculitis, and serum sickness. Symptoms will be monitored closely and should be treated per 
SoC. Appropriate medications should be readily available at the bedside per institutional 
standards, including epinephrine, hydrocortisone and diphenhydramine. 
Anaphylactic reaction: 
Administration of xenogeneic proteins may be accompanied by anaphylactic reactions that are 
mostly IgE mediated. The most probable time of onset, if occurring, is within 10 minutes after 
starting T-Guard infusions. This acute hypersensitivity reactions may be characterized by: 
cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension, 
pulmonary edema especially in participants with volume overload, seizures or coma, tachycardia, 
pruritus, urticaria, tingling, angioedema including laryngeal, pharyngeal or facial edema, 
dyspnea, bronchospasm, and airway obstruction. 
 
Capillary Leak Syndrome (CLS): 
Manifested as hypotension, fluid overload, weight gain or edema, dyspnea, anorexia, nausea, 
and in some cases confusion, and muscle damage. Investigative findings, may include, hypoxia, 
hypoalbuminemia, pulmonary edema, pleural effusion. Participants experiencing severe CLS 
(requiring pressors, dialysis, mechanical ventilator support) related to study treatment should 
have their treatment held until 72 hours after cessation of pressors, dialysis, or mechanical 
ventilator support. 
If an anaphylactic reaction is suspected, T-Guard administration should be 
discontinued immediately. Therapy should not be resumed, nor should the patient be 
exposed to other murine immunoglobulins or RTA-containing products. 


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Hypoalbuminemia: 
Severe hypoalbuminemia is a risk for CLS. Therefore, if the albumin level is less than or equal to 
1 g/dL, dosing should be held until the albumin level is greater than1 g/dL. Dosing can be based 
on the albumin level within 48 hours of dosing. If the treating physician feels that there has been 
benefit from dosing regardless of the albumin level, then further dosing can be discussed with 
the protocol chairs. 
Myalgia and serum CK-elevation: 
There is an association of myositis with Ricin-based toxicity. Therefore, participants should be 
monitored for signs of myositis. If participants experience muscle pain, then a serum CK should 
be performed. The next dosage of T-Guard should be withheld in case of a CK elevation greater 
than 5 times ULN. Dosing can resume if the CK decreases to less than or equal to 5 ULN and 
symptoms of myositis has improved to Grade 2 or less by CTCAE v.5. Dosing can proceed at 
the investigator’s discretion if deemed in the best interest of the participant. 
Other toxicities: 
Participants with another non-hematologic grade 3 or higher toxicity which is not attributable to an 
expected post-transplant event may have their study drug held at the attending physician’s 
discretion. Expected post-transplant events include steroid-related toxicity and chemotherapy 
toxicity. T-Guard should be restarted after recovery of related toxicities to grade 2 or lower or 
identification of an alternative cause for these toxicities. 
Infection: 
Participants with severe infections resulting in hemodynamic instability requiring use of 
vasopressor medication may have study drug held at the discretion of the treating physician. 
2.5.1.7 
T-Guard Discontinuation 
T-Guard treatment must be completed within 14 days of the first study drug dose. Participants 
who have missed doses may re-start T-Guard provided it is within the 14-day treatment window. 
2.5.1.8 
aGVHD Progression or Non-response 
If additional systemic aGVHD treatment, other than steroids, is added for lack of response or 
progression, T-Guard treatment must be discontinued and not re-instituted. 
2.5.2 Ruxolitinib 
2.5.2.1 
Drug Information for Ruxolitinib 
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3-
d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight 
of 404.36. 
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous 
buffers across a pH range of 1 to 8. 
Jakafi (ruxolitinib) Tablets are for oral administration. Each tablet contains ruxolitinib phosphate 
equivalent to 10 mg or 5 mg, of ruxolitinib free base together with microcrystalline cellulose, 


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lactose monohydrate, magnesium stearate, colloidal silicon dioxide, sodium starch glycolate, 
povidone and hydroxypropyl cellulose. 
2.5.2.2 
Drug Supply of Ruxolitinib 
Ruxolitinib will be provided through Day 56 for all participants. For centers in the United States, 
commercial supply of ruxolitinib will be utilized, covered for by the Sponsor until Day 56, with 
relabeling of medication per the Pharmacy Manual. Participants continuing beyond Day 56 will 
receive standard commercial supply. For centers within Europe, ruxolitinib will be provided by 
the Sponsor, labeled for this protocol, through the site pharmacy and until study treatment 
discontinuation (e.g., due to treatment failure, relapse, study withdrawal, death) or 
transformation into cGVHD.  
2.5.2.3 
Dose and Administration of Ruxolitinib 
Participants randomized to the ruxolitinib arm will receive 10mg orally twice daily to begin on 
Day 0. Dose modifications for toxicity are described below. Participants responding to treatment 
may be tapered off ruxolitinib as needed, starting no earlier than Day 56. The dose tapering 
strategy should be based on evaluation of the condition of the participant, current dosing 
regimen and the clinical judgment of the Investigator. 
2.5.2.4 
Toxicities and Guidelines for Withholding Ruxolitinib 
The following are expected toxicities associated with ruxolitinib. 
Myelosuppression:  
Treatment with ruxolitinib can cause thrombocytopenia, anemia and neutropenia.  
Manage thrombocytopenia by reducing the dose or temporarily interrupting ruxolitinib. Platelet 
transfusions may be necessary.  
Participants developing anemia may require blood transfusions and/or dose modifications of 
ruxolitinib. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by 
withholding ruxolitinib until recovery. Perform a pre-treatment complete blood count (CBC) and 
monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. 
Risk of Infection:  
Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting 
therapy with ruxolitinib until active serious infections have resolved. Observe participants 
receiving ruxolitinib for signs and symptoms of infection and manage promptly.  
Tuberculosis: Tuberculosis infection has been reported in participants receiving Jakafi. Observe 
participants receiving ruxolitinib for signs and symptoms of active tuberculosis and manage 
promptly. Prior to initiating ruxolitinib, participants should be evaluated for tuberculosis risk 
factors, and those at higher risk should be tested for latent infection. Risk factors include, but 
are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, 
close contact with a person with active tuberculosis, and a history of active or latent tuberculosis 
where an adequate course of treatment cannot be confirmed. For participants with evidence of 
active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis 


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before starting ruxolitinib. The decision to continue ruxolitinib during treatment of active 
tuberculosis should be based on the overall risk-benefit determination. 
PML: Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment 
for myelofibrosis. If PML is suspected, stop ruxolitinib and evaluate.  
Herpes Zoster: Advise participants about early signs and symptoms of herpes zoster and to 
seek treatment as early as possible if suspected.  
2.5.2.5 
Dose Modifications for Ruxolitinib 
Ruxolitinib dose will be adjusted for toxicity. Dose modification guidelines are based on the 
occurrence and intensity of specific adverse events that are suspected to be drug related. No 
dose reduction of ruxolitinib starting dose is required for concomitant strong CYP3A4 
inhibitors/dual inhibitors. The most relevant information has been provided in Table 2-1. Table 2-
2 provides dose reduction steps for ruxolitinib dosing. 
 
Table 2-1: Required Treatment Modification Guidelines for Ruxolitinib-related Toxicities 
Grade by NCI CTCAE#1 
Action2 
Neutrophil count decreased 
Grade 3: Decrease 1 dose level (see Table 2-2), monitor ANC daily until resolved to < Grade 2, 
then resume initial dose level 
Grade 4: Hold dose, monitor ANC daily until resolved until < Grade 3, the resume at next lower 
dose level. If resolves to < Grade 2, can resume initial dose level. If not resolved in < 14 days 
while holding, drug must be discontinued. 
Febrile neutropenia 
Grade 3: Hold dose until resolved, then restart at next lower dose level. 
Thrombocytopenia 
Grade 4: (plt <,20,000 – 15,000/mm3): Decrease 1 dose level until resolved to > 20,000/mm3. If 
resolved in < 7 days, then resume initial dose level. If resolved in > 7 days, then maintain the 
decreased dose. 
Grade 4: (plt <,15,000/mm3): Hold dose until resolved to > 20,000/mm3. If resolved to < Grade 3, 
can resume initial dose level. If not resolved in < 14 days while holding, drug must be 
discontinued. 
Serum creatinine 
Grade 2: Decrease 1 dose level until resolved to < Grade 1 or baseline, then resume initial dose 
level 
Grade 3: Hold dose until resolved to < Grade 2, then restart at next lower dose level. If resolves to 
< Grade 1 can resume initial dose level. 
Grade 4: Discontinue ruxolitinib. 
Total bilirubin increased 
Grade 3: (> 3.0 – 5.0 x ULN): Decrease 1 dose level until resolved to < 3.0 x ULN. Monitor LFTs 
at least weekly, until resolved to < 3.0 x ULN. If resolved < 14 days, then resume initial dose level. 
If resolved in > 14 days, then maintain the decreased dose level. 
Grade 3: (>5.0 – 10.0 x ULN): Hold dose. Monitor LFTs at least weekly until resolved to < 3.0 x 
ULN. If resolved < 14 days, then resume same dose level. If resolved in > 14 days, then restart at 
the next lower dose level. 
Grade 4: Hold dose. Monitor LFTs at least weekly until resolved to < 3.0 x ULN. If resolved < 14 
days, then resume at the next lower dose level. If resolved in > 14 days, then drug must be 
discontinued. LFTs should be monitored at least weekly until total bilirubin has resolved to 
baseline or stabilized over 4 weeks. 


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Grade by NCI CTCAE#1 
Action2 
ALT or AST increased 
4Grade 2: (for pts with normal baseline value < 3.0 x ULN) Maintain the dose level and repeat 
LFTs as soon as possible, preferably within 48-72 hours from abnormal result awareness. If 
abnormal lab values are confirmed, decrease dose to the next lower level until resolved to < 3.0 x 
ULN. Continue to monitor LFTs at least weekly until resolved to < 3.0 x ULN. If resolved < 14 
days, then resume initial dose level. If resolved > 14 days, then continue at the decreased dose 
level. 
4Grade 2: (for pts with baseline value > 3.0 – 5.0 x ULN): Maintain dose level. Monitor LFTs at 
least weekly until resolved to < baseline. 
Grade 3: (>5.0 - 10.0 x ULN): Hold dose. Repeat LFTs as soon as possible, preferably within 48-
72 hours from abnormal result awareness. Monitor LFTs at least weekly until resolved to < 5.0 x 
ULN. If resolved < 14 days, then resume same dose level. If resolved > 14 days, then continue at 
the next lower dose level. 
Grade 3: (>10.0 – 20.0 x ULN): Hold dose. Repeat LFTs as soon as possible, preferably within 
48-72 hours from abnormal result awareness. Monitor LFTs at least weekly until resolved to < 5.0 
x ULN then resume at the next lower dose level. 
Grade 4: (for pts deriving clinical benefit based on Investigator’s judgement): Hold dose. Repeat 
LFTs as soon as possible, preferably within 48-72 hours from awareness of the abnormal results. 
Monitor LFTs at least weekly,untilresolvedto≤3.0xULN(or≤5.0xULNforparticipants with 
baseline value > 3.0 -5.0 x ULN), then resume treatment at next lower dose level.  
Only 1 dose reduction is allowed; if increase reoccurs at > 5.0 x ULN, drug must be discontinued. 
Grade 4: (for all other pts without clinical benefit): Discontinue ruxolitinib. Repeat LFTs as soon as 
possible, preferably within 48-72 hours from abnormal result awareness. Monitor LFTs at least 
weekly until resolved to baseline or stabilized over 4 weeks. 
Amylase and/or lipase 
increased (asymptomatic) 
4Grade 3: Hold dose until resolved to < Grade 2. If resolved in < 7 days, the resume at same dose 
level. If resolved > 7 days, then resume at next lower dose level. 
4Grade 4: Discontinue ruxolitinib. 
Pancreatitis 
Grade > 3: Discontinue ruxolitinib.  
Diarrhea3 
4Grade 3: Decrease to the next lower dose level until resolved to < Grade 2, then resume initial 
dose level. 
Grade 4: Discontinue ruxolitinib. 
Nausea and/or vomiting 
4Grade 3: Hold dose for > Grade 3 vomiting or > Grade 4 nausea only if the vomiting or nausea 
cannot be controlled with optimal antiemetic (as per local practice) 
Hypertension 
4Grade 3: Decrease to the next lower dose level until resolved to < Grade 2, then resume initial 
dose level. 
Grade 4: Discontinue ruxolitinib. 
Rash/photosensitivity 
4Grade 3: Decrease to next lower dose level until resolved to < Grade 2. If resolved in < 7 days, 
resume initial dose level. If resolved > 7 days, then maintain at the lower dose level. 
Grade 4: Discontinue ruxolitinib. 
Other adverse event, 
determined to be related to 
ruxolitinib 
4Grade 3: Decrease to next lower dose level until resolved to < Grade 2.  
4Grade 4: Discontinue ruxolitinib. 
1Please consult NCI CTCAE Version 5 for complete Grade descriptions and note that some grades in Table 2-1 have been split based on action 
recommended or required. 
2All actions are mandatory, aside from those identified by an additional footnote. Dose levels are included in Table 2-2. 
3Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea. 
4Actions noted are recommendations only and not mandatory. 
 


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Table 2-2: Dose Reduction for ruxolitinib 
Current Dose 
First Dose Reduction 
Second Dose Reduction 
10 mg twice daily 
5 mg twice daily 
5 mg once daily 
 
Participants who have had a dose reduction of ruxolitinib in order to manage toxicity may 
resume treatment at the previous dose as noted in Table 2-2 if hematologic/non-hematologic 
parameters meet the required threshold(s) at patient eligibility. Dose re-escalation levels of 
ruxolitinib are described in Table 2-3. Dose increases may not exceed 10 mg BID, with 
increments of 5mg twice daily and not more often than every 2 weeks. 
 
Table 2-3: Dose Re-escalation for ruxolitinib 
Current Dose 
First Dose Escalation 
Second Dose Escalation 
5 mg once daily 
5 mg twice daily 
10 mg twice daily 
5 mg twice daily 
10 mg twice daily 
- 
 
2.5.2.6 
Ruxolitinib Discontinuation 
Ruxolitinib must be discontinued upon any one of the following AE attributed to ruxolitinib that 
fails to resolve to a Grade 2 or better within 14 days of holding drug, or if a lower re-start dose or 
administration schedule subsequent to any of the following non-hematologic toxicities is either 
not available or likely to be clinically ineffective: 
• 
Occurrence of a Grade 4 laboratory or non-laboratory abnormality attributable to 
ruxolitinib 
• 
Occurrence of a Grade 3 laboratory or non-laboratory abnormality attributable to 
ruxolitinib that remains at Grade 3 or worse for greater than 14 days 
• 
Withdrawal of consent by the participant 
• 
General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the investigator 
2.5.2.7 
Corticosteroid Dosing 
Participants must be on 2 mg/kg/day of methylprednisolone (or corticosteroid equivalent) at 
enrollment and continue through the start of ruxolitinib or T-Guard therapy. For participants with 
SR-aGVHD a gradual taper of steroids rather than an abrupt discontinuation of steroids is 
recommended. Corticosteroid taper may be done per institutional practice or may follow a 10% 
dose reduction every 5 days in participants demonstrating CR/PR as observed by the 
Investigator, beginning no earlier than Day 7 and continuing to approximately Day 56 to allow 7-
8 week taper. Each dosing change of corticosteroids must be reported. 
 
 


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2.5.2.8 
Calcineurin Inhibitor (CNI) Tapering 
Tapering of immunosuppression in responding patients will follow 2 steps: 
1. Taper of corticosteroids (see above), 
2. Followed by taper of calcineurin inhibitor (CNI) 
CNI (cyclosporine or tacrolimus) tapering will follow a 25% dose reduction per month starting 
from Day 56 in patients demonstrating complete resolution of all signs/symptoms of aGvHD, 
once off systemic corticosteroids. 
2.5.3 Supportive Care 
2.5.3.1 
GVHD Prophylaxis Medications 
Medications such as cyclosporine, tacrolimus, methotrexate (MTX), mycophenolate mofetil 
(MMF) may be continued, resumed, or increased to therapeutic doses per provider discretion, 
and adjusted/discontinued as necessary for renal, central nervous system (CNS) or other 
toxicity using institutional management guidelines. Close monitoring of drug levels is strongly 
recommended. Resumption of a GVHD prophylaxis agent is not considered the addition of a 
second agent. 
Overall start and stop dates of immunosuppressants will be captured for this study. However, for 
agents where dosing is tapered in response to drug levels, the medication dosing will not 
require reporting. 
2.5.3.2 
Topical and Ancillary GVHD Therapies 
Topical treatment for aGVHD is allowed and should be used according to institutional practices. 
Topical treatment, including corticosteroid creams, topical tacrolimus, oral beclomethasone or 
budesonide, topical azathioprine and ophthalmic glucocorticoids, is not considered as 
secondary systemic treatment. 
Ancillary/supportive care measures for aGVHD such as the use of anti-motility agents for 
diarrhea, including octreotide, is allowed at the discretion of the treating physician. Use of 
ursodiol to prevent/reduce gall bladder sludging or prevent transplant-related hepatic toxicity is 
also allowed according to institutional guidelines. 
2.5.3.3 
Other Supportive Care Guidelines 
In addition to study treatment, all participants should receive the following per institutional 
practice: 
• 
Transfusion support 
• 
Anti-infective prophylaxis against herpes viruses, Pneumocystis jiroveci, bacterial and 
fungal infections. 
• 
Routine CMV antigenemia/viral load testing by hybrid capture or PCR based methods 
(with preemptive treatment in participants who develop a positive assay). CMV testing is 
required weekly through at least Day +56 post randomization. Prophylaxis against CMV 
is allowed. Any CMV disease requiring treatment will be captured on an Infection Form. 


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• 
In addition to the required monitoring for EBV according to the study calendar, 
monitoring for viral infections such as EBV, adenovirus, and HHV6 is encouraged for 
participants at high risk in accordance with institutional practice. Participants with rapidly 
rising EBV DNA levels or clinical symptoms are recommended to have imaging studies 
to diagnose an EBV PTLD. EBV PTLD may rapidly progress and can be fatal if not 
treated. Management of suspected EBV PTLD should be discussed with one of the 
Protocol Chairpersons. EBV PTLD can be treated with rituximab and/or infusion of 106 
T-cells/kg from the donor. It is recommended that participants with EBV DNA levels of > 
1000 copies/mL receive 375 mg/m2 of rituximab. Those participants that continue to 
have levels above 1000 copies/mL on subsequent testing should be considered to 
receive three additional weekly infusions of 375 mg/m2 of rituximab. An accelerated 
schedule of days 1, 4, 8, 15 can be used if there is a suspicion of EBV PTLD. Rituximab 
has been shown to induce regression in 50 - 70% of cases. Note: Rituximab does not 
enter the CNS and is not effective in treating CNS disease. Donor lymphocyte infusions 
may induce regression in > 90% of cases of EBV PTLD and are effective in CNS 
disease. 
• 
Co-enrollment onto supportive care and infectious disease protocols will be allowed on 
case-by-case basis and requires approval by study chair or officer and sponsor. 
2.5.3.4 
Salvage Treatment Guidelines 
Addition of any new systemic immunosuppressive therapy by the Investigator after the start of 
T-Guard or ruxolitinib treatment is allowed: 
• 
After 7 days for participants meeting aGvHD criteria for progression or mixed response 
• 
After 14 days for participants meeting aGVHD criteria for no response 
In case T-Guard infusions are delayed (e.g., for toxicity reasons) the day 7 and 14 timepoints 
will shift accordingly. 
Requirement for initiation of new systemic immunosuppressive therapy will be considered a 
treatment failure. In this case, the participant must discontinue study treatment. 
2.5.3.5 
Prohibited Medications 
Sirolimus is prohibited from use from the time of enrollment through completion of study drug.  
Treatment with any other investigational product is not allowed while on study treatment. An 
investigational product is defined as medications without any known FDA or EMA approved 
indications. 
2.5.4 Follow-Up Post Treatment Discontinuation 
Participants may withdraw from treatment at any time for any reason. The reason should be 
documented by the study team. However, participants that have received at least one treatment 
dose are evaluable for all endpoints of the study and should continue with protocol-specific 
follow-up and data collection unless consent to study is withdrawn. Enrolled participants that do 
not receive any study treatment may be replaced. Participants that receive at least one 
treatment dose remain on study and are evaluable for all endpoints as above. 


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2.6 
STUDY CONDUCT 
This study will be conducted in accordance with the protocol, the BMT CTN 2002 protocol-
specific Manual of Procedures (MOP), and the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
The National Marrow Donor Program (NMDP) single Institutional Review Board (IRB) of Record 
will oversee this study and conduct the study-specific reviews as required by federal regulations 
and per the NMDP IRB Standard Operating Procedures (SOPs) for centers in the United States. 
For centers within Europe, the oversight and conduct of the study-specific reviews will be based 
on the country-specific regulations. 
Site personnel will enter data in the electronic case report form (eCRF) in the electronic data 
capture system (EDC) as described in the BMT CTN 2002 eCRF Completion Guide. Source 
documentation should be made available for monitoring visits, audits and regulatory inspections 
as described in the BMT CTN 2002 protocol-specific MOP.  
Participating PIs bear ultimate responsibility for training of site staff as well as the scientific, 
technical, and administrative aspects of conduct of the protocol, even when certain tasks have 
been delegated to sub-investigators or staff. The PIs have a responsibility to protect the rights 
and welfare of participants and comply with all requirements regarding the clinical obligations 
and all other pertinent requirements in 21 CFR part 312 and ICH GCP. In addition to following 
applicable federal, state, and local regulations, investigators are expected to follow ethical 
principles and standards and receive training in GCP every three years and human subjects 
training within the past 3 years and thereafter as per institutional requirements. 
2.7 
STUDY TERMINATION 
Regulatory agencies have the right to terminate the study at any time in case of safety concerns 
or if special circumstances concerning the study drug or the company itself occur, making 
further treatment of participants impossible. The study sponsor also has the right to terminate 
the study. In this event, the Investigator(s) and relevant authorities will be informed of the 
reason for study termination.  
 


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CHAPTER 3 
3 STUDY ENDPOINTS 
3.1 
ACUTE GVHD RESPONSE DEFINITIONS 
Scoring of aGVHD response on a given day is in comparison to the participant’s aGVHD staging 
on the day of randomization. Organ staging will be assessed using the MAGIC criteria (see 
APPENDIX C) and response will be scored as defined below: 
Complete response (CR) is defined as a score of 0 for the GVHD staging in all evaluable organs. 
For example, for a response to be scored as CR, the participant must still be in CR on that day 
and have had no intervening additional systemic therapy for treatment of aGVHD. 
Partial response (PR) is defined as improvement in one or more organs involved with GVHD 
symptoms without progression in others. For example, for a response to be scored as PR, the 
participant must still be in PR on that day and have had no intervening additional systemic 
therapy for treatment of aGVHD. 
Mixed response (MR) is defined as improvement in one or more organs with deterioration in 
another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new 
organ. 
No response (NR) is defined as absence of any improvement or progression as defined. 
Participants receiving additional systemic therapy will be classified as non-responders. 
Progression is defined as deterioration in at least one organ without any improvement in others. 
Loss of CR is defined as progression of aGVHD symptoms requiring additional systemic therapy 
(including escalation of corticosteroid dose to or beyond 2mg/kg methylprednisolone (or 
equivalent)); death; or if the participant develops new target organ symptoms that could qualify 
as being from either aGVHD or cGVHD (if the new symptoms are only associated with cGVHD 
then this is not considered a loss of CR). 
3.2 
RELAPSE DEFINITION 
Malignancy relapse is defined as follows: 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy. Progression of disease applies to participants with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation. The event 
is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy. 
Acute leukemia, CML and MDS – Relapse will be diagnosed when there is: 
• 
Reappearance of leukemia blast cells in the peripheral blood; or, 
• 
Greater than 5% blasts in the bone marrow, not attributable to another cause (e.g., bone 
marrow regeneration) 
• 
The appearance of previous or new dysplastic changes (MDS specific) within the bone 


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marrow with or without falling donor chimerism; or 
• 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid 
or 
• 
The reappearance of cytogenetic abnormalities present prior to transplantation 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
• 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased fluoro- deoxyglucose 
(FDG) uptake in a previously unaffected site will only be considered relapsed or 
progressive disease (PD) after confirmation with other modalities. In participants with no 
prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the 
positron emission tomography (PET) without histologic confirmation. 
• 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules). To be considered PD, a lymph node with a diameter of the short axis of 
less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm or more than 1.5 
cm in the long axis. 
• 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (less than 1.5 cm in its long axis by CT). 
• 
In addition to the criteria above, participants with chronic lymphocytic leukemia (CLL) 
who present in complete remission prior to transplantation may fulfill the relapse 
definition if there is reappearance of circulating malignant cells that are phenotypically 
characteristic of CLL. 
Multiple Myeloma – Clinical relapse is defined as meeting one or more of the following criteria: 
• 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice; 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures 
do not constitute progression); 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and greater than or equal to1 cm) increase as measured 
serially by the SPD§§ of the measurable lesion; 
• 
Hypercalcemia (greater than 11 mg/dL); 
• 
Decrease in hemoglobin of greater than or equal to 2 g/dL not related to therapy or 
other non-myeloma-related conditions; 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma; 
• 
Hyper viscosity related to serum paraprotein. 
 
 


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For the purposes of assessing relapse free survival (RFS), if the participant is in a CR, 
any one or more of the following will be considered a relapse: 
• 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis; 
• 
Development of greater than or equal to 5% plasma cells in the bone marrow; 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion, 
or hypercalcemia see above). 
Myeloproliferative Neoplasms: Relapse from CR is defined as: 
• 
Reappearance of bone marrow disease, including blasts, monocytic blast equivalents, 
or fibrosis 
• 
New extramedullary disease, including new or reappearance of splenomegaly, 
hepatomegaly, skin lesions, etc. 
*Institution of any therapy to treat persistent, progressive or relapsed malignancy, 
including the withdrawal of immunosuppressive therapy or treatment of relapse with donor 
lymphocyte infusion, will be considered evidence of relapse/progression regardless of 
whether the criteria described above were met. The use of preemptive donor lymphocyte 
infusion is not considered as relapse.  
Non-malignant Diseases: Non-malignant diseases will be considered to have a transplant 
status of persistent/active disease. Graft failures will be considered recurrence. 
3.3 
PRIMARY ENDPOINT 
The primary endpoint is the proportion of participants with a CR on Day 28 after randomization. 
3.4 
SECONDARY ENDPOINTS 
3.4.1 Key Secondary Endpoints: 
3.4.1.1 
Overall Survival (OS) 
OS will be assessed at Days 60, 90 and 180 post-randomization. An event for this analysis is 
death from any cause and time will be calculated from randomization until date of death. 
3.4.1.2 
Duration of Complete Response (DoCR) 
DoCR is defined as the time from Day 28 until an aGVHD target organ worsens by at least 1 
stage and requires a significant escalation in treatment (defined below), or death. The transient 
worsening of symptoms that resolve without significant escalation of treatment is not considered 
a loss of CR. A significant escalation in treatment is defined as initiation of new systemic 
treatment for GVHD and/or escalation in methylprednisolone dose (or equivalent). 
Methylprednisolone dose increases must be greater than 25% of the current dose and increase 
at least 8 mg/day (or other steroid equivalent) to be considered an escalation of 
methylprednisolone.  DoCR will be evaluated in the set of participants who are in CR on Day 28 
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3.4.2 Other Secondary Endpoints: 
3.4.2.1 
Time to Complete Response 
The time from randomization to first observation of CR will be evaluated. 
3.4.2.2 
Overall Response Rate (ORR) 
ORR is defined as having a complete or partial response (CR+PR). The ORR will be estimated at 
Days 14, 28, and 56 post-randomization. 
3.4.2.3 
Proportion of Response 
The proportion of participants in each aGVHD response category will be described at Days 6, 
14, 28 and 56 post-randomization. 
3.4.2.4 
Non-relapse Mortality (NRM) 
Events for NRM are death from any cause other than relapse/progression of the underlying 
malignancy. Relapse will be considered a competing risk. Time for NRM will be from time of 
randomization until the earlier of death from a non-relapse cause or relapse (competing risk). 
NRM will be estimated at Days 90 and 180 post-randomization. 
3.4.2.5 
Relapse-free Survival (RFS) 
Events for RFS are death from any cause or relapse/progression of the underlying malignancy. 
Time will be calculated from randomization until the earlier of death or relapse/progression of 
the underlying malignancy. RFS will be estimated at Day 180 post-randomization. 
3.4.2.6 
GVHD-free Survival 
Participants alive, in CR and without cGVHD will be considered a success for this endpoint. 
GVHD-free survival will be estimated at Days 90 and 180 post-randomization. 
3.4.2.7 
Chronic GVHD (cGVHD) 
cGVHD is defined per NIH Consensus Criteria (see APPENDIX D). Time will be calculated from 
randomization until the earlier of diagnosis of cGVHD or death from any cause, with death 
treated as a competing risk. The cumulative incidence of cGVHD at Day 180 post-randomization 
will be estimated and maximum severity (mild/moderate/severe) will be described. 
3.4.2.8 
Relapse/Progression of Underlying Malignancy 
The cumulative incidence of malignancy relapse/progression will be estimated with death prior to 
relapse/progression considered a competing risk. The cumulative incidence of 
relapse/progression at Day 180 post-randomization will be described. 
3.4.2.9 
Incidence of Infections 
All Grade 2-3 infections (as defined by Appendix G) from randomization will be reported by site 
of disease, date of onset, and severity. Grade 1 CMV infections requiring treatment that occur 
post-randomization will also be reported. Incidence of infections will be described in participants 


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from randomization to 90 days post-randomization. The cumulative incidence of treated CMV 
post-randomization will be described. 
3.4.2.10 Incidence of Toxicities 
All Grade 3-5 toxicities according to CTCAE v5 occurring from randomization to Day 56 post- 
randomization will be described. 
3.4.2.11 Pharmacokinetics of T-Guard 
A population pharmacokinetic model will be developed for T-Guard based on the SPV-T3a- RTA 
and WT1-RTA levels measured in samples obtained before each infusion and at the following 
post-infusion timepoints: 4, 5, 6, 8, and 24 hours for the first infusion, 4, 6, and 24 hours for the 
second and third infusions, and 4, 6, 24 and 48 hours for the fourth infusion. The time points for 
blood sampling were based on the t1/2 and Cmax values as determined in the previous studies. 
The Population PK model will be used to describe the following metrics: 
• 
Cinf: Observed and model-predicted concentration at the end of infusion 
• 
CL: Systemic clearance 
• 
AUC: Model-predicted area under the curve from the start of the current infusion 
until the next infusion or until 48 hours following for the last infusion 
• 
t1/2: Model-predicted terminal half-life 
• 
Vc: Volume of the central compartment 
Additionally, the impact of various factors on these measures will be evaluated, including age, 
weight, BSA, BMI, disease status, and ADA. 
3.4.2.12 Immunogenicity of T-Guard 
ADA responses in the form of human anti-SPV-T3a-RTA and anti-WT1-RTA antibodies will be 
evaluated with validated bioluminescence assays in serum samples obtained at baseline and at 
Days 6, 14, 28, 90, and 180 after initiation of treatment in T-Guard treated participants only. 
3.5 
EXPLORATORY ENDPOINTS 
3.5.1.1 
Discontinuation of Systemic Steroids 
The proportion of participants that is free of systemic steroid therapy at Day 180 post-
randomization will be described. 
3.5.1.2 
Incidence of CMV Reactivation 
The proportion of participants requiring new systemic treatment for a CMV PCR level per 
institutional practice (participants receiving only SoC viral prophylaxis will not be included in this 
assessment) for CMV-reactivation by Day 180 post-randomization will be described. 
3.5.1.3 
Incidence of EBV-associated Lymphoproliferative Disorder 
The proportions of participants with EBV-associated lymphoproliferative disorder and EBV 
reactivation requiring therapy with rituximab by Day 180 post-randomization will be described. 


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3.5.1.4 
Evolution of Cell Populations 
The evolution and characterization of specific cell populations over the whole180 day follow-up 
period will be evaluated in both treatment arms in selected centers. Samples of approximately 
50 participants (25 T-Guard, 25 ruxolitinib) will be taken at Day 0, 14, 28, 56 and 180 and either 
collected in CytoChex preservation tubes, or stored as viably frozen PBMCs, to allow for 
phenotypic and functional analysis of specific cell subsets, including e.g., FCM and V-beta 
repertoire analysis. FCM analysis will included the measurement of the following cell 
populations: Inflammatory Monocytes & Dendritic Cells, Recent Thymic Emigrants, CD4+, CD8+ 
Naïve & Memory Cells,CD4+TRegulatoryCells,NKCells,γδTCells,andB cells. 
3.5.1.5 
GVHD-related Biomarkers 
GVHD-related biomarker concentrations including serum Interleukin 1 receptor-like 1 (ST2) and 
Regenerating Family Member 3 Alpha (REG3α) concentrations and urine 3-Indoxyl Sulfate (3-
IS) concentrations at baseline and at Day 6, 14, and 28 post-randomization will be used to 
estimate the probability of NRM at Day 180 post-assessment for each participant, using the 
NRM risk model from (Major-Monfried, Renteria et al. 2018). The proportion of participants with 
high-risk biomarker status (defined as estimated NRM greater than 0.29) will be described at 
each time point. 
3.5.1.6 
Patient Reported Outcomes (PROs) 
Patient reported outcomes will be assessed using a subset of the PROMIS measures described 
in APPENDIX E. PROs will be assessed at baseline and Days 28, 90, and 180 post-
randomization. 
3.5.1.7 
Incidence of TMA 
Incidence of TMA as defined in the section 2.4.2 will be assessed at Day 6, 14, 21, and 28 post-
randomization. A blinded review panel will used to review any participants that develop TMA 
criteria after randomization and treatment. 
3.5.1.8 
EASIX Score 
EASIX score at time of screening will be described.  
3.6 
ENDPOINT REVIEW PROCESS 
Upon completion of participant follow-up, an Endpoint Review Committee (ERC) will conduct an 
independent review of site-reported data on a key study endpoint, Day 28 aGVHD response, in 
order to determine the data to be presented in the primary manuscript and final analysis. This 
Committee will consist of independent members from centers that are not participating on the 
study in order to remain unbiased. Each participant’s data will be reviewed by ERC clinicians. 
The adjudicated Day 28 aGVHD response data for each participant will be determined by 
consensus of the reviewers. 
Data will be obtained from the relevant eCRFs and source documents and will be provided to 
reviewers in a blinded manner with respect to treatment assignment, treatment center, and 
participant identifier. These data will be kept confidential and will not be discussed outside the 


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Committee or presented in a public forum. The ERC charter will provide further details on the 
ERC membership and adjudication process. 
 


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CHAPTER 4 
4 PATIENT ENROLLMENT AND EVALUATION 
4.1 
APPROACHING PATIENTS, ELIGIBILITY SCREENING, AND OBTAINING 
CONSENT 
Patients with Grade III or IV SR-aGVHD will be approached as soon as possible after diagnosis. 
The investigator or designee at each study site will evaluate participant eligibility. Informed 
consent will be obtained via a signature on the IRB or Institutional Ethics Committee (IEC) 
approved ICF prior to performing study specific procedures. The process of obtaining informed 
consent must comply with applicable ICH GCP E6 guidelines as implemented in US guidelines, 
GCP guidelines and national regulatory requirements. 
4.2 
ENROLLMENT 
Once the participant has provided a signed consent and eligibility is confirmed, patients will be 
enrolled and randomized onto the study using the EDC system and assigned a participant 
identification number. Participants will be randomized to T-Guard versus ruxolitinib in a 1:1 ratio. 
The following procedures shall be followed: 
1. An authorized user at the clinical center completes the initial screening by entering 
patient demographics and Segment A information (consent date, inclusion/exclusion 
criteria) on the Eligibility Form. 
2. If the patient is eligible, a participant ID number and random treatment assignment is 
generated upon successful completion of the enrollment form. 
3. The confirmation of randomization will be displayed for printing. 
If a connection is interrupted during an enrollment session, the process is completely canceled 
and logged. A backup manual enrollment system will also be available to provide for short-term 
system failure or unavailability. 
4.2.1 Treatment 
Treatment should be initiated as soon as possible after randomization, ideally within 24 hours. A 
maximum of 72 hours (3 days) after randomization is allowable. 
4.3 
STUDY MONITORING 
4.3.1 Follow-up Schedule 
The Follow-up Schedule for scheduled study visits is outlined in Table 4-1. 
The timing of follow-up visits is based on the date of randomization (Day 0). A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
 
 


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Table 4-1: Follow-up Schedule 
Assessment Time 
Target Day 
(Days Post-
Randomization) 
1 week 
6 days1 
2 weeks 
14 days2 
3 weeks 
21 days2 
4 weeks 
28 days≠ 
5 weeks 
35 days2 
6 weeks 
42 days2 
7 weeks 
49 days2 
8 weeks 
56 days2 
10 weeks 
70 days3 
90 days 
90 days3 
6 months 
180 days4 
1Target day window for Ruxolitinib arm only is +/-3 days (see section 
2.5.1.5 for guidance on T-Guard infusion delays) 
2Target day window is +/-3 days 
3Target window is +/-14 days 
4Target window is +/-28 days 
≠Target day window is +/-2 days 
 
Data Collection: The investigator or site designee will enter data collected using an electronic 
data capture system. In the interest of collecting data in the most efficient manner, the 
investigator or site designee should transcribe data (including laboratory values, if applicable) in 
the eCRF in a timely manner after the participant visit unless otherwise noted. The BMT CTN 
DCC will be reviewing form submission regularly and will follow-up to assure data is submitted 
promptly. 
The investigator or site designee is responsible for ensuring that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. 
The monitor will verify a subset of the data in the eCRFs with source documents and confirm 
that there are no inconsistencies between them. 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide. Forms that are not entered in 
the EDC system within the specified time will be considered delinquent. Transplant Centers can 
view past due forms via the EDC system. A missing form will continue to appear until the form is 
entered into the EDC system, or until an exception is granted and entered into the Missing Form 
Exception File, as detailed in the Data Management Handbook and User’s Guide. 


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Reporting Participant Deaths: The Recipient Death Information must be entered into the EDC 
system within 24 hours of knowledge of a participant’s death even if the cause of death is 
unknown at that time. Once the cause of death is determined, the form must be updated. 
Study Documentation: Study documentation includes, but is not limited to, all eCRFs, 
workbooks, source documents, monitoring logs and appointment schedules, sponsor-
investigator correspondence, and signed protocol and amendments, IRB/IEC correspondence 
and approved current and previous consent forms and signed participant consent forms. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. The original recording of an observation should be retained as the source document. If 
the original recording of an observation is the electronic record, that will be considered the 
source. 
Clinical Study Monitoring: The Sponsors or delegated Clinical Research Organizations 
(CROs) are responsible for monitoring the clinical study to ensure that the participant’s human 
rights, safety and well-being are protected, that the study is properly conducted in adherence 
with the current protocol and GCP and study data reported by the investigator/sub-investigator 
are accurate and complete, and that they are verifiable with study-related records such as 
source documents. The Sponsors or delegated CROs are responsible for assigning study 
monitor(s) to this study for proper monitoring. The protocol will be monitored in accordance with 
planned monitoring procedures. 
Center for International Blood and Marrow Transplant Research (CIBMTR) Data 
Reporting: Centers participating in BMT CTN trials must register pre and post-transplant 
outcomes on all consecutive HCTs done at their institution during their time of participation to 
the CIBMTR. Registration is done using procedures and forms of the Stem Cell Transplant 
Outcomes Database (SCTOD) (Note: Federal legislation requires submission of these forms for 
all US allotransplant recipients). CIBMTR post- transplant Report Forms must continue to be 
submitted for all participants enrolled on this trial. Long-term follow-up of US participants on this 
study will continue through routine CIBMTR mechanisms. Centers within Europe participating in 
BMT CTN 2002 should report additional data, including long-term follow-up, per European 
requirements. 
4.3.2 Assessments 
Assessment and/or reporting of the following is required for participants enrolled on this study. All 
assessments are considered standard-of-care unless identified below by “*”. Assessments 
indicated by “*” are for research purposes. 
Prior to Enrollment 
The following pre-enrollment assessments must be completed prior to enrolling the participant in 
the EDC system and within the designated timeframe listed below. 
1. Complete aGVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin, within 24 - 72 hours prior to enrollment. Biopsy 
results of involved tissue, if performed as SoC, should also be reported. 
2. Medical history within 24 – 72 hours prior to enrollment. 


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3. Albumin and CK level within 24 – 72 hours prior to enrollment. 
4. Complete blood count (CBC) with differential and platelet count within 24 - 72 hours prior 
to enrollment. 
5. Renal function (blood urea and/or blood urea nitrogen, creatinine) within 24 - 72 hours 
prior to enrollment. 
6. Schistocytes, haptoglobin and LDH within 24 - 72 hours prior to enrollment. 
7. Pregnancy test (urine or serum) for females of child-bearing potential within 30 days prior 
to enrollment. 
8. Recording of Concomitant medications starting at 7 days prior to randomization 
Baseline Assessments 
Baseline assessments listed below must be completed at time of enrollment and prior to the first 
dose of study therapy unless otherwise specified. 
1. Physical exam including height and weight, participant disease/transplantation baseline 
variables 
2. Karnofsky Performance Status (may be completed pre- or post-enrollment) 
3. Baseline patient-reported outcome measures (see APPENDIX E) 
4. Peripheral blood for EBV and CMV viral load (within 72 hours prior to first dose of study 
drug) 
5. CBC with differential and platelet count 
6. Recording and review of Concomitant medications 
a. For all immunosuppressant agents, the overall start and stop date will be captured. 
For agents where dosing is tapered in response to drug levels, the medication 
dosing will not require reporting. 
b. Dosing for corticosteroids will be captured for all dosing changes.  
7. Peripheral blood* for Peripheral Blood Mononuclear Cells (PBMC) testing  (See 
APPENDIX B) 
8. Peripheral blood* for Flow Cytometry and Immune Profiling (See APPENDIX B) 
9. Peripheral blood* for humoral response (ADA) testing for T-Guard arm only(See 
APPENDIX B) 
10. Peripheral blood* and urine sample* for GVHD biomarker testing (See APPENDIX B) 
T-Guard Treatment Assessments 
The assessments listed below are to be completed on days of treatment for participants 
randomized to receive T-Guard. Assessments should be done prior to infusion, unless 
otherwise specified. 
1. Complete aGVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin on Days of infusion  
2. Vital signs (temperature, pulse, respiratory rate, blood pressure) on Days of infusion . 
Vital signs should be taken just before starting the infusion, 15 and 30 minutes after the 
start of the infusion, then every 30 minutes during the infusion, and at 1 hour post-
infusion. Deviation of +/- 5 minutes may occur for all vital sign collection timepoints. 
3. Albumin on Days of infusion 
4. CBC with differential and platelet count on Days of infusion 


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5. Renal function (blood urea and/or blood urea nitrogen, creatinine) on Day of 4th infusion 
6. Schistocytes, haptoglobin and LDH on Day of 4th infusion  
7. Peripheral blood for EBV and CMV viral load on Day of 4th infusion  
8. Recording and review of Concomitant medications on Days of infusions 
a. For all immunosuppressant agents, the overall start and stop date will be captured. 
For agents where dosing is tapered in response to drug levels, the medication 
dosing will not require reporting. 
b. Dosing for corticosteroids will be captured for all dosing changes. 
9. Recording of AE/SAEs as described in Section 4.4 Adverse Event Reporting 
10. Recording of infections 
11. Peripheral blood* for humoral response (ADA) on Day of 4th infusion (See APPENDIX B) 
12. Peripheral blood* for PK at the following timepoints (See APPENDIX B): 
a. 1st infusion: pre-infusion and at 4, 5, 6, 8, and 24 hours after start of infusion 
b. 2nd infusion: pre-infusion and at 4 and 24 hours after start of infusion 
c. 3rd infusion: pre-infusion and at 4 and 24 hours after start of infusion 
d. 4th infusion: pre-infusion and at 4, 6, 24, and 48 hours after start of infusion 
Pre-infusion samples should be drawn prior to T-Guard administration. A window of +/- 15 
minutes is allowed for samples drawn at 4 hours after the start of infusion, a window of +/-30 
minutes for the sample drawn 5, 6, or 8 hours after the start of infusion, and a window of +/- 1 
hour for samples drawn 24 or 48 hours after the start of infusion. Every effort should be made to 
collect PK samples at all timepoints; however, no PK sampling is required on weekend days. 
Please refer to Section 2.5.1.5 for more information regarding T-Guard infusion delays. 
Post-Randomization Assessments 
The following assessments and observations must be completed at the timepoints designated 
below. 
1. Complete aGVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin at Days 0, 6, 14, 21, 28, 35, 42, 49, 56, 70, 90, 
and 180 
2. cGVHD evaluation (if present) Day 28, 56, 90, and 180 
3. Blood pressure at Days 0, 6, 14, 21, 28, 35, 42, 49, 56, 70, 90, and 180 
4. Albumin at Days 0, 6, 28, 56, 90, and 180 
5. CBC with differential and platelets at Days 0, 6, 14, 21, 28, 56, 90, and 180 
6. Renal function (blood urea and/or blood urea nitrogen, creatinine) on Days 6, 14, 21 and 
28 
7. Schistocytes, haptoglobin and LDH on Days 6, 14, 21 and 28 
8. Karnofsky performance status at Days 28, 56, 90, and 180 
9. Peripheral blood for EBV and CMV viral load at Days 6, 14, 21, 28, 35, 42, 49, 56 and 
180 
10. Recording and review of Concomitant medications other than immunosuppressant 
agents will be collected starting at 7 days prior to randomization through 30 days post-
last treatment dose for T-Guard and through Day 44 for ruxolitinib. Recording of all 
systemic immune suppressive therapy (as appropriate: tacrolimus, cyclosporine, etc.), as 
well as topical agents, and all anti-infectives used for prophylaxis or treatment at Days 6, 


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14, 21, 28, 35, 42, 49, 56, 70, 90, and 180 
a. For all immunosuppressant agents, the overall start and stop date will be captured. 
For agents where dosing is tapered in response to drug levels, the medication 
dosing will not require reporting. 
b. Dosing for corticosteroids will be captured for all dosing changes. 
11. Patient reported outcomes at Days 28, 90 and 180 (see APPENDIX E) 
12. Recording of toxicities on Days 56, 70, 90, and 180 
13. Recording of AE/SAEs as described in Section 4.4 Adverse Event Reporting 
14. Recording of infections through Day 180 
15. Recording of primary disease relapse through Day 180 
16. Peripheral blood* for Peripheral Blood Mononuclear Cells (PBMC) testing at Days 14, 
28, 56, and 180 (See APPENDIX B) 
17. Peripheral blood* for ADA testing for T-Guard arm only at Days 14, 28, 90, and 180 
18. Peripheral blood* for Flow Cytometry and Immune Profiling at Days 14, 28, 56, and 180 
(See APPENDIX B) 
19. Peripheral blood* and urine sample* for GVHD biomarker testing at Days 6, 14, and 28 
(See APPENDIX B) 
 
Please refer to APPENDIX K at the end of the protocol for the Schedule of Assessments tables. 
4.4 
ADVERSE EVENT REPORTING 
AE reporting requirements are summarized below. 
4.4.1 Definitions 
Adverse Event: An AE is any untoward medical occurrence in a participant administered an 
investigational product or has undergone study procedures and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease that is 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets 1 of the following 
criteria: 
• 
Induces clinical signs or symptoms. 
• 
Requires active intervention. 
• 
Requires interruption or discontinuation of study drug. 
• 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
 
 


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Serious Adverse Event: An SAE, as defined by per 21 CFR 312.32, is any adverse event that 
results in one of the following outcomes, regardless of causality and expectedness: 
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical 
events may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require intervention to prevent one of the outcomes listed in 
the definition above (e.g., suspected transmission of an infectious agent by a medicinal product 
is considered an SAE). Any event is considered a SAE if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. All SAEs are to be 
followed up until resolved, judged to be no longer clinically significant, or until they become 
chronic to the extent that they can be fully characterized. 
An adverse event can be Anticipated or Unanticipated: 
• 
Anticipated adverse events are those that have been previously identified as resulting 
from the underlying disease, the HCT, or aGVHD and not related to study drug. 
• 
Unanticipated adverse events are those that vary in nature, intensity, or frequency 
from information in the current anticipated event list, the Investigator’s Brochure, the 
package insert, or when it is not included in the informed consent document as a 
potential risk. Unanticipated events would also include those that have not been 
previously described as a result of the underlying disease requiring HCT, the HCT or 
aGVHD. 
4.4.2 Classification of Adverse Events by Severity 
The severity refers to the intensity of the reported event. The Investigator must categorize the 
severity of each reportable SAE according to the NCI CTCAE Version 5.0. CTCAE guidelines 
can be referenced at the following website: http://ctep.cancer.gov/reporting/ctc.html. For any 


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term that is not specifically listed in the CTCAE scale, intensity will be assigned a grade of one 
through five using the following CTCAE guidelines: 
• 
Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self- care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
4.4.3 Classification of Adverse Events by Relationship to Investigational Product 
The relationship of each reported event to the study treatment will be assessed by the 
Investigator; after careful consideration of all relevant factors such as (but not limited to) the 
underlying study indication, coexisting disease, concomitant medication, relevant history, 
pattern of the SAE, temporal relationship to any study treatment interventions and de-challenge 
or re-challenge according to the following guidelines: 
• 
Possibly, Probably, or Definitely Related: there is a reasonable possibility that the 
study treatment caused the event. A relationship of possibly, probably, or definitely 
related to the investigational product is considered related for the purposes of regulatory 
authority reporting. 
• 
Unlikely, or Not Related: There is no reasonable possibility that the investigational 
product caused the event. An unlikely or not related relationship to the investigational 
product is not considered related for the purposes of regulatory authority reporting. 
4.4.4 Required Adverse Event Reporting 
The required adverse event reporting for the BMT CTN 2002 protocol is outlined below. 
• 
T-Guard arm: all adverse events, including SAEs, must be reported from randomization 
through 30 days following the last dose of T-Guard. 
• 
Ruxolitinib arm: all adverse events, including SAEs, must be reported from 
randomization through Day 44 (to algin with the maximum reporting period for 
participants in the T-Guard arm). 
• 
Any SAEs occurring after that period, but assessed as related to the investigational 
product, must be reported. 
• 
Any unanticipated SAEs from time of enrollment through the study defined follow-up are 
required to be reported.. 
• 
Any grade 4 anticipated event not collected on the calendar-driven toxicity or specified 
event-driven form must also be reported. 
• 
Special Situations and Adverse Events of Special Interest (AESIs) must be reported 
from randomization through the study defined follow-up period. 


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• 
Grade 1 CMV infections, as defined in Appendix G, requiring treatment should be 
reported from randomization through the study defined follow-up period. 
SAEs that require reporting will be reported through an expedited AE reporting system via the 
EDC system. All SAEs, Special Situations, and AESIs must be reported within 24 hours of 
knowledge of the event. Events entered in EDC will be reported using NCI’s CTCAE Version 
5.0. If there are network outages, a paper copy of the AE form must be completed and emailed to 
Emmes to initiate Sponsor review. Once the system is available, the event information must be 
entered into the system. 
The Sponsor has a list of events classified as Special Situations. These events are 1) 
medication error, 2) overdose and 3) pregnancy. These events must be reported, regardless of 
grade or seriousness, following the reporting process for SAEs. 
The Sponsor has a list of AESIs to be reported. These events include any grade of 1) TMA, 2) 
CRS, 3) CLS, 4) Myalgia, or 5) CK elevation and 6) grade 3 or higher cytopenias. These events 
must be reported, regardless of grade or seriousness, following the reporting process for SAEs. 
Infections of Grade 2 or 3 by Appendix G are collected separately in eClinical as this is a study 
endpoint; however, should an infection meet the SAE criteria, the infection must also be reported 
following the SAE reporting criteria outlined above. Grade 1 CMV infections requiring treatment 
that occur post-randomization will also be reported using the SAE reporting process. 
GVHD and underlying disease relapse events are also collected separately in eClinical because 
they are part of the endpoint analysis. Events of GVHD and underlying disease relapse are not 
to be reported as AEs/SAEs for this study. 
Anticipated AEs will be reported using NCI’s CTCAE Version 5.0 at regular intervals as defined on 
the Form Submission Schedule, including calendar-driven eCRFs (e.g., Toxicity and GVHD) or 
event-driven eCRFs (e.g., Relapse/Progression, Infection, and Death). 
The Data and Safety Monitoring Board (DSMB) will receive expedited reports of all 
unanticipated and unexpected SAEs upon review by the BMT CTN Medical Monitor and the 
Xenikos Medical Monitor. Summary reports for all reported SAEs will be reviewed by the DSMB 
on an annual basis. 
4.4.5 Procedure in Case of Pregnancy 
If a female participant becomes pregnant during the study dosing period or within 90 days from 
the last dose of study drug, the investigator should report the information through an expedited 
AE reporting system via the EDC system. The expected date of delivery or expected date of the 
end of the pregnancy, last menstruation, estimated conception date, pregnancy result, neonatal 
data and other related information will be requested. If a participant becomes pregnant during 
the study dosing period, the investigational product will be discontinued. 
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome. Additional information regarding the outcome 
of a pregnancy (which is categorized as an SAE) is mentioned below. 
• 
“Spontaneous abortion” includes miscarriage, abortion, and missed abortion 
• 
Death of an infant within 30 days after birth should be reported as an SAE regardless of 


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its relationship with the study drug 
• 
If an infant dies more than 30 days after birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by 
the investigator 
• 
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at the 
birth 
• 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
Information will be collected at the time of delivery/birth and 180 and 360 days after birth. 
 


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CHAPTER 5 
5 STATISTICAL CONSIDERATIONS 
5.1 
STUDY DESIGN AND OBJECTIVE 
This trial is a randomized, open-label, multi-center Phase 3 study designed to compare the 
efficacy and safety of T-Guard to ruxolitinib treatment of participants with Grade III-IV SR-
aGVHD. A total of 246 participants will be enrolled from approximately 75 transplant centers in 
the US and Europe. All participants will be followed at minimum through Day 180 post-
randomization. 
The study will begin with a safety run-in phase of 24 randomized participants (12 to each arm), 
after which the remaining participants will be enrolled provided that safety concerns do not arise 
during the run-in. 
5.1.1 Accrual and Study Duration 
Accrual is estimated to require 34 months (9-10 participants enrolled per month at full 
enrollment) to complete with a total study duration of 40 months.  
5.1.2 Randomization and Blinding 
Participants will be randomized at the time of enrollment in a 1:1 ratio to the treatment arms. 
Randomization will be stratified by center region (US vs. Europe) and age group (at least 55 
years vs. under 55). Stratified treatment assignments will be generated using permuted blocks 
of random sizes. 
As this is an open-label trial, no blinding will be performed. 
5.1.3 Analysis Populations 
The primary analysis population will include all randomized participants classified according to 
the intention-to-treat (ITT) principle, that is, according to their randomized assignment. 
A secondary, supportive analysis of a per protocol (PP) population will be performed. The PP 
population will consist of all participants from the ITT population who received at least one dose 
of the assigned treatment. 
A PK analysis population will be defined for the assessment of pharmacokinetic and 
immunogenicity endpoints in the T-Guard arm only. This will consist of the participants 
randomized to T-Guard from whom samples have been collected and evaluated for these 
endpoints. 
Note that because the safety run-in phase is randomized, the inclusion of its participants in the 
analysis will not contribute bias. Therefore, run-in participants will be included in the ITT 
population and in the PP and PK populations as long as the other requirements for inclusion are 
satisfied. 


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5.1.4 Primary Hypothesis 
The primary endpoint is the attainment of a CR at Day 28 post-randomization. This requires 
three conditions to be satisfied: (i) a score of 0 for  aGVHD staging in target organs at Day 28; 
(ii) the participant is still alive at Day 28; and (iii) no additional systemic treatment for aGVHD 
has been administered through Day 28. 
The primary hypothesis is that the proportion of participants with a CR at Day 28, called the Day 
28 CR rate, is greater for the T-Guard arm compared to the ruxolitinib arm. This hypothesis will 
be evaluated by comparing the null hypothesis that the Day 28 CR rate under T-Guard 
treatment is no better than this rate under ruxolitinib treatment to the alternative hypothesis that 
this rate is superior for the T-Guard arm. This evaluation will be performed by a one-sided test 
at a 2.5% significance level, adjusted for the factors used to stratify the randomization (region 
and age) and for acute GVHD grade at randomization (III vs. IV). 
5.1.5 Sample Size and Power Considerations 
Data on participants with Grade III-IV SR-aGVHD were examined from three previous T-Guard 
studies in a meta-analysis: the Phase 1/2 study (XenTG001), an Expanded Access Program for 
this study (Named Participants), and the Phase 3 study BMT CTN 1802. Estimates of Day 28 
CR rates for each cohort and for the combined participant populations are displayed in  
Figure 5-1. Aggregating data from these 30 participants gives an estimated CR rate under T-
Guard treatment of 43.3% (95% CI: 27.1% - 61.2%). Among the 101 Grade III-IV SR-aGVHD 
participants in the ruxolitinib arm of the REACH2 trial, the CR rate was 25.7% (95% CI: 18.2% - 
35.1%). These data suggest Day 28 CR rates of approximately 43% and 26% for T-Guard and 
ruxolitinib, respectively. 
 
Figure 5-1: Day 28 CR Rates from Meta-analysis of Previous T-Guard Trials 
 
 
 
 


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The primary hypothesis will be evaluated by comparing the proportion of participants attaining a 
Day 28 CR in each arm, aiming to detect an improvement for T-Guard treatment over ruxolitinib. If 
the true CR rates for T-Guard and ruxolitinib match the respective rates of 43% and 26% seen in 
previous studies, the difference in rates is 17% favoring T-Guard. With the inclusion of interim 
analyses for efficacy and futility as detailed in Section 5.2, 246 participants are required to detect 
this difference with 80% power and a one-sided type I error rate of 2.5%. The pivotal analysis will 
also adjust for the stratification factors used for randomization. This practice is known to 
increase statistical power beyond that of an unadjusted two-arm comparison (Kahan and Morris 
2012), so 80% is a conservative estimate of the true power. 
5.2 
STUDY ANALYSIS SCHEDULE 
Figure 5-2 illustrates the study design and the analyses to be conducted during the course of 
the trial. 
After accrual of 12 T-Guard participants (~24 participants in combined arms), the study 
enrollment will be paused to permit the DSMB to perform a comprehensive review of safety data 
and confirm that the study may continue (see section 5.3.1). Efficacy of T-Guard will not be 
formally evaluated during this safety review. Upon DSMB approval, the study will continue for 
full enrollment. 
Once 23 T-Guard participants (~46 participants in combined arms) complete follow-up through 
Day 28, a futility analysis (see section 5.2.1.1) will compare the CR rate in T-Guard participants 
to a historical therapy CR rate of 20%. 
After 150 participants reach Day 28, two separate analyses will be performed to test whether T-
Guard’s Day 28 CR rate is superior to:  
1. Historical therapy (see section 5.2.1.2), to support T-Guard approval from US regulatory 
authorities (FDA). 
2. Ruxolitinib treatment (see section 5.2.2), to support T-Guard approval from European 
regulatory authorities (EMA). The superiority of the Day 28 CR rate for T-Guard treatment 
compared to ruxolitinib treatment will be evaluated. The analysis will take place when: 
a. 
150 participants have reached their day 28 assessment and 100 participants have at 
least 6 months follow-up. 
b. 
If efficacy is not found at this analysis, an analysis will follow once all 246 participants 
have been enrolled and reached their day 28 assessment (see section 5.2.2). This 
analysis serves as the final analysis of the primary endpoint. The final analysis of other 
endpoints will be conducted once all 246 participants complete the 180-day follow-up 
period. 
 
 


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Figure 5-2: BMT CTN 2002 Study Design and Interim Analysis Plan 
 
 
5.2.1 Simon’s Two-Stage Design for Demonstrating Superiority of T-Guard to 
Historical Therapies for Grade III-IV SR-aGVHD 
Single arm evaluations of the T-Guard CR rate alone will be performed to demonstrate 
improvement over a clinically relevant Day 28 CR rate for patients with Grade III-IV SR-aGVHD, 
as requested by the FDA. This CR rate will serve as the null hypothesis for the Simon’s two-
stage analysis. This clinically relevant response rate was determined taking the following into 
account:  
• 
A meta analysis was performed of the Day 28 CR rates observed in patients with Grade III-
IV SR-aGVHD in the REACH1 (ruxolitinib) and REACH2 (ruxolitinib and BAT) studies and in 
Grade III-IV SR-aGVHD patients from the MAGIC database (see Figure 5-3) who received 
second line therapy. This analysis included 304 patients in total and observed a Day 28 CR 
rate of 20.7% in the combined cohort. 
• 
FDA’s approval of ruxolitinib for the treatment of SR-aGVHD is based on the Day 28 ORR 
rate observed in the 47 patient efficacy cohort of the REACH1 registration study of patients 
with Grade II-IV SR-aGVHD. Among patients in this efficacy cohort with Grade III-IV SR-
aGVHD, ruxolitinib induced a Day 28 CR rate of 19.4% (95% CI: 8.2 - 36.0%).  
Based on the above, the study team considers a Day 28 CR rate of 20% to be clinically 
relevant. The two-stage design is organized such that if efficacy of T-Guard is found, the entire 
95% CI for the T-Guard Day 28 CR rate will lie above this 20% rate. In particular, it will exclude 
the 19.4% CR rate observed in Grade III-IV SR-aGVHD patients treated by ruxolitinib in the 
efficacy cohort of REACH1. 
 
 
 


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Figure 5-3: Day 28 CR Rates from Meta-analysis of Previous Ruxolitinib and Best 
Available Therapy Studies 
 
 
Per FDA requirement, the primary endpoint for the FDA analysis is the attainment of a CR at 
Day 28 post-T-Guard initiation. The FDA analysis population will include patients who are 
randomized to T-Guard and initiate this treatment. This approach is consistent with the analysis 
employed in the single arm REACH1 trial. A secondary analysis of this endpoint will add to the 
FDA analysis population patients who were randomized to T-Guard but failed to initiate 
treatment, classifying these patients as non-responders. 
The superiority of this T-Guard CR rate to a historical, clinically relevant therapy rate of 20% will 
be tested using a Simon’s two-stage design at a type I error rate of 2.5%. The design is 
summarized in Table 5-1. Stage 1 will evaluate 23 T-Guard participants and declare futility if 4 
or fewer CRs are observed. Stage 2 will evaluate 75 T-Guard participants and declare efficacy 
in contrast to historical therapies if 23 or more CRs are seen. This testing procedure provides 
98% power to detect a 23% improvement in the T-Guard CR rate over the 20% historical 
therapy rate. The use of these stages for decision making is described in subsequent sections. 
 
Table 5-1: Simon’s Two-Stage Design for Comparing T-Guard to Historical Therapies 
Stage 
Number of 
T-Guard 
Participants 
Futility Boundary – 
 # of CRs (CR rate) 
Probability of Declaring Futility Under True 
T-Guard CR Rate Below 
20% 
26% 
43% 
1 
23 
4 (17.4%) 
50.1% 
24.8% 
0.9% 
2 
75 
22 (29.3%) 
- 
- 
- 
 
5.2.1.1 
Futility Analysis (Stage 1) 
An interim analysis for futility will be performed when 23 participants on the T-Guard arm 
complete the Day 28 assessment. This futility analysis will be based on the first stage of the 
two-stage design (see Table 5-1), with futility declared if 4 or fewer CRs are observed out of the 
23 participants (observed CR rate of 17.4% or less). This is a non-binding futility analysis in that 
the overall type I error rate will not be inflated should the futility rule not be followed exactly. 


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5.2.1.2 
Efficacy Analysis Toward FDA Approval (Stage 2) 
An analysis of the T-Guard CR rate will be performed toward obtaining FDA approval once 150 
participants (75 per arm) complete the Day 28 assessments and 100 participants have 
completed the Day 180 assessment. This analysis will consider the CR rate specifically in the 
75 participants in the T-Guard arm and will compare this to historical therapies using the second 
stage of the Simon’s design (see Table 5-1). If 23 or more CRs are observed in this set (30.7% 
or higher), this will provide evidence of superiority of T-Guard in comparison to historical 
therapies and will support a request for FDA regular approval. Point and interval estimates of 
the T-Guard CR rate will be provided for this analysis using the minimum variance unbiased 
estimator and stagewise ordering confidence intervals proposed in Koyama et al. 2008. The 
additional requirement of 100 participants with 180 days of follow-up will ensure that sufficient 
data are available for a safety analysis that would be provided with the application for FDA 
approval. 
5.2.2 Efficacy Analysis for Demonstrating Superiority of T-Guard to Ruxolitinib 
Toward EMA Approval 
An interim analysis for efficacy will be conducted once 150 participants (75 per arm) complete 
the Day 28 assessments and 100 participants have completed the Day 180 assessment. This 
analysis will compare the Day 28 CR rates between trial arms (T-Guard vs. ruxolitinib) using 
logistic regression while adjusting for the stratification factors. An error spending approach will 
be employed to control the overall type I error rate using the O’Brien-Fleming spending function. 
Operating characteristics for this design are shown in Table 5-2. This analysis in 150 
participants will correspond to a one-sided significance level of approximately 0.44% as shown 
in the table. If superiority is not found at this analysis, a final analysis will follow once all 246 
participants have completed the Day 28 assessment, at which the remaining type I error rate will 
be spent. A finding of efficacy for T-Guard at either this interim or final analysis will be used to 
support an application for EMA approval. 
 
Table 5-2: Operating Characteristics for Trial Design 
Efficacy 
Analysis 
Sample 
Size 
Information 
Fraction 
Efficacy Boundary 
Cumulative 
Type I Error 
Rate 
Cumulative 
Power Under 
Alternative 
Difference in 
CR Rates 
Z Statistic 
1 
150 
61.0% 
20.19% 
2.6562 
0.44% 
34.14% 
2 
246 
100.0% 
11.82% 
1.9817 
2.37% 
80.56% 
*Type I error rate / power calculations obtained from 100,000 Monte Carlo simulations while accounting for 
futility analysis in Section 5.2.1.1 
 
5.3 
GUIDELINES FOR SAFETY MONITORING AND RUN-IN PHASE 
The occurrence of adverse events, toxicity, and other safety endpoints will be monitored 
regularly. These data will be reported to the DSMB at annual meetings at a minimum; in the 
event that any safety concerns arise, these data will be conveyed to the DSMB expeditiously. 
The policies and composition of the DSMB are described in the BMT CTN 2002 protocol-specific 


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MOP. In addition, monitoring of key safety endpoints will be conducted daily. If their rates 
significantly exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be 
advised. These monitoring guidelines serve as triggers for consultation with the DSMB for 
additional review and are not formal “stopping rules” that mandate automatic closure of study 
enrollment. 
5.3.1 Safety Run-in Phase 
The first portion of the trial will consist of a run-in phase, comprised of the first 12 patients 
randomized to the T-Guard arm and concurrently enrolled patients randomized to the ruxolitinib 
arm (approximately 24 patients total). During this phase: 
• 
A stopping rule will monitor the Day 30 mortality rate in the T-Guard arm (see section 5.3.2). 
• 
While the first 6 T-Guard patients are accrued, enrollment will be paused if this T-Guard arm 
monitoring rule (see Table 5-3) can possibly be triggered under the current enrollment and 
will be resumed when an additional T-Guard patient survives past Day 30. Specifically: 
o After 3 T-Guard patients are enrolled, additional enrollment will be permitted when 1 
T-Guard patient has survived past Day 30. 
o After 4 T-Guard patients are enrolled, additional enrollment will be permitted when 2 
T-Guard patients have survived past Day 30. 
o After 6 T-Guard patients are enrolled, additional enrollment will be permitted when 3 
T-Guard patients have survived past Day 30. 
• 
An additional stopping rule will compare the Day 60 mortality rates between the T-Guard 
and ruxolitinib arms throughout the run-in and post run-in phases of the trial (see section 
5.3.2 and Table 5-7.) 
• 
The DSMB will conduct two comprehensive reviews of early safety data: once 6 participants 
in the T-Guard arm have completed follow-up through Day 30, and when 12 participants in 
this arm have reached Day 30.  
Enrollment will be paused following enrollment of the 12th T-Guard patient in order to permit the 
DSMB to thoroughly examine these participants’ data and certify that the trial should open to 
unrestricted enrollment.  
5.3.2 Safety Endpoint Monitoring 
A key safety endpoint for this study is Day 30 overall mortality post-randomization. Based on 
historical data from the REACH trials and MAGIC, the expected probability of Day 30 mortality 
in Grade 3-4 SR-aGVHD participants is 15-20%, while a rate of 30% is considered to be 
unacceptable. A sequential probability ratio test (SPRT) for binary data will be used for daily 
monitoring of the Day 30 mortality rate within the T-Guard arm during the run-in phase, 
comparing a rate of 15% under the null hypothesis to a rate of 30% under the alternative 
hypothesis. 
This sequential testing procedure preserves the type I error rate at a prespecified level across 
all of the daily examinations. The binary SPRT can be represented graphically, with the 
continuation region of the SPRT defined by two parallel lines. At each examination, the number 


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of evaluable participants is plotted against the cumulative number of events. Only the upper 
boundary will be used for monitoring in order to protect against excessive Day 30 mortality. If 
the cumulative number of deaths meets or exceeds the upper boundary, the SPRT rejects the 
null hypothesis and concludes that more deaths occurred than should be expected in the 
observed number of evaluable participants. Otherwise, the SPRT continues until the run-in 
phase enrollment reaches the target sample size of 12 participants in the T-Guard arm. Nominal 
respective type I and type II error rates of 15% and 10% each were used to specify the rejection 
boundary. 
Table 5-3 displays the SPRT in a tabular form, showing the rejection boundaries for the number 
of Day 30 mortality events corresponding to the number of evaluable participants. At least three 
deaths must be observed in order to trigger review. 
 
Table 5-3: Sequential Monitoring Plan of Day 30 Overall Mortality in T-Guard Arm During 
Run-in Phase 
Number of Evaluable Participants 
Rejection Boundary for Number of Day 30 Deaths 
3 - 4 
3 
5 - 9 
4 
10 - 12 
5 
 
The operating characteristics of the truncated test are shown in Table 5-4. They were obtained 
from a simulation study that assumed uniform accrual of 12 participants to the T-Guard arm 
during the run-in phase. During the run-in phase, this procedure rejects the null hypothesis in 
favor of the alternative 4.6% of the time when the true Day 30 mortality rate is 15% and 74.5% 
of the time when the rate is 45%. If the true Day 30 mortality rate is 45%, the DSMB will, on 
average, be consulted when 4 events have been observed in 9 T-Guard arm participants. The 
limited size of the run-in phase permits reliable detection only of a true mortality rate in excess 
of 40% but provides some assurance of the safety of T-Guard before proceeding with full 
enrollment. 
 
Table 5-4: Operating Characteristics of the Binary SPRT for Single Arm Day 30 Overall 
Mortality Monitoring During Run-in Phase 
True Day 30 Mortality Rate 
15% 
20% 
25% 
30% 
35% 
40% 
45% 
50% 
Probability of Early Stopping 
4.6% 
11.4% 
21.6% 
34.5% 
48.6% 
62.3% 
74.5% 
84.1% 
Mean # Deaths by Day 30 
1.8 
2.3 
2.8 
3.1 
3.4 
3.6 
3.7 
3.7 
Mean # T-Guard Participants 
Enrolled 
11.8 
11.6 
11.2 
10.8 
10.2 
9.5 
8.8 
8.2 
*Operating characteristics obtained from 100,000 Monte Carlo simulations 
 
A second monitoring rule will evaluate whether the Day 60 mortality risk post-randomization for 
the T-Guard arm exceeds that for the ruxolitinib arm throughout the trial. Based on historical 


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data from the REACH trials and MAGIC, the expected probability of Day 60 mortality in Grade 
3-4 SR-aGVHD participants is 40%, while a rate of 65% is considered to be unacceptable. The 
presence of excess Day 60 mortality risk in the T-Guard arm evaluated using an SPRT that 
compares a null odds ratio of 1 for Day 60 mortality risk under T-Guard vs. ruxolitinib to an 
alternative value of 2.79. The alternative odds ratio of 2.79 corresponds to the increase in risk 
produced if the ruxolitinib rate equals 40% as expected while the T-Guard mortality rate is 
higher at 65%.This rule will only consider early stopping to reject the null hypothesis of equal 
mortality risk. An aggressive rejection boundary will be used during the run-in phase in order to 
provide enhanced vigilance in comparing risk between arms, determined by nominal type I and 
II error rates of 20.5% and 25%, respectively. Following the run-in, the rejection boundary is 
determined by nominal type I and II error rates of 5% and 10%. 
At each evaluation, this SPRT will use the conditional likelihood of the odds ratio given the 
total number of deaths observed in both arms, with excess risk for T-Guard indicated if a 
disproportionately high number of deaths occurred in that arm. As with the binary SPRT for 
single arm monitoring, this procedure preserves the type I error rate at a prespecified level 
across all of the daily examinations. Additional details for this monitoring rule are included in 
APPENDIX F. 
The probability of stopping early under the monitoring scheme, that is triggering at least one 
monitoring rule (single arm and/or comparative), is shown in Table 5-5.under a range of 
potential Day 60 mortality rates for the T-Guard and ruxolitinib arms. These were obtained from 
a simulation study that assumed uniform accrual of 123 participants per arm over the entire trial 
duration. The entries on the main diagonal correspond to situations where the mortality risk is 
identical between arms; for these, the testing procedure rejects the null hypothesis of equal risk 
approximately 10 - 12% of the time when the common mortality rate is 40% or less, indicating 
that the type I error rate lies within this range. For scenarios where the risk under T-Guard is 
20% higher than that for ruxolitinib, the SPRT rejects the null hypothesis in approximately 84-
87% of cases, demonstrating that this testing procedure offers 84+% power to detect T-Guard 
mortality rates that are 20+% higher than ruxolitinib.  
Table 5-6 displays the average number of deaths for each arm under the monitoring scheme for 
the range of true mortality rates considered, accounting for any early stopping that may occur as 
described in Table 5-5. 


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Table 5-5: Probability of Early Stopping for Day 60 Overall Mortality Signal under 
Combined Monitoring Scheme During the Entire Trial 
Stopping 
Probability 
True T-Guard Mortality Rate 
30% 
35% 
40% 
45% 
50% 
55% 
60% 
65% 
70% 
True 
Ruxolitinib 
Mortality 
Rate 
30% 
10.7% 
22.2% 
41.4% 
65.9% 
85.6% 
96.2% 
99.4% 
99.9% 100.0% 
35% 
5.9% 
11.6% 
22.2% 
40.5% 
64.1% 
84.9% 
95.8% 
99.4% 100.0% 
40% 
3.7% 
6.7% 
12.2% 
22.4% 
40.3% 
63.8% 
84.6% 
95.9% 
99.4% 
45% 
2.3% 
4.3% 
7.2% 
13.1% 
23.0% 
40.7% 
64.3% 
85.3% 
96.5% 
50% 
1.4% 
2.7% 
4.7% 
8.2% 
13.9% 
24.6% 
42.7% 
66.9% 
87.6% 
55% 
0.9% 
1.8% 
3.1% 
5.4% 
9.2% 
15.8% 
27.4% 
46.9% 
71.5% 
60% 
0.5% 
1.1% 
2.1% 
3.8% 
6.7% 
11.5% 
19.2% 
32.5% 
53.4% 
65% 
0.4% 
0.7% 
1.5% 
2.8% 
5.4% 
9.5% 
15.8% 
25.6% 
40.9% 
70% 
0.2% 
0.5% 
1.0% 
2.3% 
4.6% 
8.4% 
14.5% 
23.2% 
35.5% 
*Operating characteristics obtained from 100,000 Monte Carlo simulations. 
 Rejection criteria of both the single arm and double arm monitoring rules considered. 
 
Table 5-6: Average Number of Deaths by Day 60 by Arm under Combined Monitoring 
Scheme During the Entire Trial 
# T-Guard Deaths, 
# Rux Deaths 
True T-Guard Mortality Rate 
30% 
35% 
40% 
45% 
50% 
55% 
60% 
65% 
70% 
True 
Ruxolitinib 
Mortality 
Rate 
30% 
33.6, 
33.6 
35.9, 
30.7 
35.3, 
26.5 
31.1, 
20.7 
25.2, 
15.1 
19.2, 
10.5 
14.7,  
7.4 
11.6,  
5.4 
9.5,  
4.1 
35% 
35.0, 
40.7 
38.8, 
38.8 
40.7, 
35.6 
39.5, 
30.7 
34.9, 
24.4 
27.8, 
17.7 
21.1, 
12.3 
15.7,  
8.5 
12.2,  
6.1 
40% 
35.7, 
47.5 
40.4, 
46.2 
44.0, 
44.0 
45.6, 
40.5 
43.7, 
35.0 
38.2, 
27.7 
30.1, 
20.1 
22.3, 
13.7 
16.3,  
9.3 
45% 
36.1, 
54.2 
41.3, 
53.2 
46.0, 
51.7 
49.1, 
49.0 
50.2, 
45.1 
47.5, 
38.9 
40.7, 
30.5 
31.3, 
21.7 
22.4, 
14.4 
50% 
36.4, 
60.7 
41.9, 
60.0 
47.1, 
58.8 
51.2, 
56.9 
54.0, 
54.0 
54.2, 
49.3 
50.3, 
41.9 
41.8, 
32.2 
30.9, 
22.1 
55% 
36.6, 
67.1 
42.3, 
66.5 
47.8, 
65.6 
52.6, 
64.2 
56.3, 
61.9 
58.2, 
58.2 
57.1, 
52.4 
51.3, 
43.4 
40.8, 
32.0 
60% 
36.7, 
73.4 
42.6, 
73.1 
48.2, 
72.4 
53.4, 
71.2 
57.7, 
69.2 
60.5, 
66.0 
61.2, 
61.2 
58.0, 
53.5 
49.8, 
42.6 
65% 
36.8, 
79.7 
42.8, 
79.4 
48.5, 
78.8 
53.9, 
77.8 
58.4, 
75.9 
61.7, 
72.9 
63.1, 
68.3 
61.5, 
61.5 
55.6, 
51.7 
70% 
36.8, 
85.9 
42.9, 
85.7 
48.7, 
85.3 
54.2, 
84.3 
58.8, 
82.4 
62.4, 
79.4 
63.9, 
74.6 
62.9, 
67.7 
58.3, 
58.3 
*Operating characteristics obtained from 100,000 Monte Carlo simulations. 
 Rejection criteria of both the single arm and double arm monitoring rules considered. 
 
 
 


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The halting criteria are summarized in Table 5-7 for the first 6 participants per arm. Because the 
halting rule at any given examination depends on the numbers of events and evaluable 
participants in both arms, the rule cannot be easily tabulated for the entire run-in phase or trial. 
The table includes the decisions made in situations where the T-Guard arm has 1 or more 
excess deaths in comparison to the ruxolitinib arm. 
 
Table 5-7: Safety Monitoring Scheme for Day 60 Mortality within First 6 Participants per 
Arm for Event Scenarios of Special Interest 
  
  
T-Guard (# Day 60 Deaths / # Evaluable) 
2/3 
3/3 
2/4 
3/4 
4/4 
3/5 
4/5 
5/5 
3/6 
4/6 
5/6 
6/6 
Ruxolitinib 
(# Day 60 Deaths / 
 # Evaluable) 
0/3  
 
 
 
 
 
 
 
 
 
 
 
1/3  
 
 
 
 
 
 
 
 
 
 
 
0/4  
 
 
 
 
 
 
 
 
 
 
 
1/4  
 
 
 
 
 
 
 
 
 
 
 
0/5  
 
 
 
 
 
 
 
 
 
 
 
1/5  
 
 
 
 
 
 
 
 
 
 
 
2/5  
 
 
 
 
 
 
 
 
 
 
 
0/6  
 
 
 
 
 
 
 
 
 
 
 
1/6  
 
 
 
 
 
 
 
 
 
 
 
2/6  
 
 
 
 
 
 
 
 
 
 
 
* Green = continue; red = pause 
 
5.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for all participants and by 
treatment arm. Characteristics to be examined include age, gender, race/ethnicity, performance 
status, primary disease, primary disease status, disease risk index (DRI), time from steroid 
initiation to enrollment, aGVHD grade and organ staging, graft source, GVHD prophylaxis, 
conditioning regimen, time from disease diagnosis to transplant, time from transplant to 
enrollment, time from aGVHD onset to enrollment, and EASIX score. 
Counts and percentages will be used to describe categorical variables, while the median, mean, 
standard deviation, and range will be used to summarize continuous variables. 
5.5 
ANALYSIS OF PRIMARY ENDPOINT 
The primary endpoint of this trial is the attainment of a CR at Day 28 post-randomization. The 
primary hypothesis is that the proportion of participants with a CR at Day 28, called the Day 28 
CR rate, is greater for the T-Guard arm compared to the ruxolitinib arm. This hypothesis will be 
evaluated by comparing the null hypothesis that the Day 28 CR rate under T-Guard treatment is 
no better than this rate under ruxolitinib treatment to the alternative hypothesis that this rate is 
superior for the T-Guard arm. 


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The estimand for Day 28 CR is based on the composite strategy, where a participant is 
classified as a CR provided three conditions are satisfied: 
1. Stage 0 aGVHD in target organs at Day 28 
2 .  The participant is still alive at Day 28 
3 .  No additional systemic treatment for aGVHD has been administered through Day 28 
Participants who do not satisfy all three criteria will be classified as failures for CR. 
The following intercurrent events could potentially impact the pivotal analysis: discontinuation of 
study drug before Day 28, and missingness of the Day 28 GVHD assessment. The pivotal 
analysis accounts for these events as follows: 
• 
Discontinuation of study drug will be carefully monitored. Under the ITT principle, the 
analysis includes all randomized participants, so treatment discontinuation itself has no 
effect on the analysis because it produces no changes to the participant population or 
evaluation of CR criteria. Initiation of additional systemic aGVHD treatment following 
discontinuation would be considered a failure for CR per the composite strategy 
described above. 
• 
Participants whose Day 28 GVHD assessment is missing for any reason (including loss 
to follow-up, withdrawal from study, or a missed visit) will be classified as failures (non-
CRs) for the primary endpoint. 
The pivotal analysis for this study involves comparison of the Day 28 CR rate between arms in 
the primary (ITT) analysis population. The summary measure used to compare Day 28 CR rates 
between T-Guard and Ruxolitinib is the odds ratio, to be evaluated using logistic regression 
while adjusting for region (US vs. Europe) and age (at least 55 years vs. under 55) and acute 
GVHD grade at randomization (Grade III vs. IV). Testing will be one-sided at an overall 
significance level of 0.025. Two efficacy analyses for the primary endpoint will be performed as 
described in Section 5.2.2, one interim and one final, with the O’Brien-Fleming error spending 
function used to determine the appropriate critical values for each analysis. 
The Day 28 CR rate will be described for each arm using the sample proportions and 
corresponding 95% confidence intervals. 
A secondary analysis will assess the proportions of treated participants who attain a CR at Day 
28 post-treatment initiation. This set of participants will include those from the PP population 
who are not in CR at the time of treatment initiation, with symptoms compared from the time of 
initiation to 28 days following initiation to determine CR status. This Day 28 CR rate will be 
described for each arm using the sample proportions and corresponding 95% confidence 
intervals. Day 28 CR rates will be compared between T-Guard and ruxolitinib using logistic 
regression while adjusting for region (US vs. Europe) and age (at least 55 years vs. under 55) 
and acute GVHD grade at randomization (Grade III vs. IV). 
5.6 
ANALYSIS OF SECONDARY ENDPOINTS 
The analysis of secondary endpoints will be based on the primary ITT analysis population. A 
supplemental analysis will also be performed in the PP population. 


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Key Secondary Endpoints: 
The study has two key secondary endpoints: OS and DoCR. The comparison of OS between 
treatment arms will be alpha-protected; to protect the familywise type I error rate of 2.5%, a 
gatekeeping procedure will be employed where OS will be tested for superiority of T-Guard to 
ruxolitinib only if a significant benefit of T-Guard is found in the pivotal analysis of the primary 
endpoint. 
5.6.1 Overall Survival (OS) 
OS is defined as survival of death from any cause. The time from randomization until death from 
any cause will be described for each arm using the Kaplan-Meier estimator. Estimates and 95% 
CIs for OS will be provided at Days 60, 90 and 180 post-randomization for each arm. 
Provided that the pivotal analysis demonstrates superiority of T-Guard to ruxolitinib, a Cox 
proportional hazards model will compare the overall mortality hazard rates between the T-Guard 
and ruxolitinib arms through Day 180 while adjusting for the stratification factors and for acute 
GVHD grade at randomization (Grade III vs. IV). 
5.6.2 Duration of Complete Response (DoCR) 
DoCR will be evaluated only in the set of participants who are in CR at Day 28 post-
randomization. The primary definition of DoCR is the time from Day 28 until an aGVHD target 
organ worsens by at least 1 stage and requires a significant escalation in treatment ( defined 
below), or death. The transient worsening of symptoms that resolve without significant 
escalation of treatment is not considered a loss of CR. A significant escalation in treatment is 
defined as initiation of new systemic treatment for GVHD and/or escalation in 
methylprednisolone dose (or equivalent). Methylprednisolone dose increases must be greater 
than 25% of the current dose and increase at least 8 mg/day (or other steroid equivalent) to be 
considered an escalation of methylprednisolone.  DoCR will be described for each arm using 
the Kaplan-Meier estimator, with estimates and 95% CIs for the median of DoCR obtained from 
this estimator using the method described in Andersen et al. 1993, Chapter IV. 
A Cox proportional hazards model will compare the hazard rates of loss of CR between the T-
Guard and ruxolitinib arms through Day 180 while adjusting for the stratification factors. This will 
include DoCR events as defined in the previous paragraph. 
A secondary analysis will use an alternative definition of DoCR as the time from Day 28 until 
death or a significant escalation  of aGVHD therapy occurs, as defined in the primary analysis of 
DoCR.DoCR defined in this manner will be described for each arm using the Kaplan-Meier 
estimator, with estimates and 95% CIs for the median of DoCR obtained from this estimator 
using the method described in Andersen et al. 1993, Chapter IV. 
Other Secondary Endpoints: 
5.6.3 Time to Complete Response (CR) 
The time from randomization until first attaining a CR will be described for each treatment arm 
using the Aalen-Johansen estimator, with death and additional systemic treatment for aGVHD 
treated as competing risks. Estimates and 95% CIs of the cumulative incidence of CR will be 


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provided at Days 28 and 56 post-randomization. The cause-specific hazards of CR will be 
compared between arms using a Cox proportional hazards model with adjustment for the 
stratification factors and for acute GVHD grade at randomization (Grade III vs. IV). 
5.6.4 Overall Response Rate (ORR) 
Overall response is defined as either a complete or participant response (CR+PR). The ORR 
will be estimated at Days 14, 28, and 56 post-randomization for each treatment arm using 
sample proportions and 95% Wilson score or Clopper-Pearson CIs, as appropriate. ORRs will 
be compared between arms by evaluating the odds ratio of CR/PR for T-Guard vs. ruxolitinib 
using logistic regression with adjustment for the stratification factors and for acute GVHD grade 
at randomization (Grade III vs. IV). 
5.6.5 Proportion of Response 
The proportion of participants in each aGVHD response category will be described at Days 6 
14, 28 and 56 post-randomization for each treatment arm. These proportions will be compared 
between arms using Pearson’s chi-square test or Fisher’s exact test as appropriate. 
5.6.6 Non-relapse Mortality (NRM) 
NRM is defined as death from any cause other than malignancy relapse/progression. The time 
from randomization until NRM will be described for each treatment arm using the Aalen-
Johansen estimator, with malignancy relapse/progression treated as a competing risk. 
Estimates and 95% CIs of the cumulative incidence of NRM will be provided at Days 100 and 
180 post-randomization. The cause-specific hazards of NRM will be compared between arms 
using a Cox proportional hazards model with adjustment for the stratification factors and for 
acute GVHD grade at randomization (Grade III vs. IV). 
5.6.7 Relapse-free Survival (RFS) 
RFS is defined as being alive and free of malignancy relapse/progression. The time from 
randomization until malignancy relapse/progression or death will be described for each arm 
using the Kaplan-Meier estimator. Estimates and 95% CI for RFS at Day 180 post-
randomization will be provided. A Cox proportional hazards model will compare the hazard 
rates of relapse/progression/mortality between the T-Guard and ruxolitinib arms with 
adjustment for the stratification factors and for acute GVHD grade at randomization (Grade III 
vs. IV). 
5.6.8 GVHD-free Survival 
GVHD-free survival is defined as being alive, in CR, and free of cGVHD. The proportion of 
participants with GVHD-free survival at Days 90 and 180 post-randomization will be estimated 
for each treatment arm using sample proportions and 95% Wilson score or Clopper-Pearson 
CIs, as appropriate. The proportions of participants with GVHD-free survival at Day 180 will be 
compared between arms using logistic regression with adjustment for the stratification factors 
and for acute GVHD grade at randomization (Grade III vs. IV). 


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5.6.9 Chronic GVHD (cGVHD) 
cGVHD severity is defined per the 2014 NIH Consensus Criteria (see APPENDIX D). The 
maximum severity of cGVHD through Day 180 post-randomization will be tabulated by arm. 
The time from randomization until onset of cGVHD of any severity (mild, moderate, or severe) 
will be described for each treatment arm using the Aalen-Johansen estimator, with death prior 
to cGVHD onset treated as a competing risk. Estimates and 95% CIs of the cumulative 
incidence of cGVHD will be provided at Day 180 post-randomization. The cause-specific 
hazards of cGVHD will be compared between arms using a Cox proportional hazards model 
with adjustment for the stratification factors and for acute GVHD grade at randomization 
(Grade III vs. IV). 
5.6.10 Relapse/Progression of Underlying Malignancy 
The time from randomization until malignancy relapse/progression will be described for each 
treatment arm using the Aalen-Johansen estimator, with death prior to relapse/progression 
treated as a competing risk. Estimates and 95% CIs of the cumulative incidence of malignancy 
relapse/progression will be provided at Day 180 post-randomization. The cause-specific 
hazards of relapse/progression will be compared between arms using a Cox proportional 
hazards model with adjustment for the stratification factors and for acute GVHD grade at 
randomization (Grade III vs. IV). 
5.6.11 Incidence of Infections 
The frequency of Grade 2-3 infections occurring from randomization until Day 90 post-
randomization will be tabulated by infection site, date of onset, and severity, with Grade 
defined per Appendix G. Grade 1 CMV infections requiring treatment that occur post-
randomization will also be summarized. The cumulative incidence of Grade 2-3 infections at 
Day 90 post-randomization will be described by treatment arm using the Aalen-Johansen 
estimator and its 95% CI, with death prior to infection treated as a competing risk. The 
cumulative incidence of treated CMV will similarly be estimated at Day 90 for each arm. 
5.6.12 Incidence of Toxicities 
The frequency of Grade 3-5 toxicities per CTCAE Version 5 occurring from randomization until 
56 days post-randomization will be tabulated by organ system for each treatment arm. The 
maximum severity of reported toxicities during that period will also be summarized. The 
proportions of participants reporting Grade 3-5 toxicities through Day 56 will be compared 
between arms using logistic regression with adjustment for the stratification factors and for 
acute GVHD grade at randomization (Grade III vs. IV). 
5.6.13 Subgroup Analyses of Day 28 CR Rate 
In a secondary analysis of the primary endpoint, the CR rate at Day 28 post-randomization will 
be described for each age group (55 years or over vs. under 55), gender, race, ethnicity, 
center region (US vs. Europe), and aGVHD grade (III vs. IV). Sample proportions and 95% 
Wilson score or Clopper-Pearson CIs will estimate the Day 28 CR rate of each subgroup by 
treatment arm. For each subgroup, the difference in CR rates between arms will be described 
using a point estimate and 95% CI. 


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5.7 
ANALYSIS OF PHARMACOKINETIC / PHARMACODYNAMIC ENDPOINTS (T-
GUARD ONLY) 
The analysis of pharmacokinetic / pharmacodynamic endpoints will be based on the PK analysis 
population. 
5.7.1 Pharmacokinetics 
A population pharmacokinetic model will be developed for T-Guard based on the SPV-T3a- 
RTA and WT1-RTA levels measured in samples obtained before each infusion and at pre-
defined timepoints after infusion (see Table K-1). The model will be used to evaluate the 
following metrics: 
• 
Cinf: Observed and model-predicted concentration at the end of infusion 
• 
CL: Systemic clearance 
• 
AUC: Model-predicted area under the curve from the start of the current infusion until 
the next infusion or until 48 hours following for the last infusion 
• 
t1/2: Model-predicted terminal half-life 
• 
Vc: Volume of the central compartment 
Additionally, the impact of various factors on these measures will be evaluated, including age, 
weight, BSA, BMI, disease status, and ADA. 
5.7.2 Immunogenicity 
ADA responses in the form of anti-SPV-T3a-RTA and anti-WT1-RTA antibodies will be 
evaluated using serum samples obtained at baseline and at Days 6, 14, 28, 90, and 180 
following initiation of T-Guard treatment. Antibody levels will be described using descriptive 
statistics at each time point. Changes in levels from baseline will be evaluated using Wilcoxon 
signed rank tests. 
5.8 
ANALYSIS OF EXPLORATORY ENDPOINTS 
The analysis of exploratory endpoints will be based on the ITT analysis population. 
5.8.1 Discontinuation of Systemic Steroids 
The proportion of participants that is free of systemic steroids at Day 180 post-randomization 
will be described by treatment arm using sample proportions and 95% Wilson score or Clopper-
Pearson CIs. The proportions of steroid-free participants at Day 180 will be compared between 
arms using Barnard’s exact test. 
5.8.2 CMV Reactivation 
Among participants who were CMV positive at enrollment, the cumulative incidence of initiation 
of systemic treatment for CMV-reactivation will be described for each treatment arm using the 
Aalen-Johansen estimator, with death treated as a competing risk. Estimates and 95% CIs of 
the cumulative incidence of CMV reactivation will be provided at Day 180 post-randomization. 
The cumulative incidence of CMV will be compared between arms using Gray’s test. 


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5.8.3 EBV-associated Lymphoproliferative Disorder 
The cumulative incidence of either EBV-associated lymphoproliferative disorder or EBV 
reactivation requiring therapy with rituximab will be described for each treatment arm using the 
Aalen-Johansen estimator, with death treated as a competing risk. Estimates and 95% CIs of 
the cumulative incidence of EBV-associated lymphoproliferative disorder/EBV reactivation will 
be provided at Day 180 post-randomization. The cumulative incidence of EBV-associated 
lymphoproliferative disorder/EBV reactivation will be compared between arms using Gray’s 
test. 
5.8.4 Evolution of Cell Populations 
The evolution of specific cell populations over the 180-day follow-up period will be evaluated 
using samples obtained from approximately 50 participants (25 T-Guard and 25 ruxolitinib 
participants) at Days 0, 14, 28, 90 and 180 post-randomization. Specimens will either be 
collected and stored as viably frozen PBMCs to allow for phenotypic and functional analysis of 
specific cell subsets or collected in CytoChex blood preservation tubes for FCM analysis.  
The following cell populations, amongst others, will be measured by flow cytometry analysis: 
Inflammatory Monocytes & Dendritic Cells, Recent Thymic Emigrants, CD4+, CD8+ Naïve & 
MemoryCells,CD4+TRegulatoryCells,NKCells,γδTCells,andBcells. 
The level of each cell population will be summarized for each arm using descriptive statistics at 
each assessment time considered. Changes in levels from baseline to each follow-up 
assessment time will be evaluated by arm using Wilcoxon signed rank tests. For the PBMC 
subsets collected from both arms, Wilcoxon rank sum tests will compare the changes between 
arms at each follow-up time point. 
5.8.5 GVHD-related Biomarkers 
Using the biomarker risk model from Major-Monfried, Renteria et al. 2018, the serum levels of 
GVHD-related biomarkers including REG3αandST2and the 3-IS urine levels at enrollment 
and Day 6, 14, and 28 post-randomization will be used to estimate NRM probabilities for each 
participant at Day 180 following each assessment time point. The proportions of participants 
with high risk (defined as an estimated NRM greater than 0.29) will be described at each 
assessment time by treatment arm. 
Moreover, the proportions of participants within each treatment arm experiencing a Day 28 CR 
will be described separately for participants with high risk vs. not at enrollment within each 
treatment arm using sample proportions and 95% Wilson score or Clopper-Pearson CIs, as 
appropriate. A logistic regression model will evaluate the prognostic value of biomarker risk 
(high vs. not) on the chance of attaining a Day 28 CR while adjusting for treatment arm. 
5.8.6 Patient Reported Outcomes (PROs) 
Patient self-reported measures will be assessed using selected PROMIS domains for 
gastrointestinal symptoms, physical function, and satisfaction with participation in social roles, 
described in APPENDIX E. These instruments will be scored according to the recommendation 
of the developers. For each PROMIS domain, scores at baseline and at Day 28, 90, and 180 


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post-randomization will be described by treatment arm using descriptive statistics. Wilcoxon 
signed rank tests will be used to evaluate changes from baseline to each follow-up time point for 
each arm. Wilcoxon rank sum tests will compare the changes between arms at each of these 
time points. 
5.8.7 Thrombotic Microangiopathy (TMA) 
The frequency of TMA events will be tabulated for each treatment arm. The cumulative 
incidence of TMA will be described by arm using the Aalen-Johansen estimator, with death 
treated as a competing risk. Estimates and 95% CIs of the cumulative incidence of TMA will be 
provided at Day 28 post-randomization. The cumulative incidence of TMA will be compared 
between arms using Gray’s test. 
5.8.8 EASIX Score 
EASIX score at enrollment will be summarized by treatment arm using descriptive statistics. 
The proportion of participants with high EASIX OS risk (defined as an EASIX score greater 
than 3.43) and high EASIX NRM risk (EASIX score greater than 3.61) at the time of enrollment 
will also be described for each arm, the risk classifications proposed in Luft et al. 2017. 
Validation of these EASIX risk categories will be performed in the context of SR-aGVHD 
treatment considered in the current trial. OS and NRM at Day 180 post-randomization will be 
estimated for each EASIX risk group (high vs. not) by treatment arm using the Kaplan-Meier 
and Aalen-Johansen estimators, respectively. A Cox proportional hazards model will evaluate 
the prognostic value of EASIX OS risk (high vs. not) on the hazard rate of overall mortality 
while adjusting for treatment arm and a EASIX risk-treatment arm interaction term to permit 
possible differential effects of the treatments based on EASIX classification. A similar Cox 
model of the cause-specific hazard rate of NRM will evaluate the prognostic value of EASIX 
NRM risk (high vs. not) while adjusting for treatment arm and a EASIX risk-treatment arm 
interaction term. 
 


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APPENDIX A: HUMAN SUBJECTS 
 
1. Subject Consent 
Candidates for the study will be identified as described in Chapter 4 of the protocol. The PI or 
his/her designee at each transplant center will contact the candidates, provide the participant 
with information about the purpose of the study, and obtain consent. The BMT CTN will provide 
a template of the consent form to each center. Each center will customize the templates 
according to their local requirements and submit for review by the DCC for adequacy prior to 
submitting to the NMDP IRB of Record. Each center must provide evidence of IRB approval to 
the DCC. 
2. Confidentiality 
Confidentiality will be maintained by individual names being masked and assigned a 
participant identifier code. The code relaying the patient’s identity with the ID code will be kept 
separately at the center. The ID code will be generated by and kept on file at the BMT CTN 
Data and Coordinating Center upon enrollment. 
3. Participation of Children, Women and Minorities 
Women, ethnic minorities, and other populations will be included in this study. Children are not 
eligible for this study given lack of applicable safety and PK data with T-Guard. Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of high risk 
aGVHD in these groups. Centers will be notified if their rates differ significantly from those 
expected and asked to develop appropriate recruitment reports. 
 
 


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APPENDIX B: LABORATORY PROCEDURES 
 
Collection of Mandatory Research Samples for Protocol-Defined Correlative Studies 
Research samples will be collected for patients who consent to the BMT CTN 2002 study. 
Required research samples for study-specific exploratory endpoints include the collection of 
peripheral blood and urine samples as summarized in the table below. The following planned 
studies will be performed and remaining biospecimens made available to approved 
investigators for meritorious ancillary correlative laboratory studies with the potential to extend 
the findings of the current study portfolio. 
• 
Analysis of serum cytokines before and after study treatment 
• 
Evaluation of serum and urine biomarkers associated with aGVHD 
• 
PK of T-Guard - development of a population pharmacokinetic model 
• 
Evaluation of potential humoral responses (ADA) to T-Guard infusions 
• 
Evaluation of study treatment on targeted and non-target immune cell subsets and 
presence of alloreactive and CMV/EBV specific T-cells 
• 
Evaluation of free-mAb and free-RTA in serum in T-Guard treated patients 
Once the samples are collected at specified time points, they will either be shipped on the day 
of collection or aliquoted and stored on site until batch-shipping to the specified lab. The 
collection and shipment of these blood and urine samples will be tracked. Detailed procedures 
regarding specimen collection schedules, sample handling/processing procedures and 
shipping instructions will be found in the BMT CTN 2002 Research Sample Information Guide. 
 
 


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Subjects 
Sample Type 
Sample Collection Time 
Points 
Sample Collection and 
Sample Processing 
Summary 
Shipping Specifications 
T-Guard 
Participants 
Only 
Peripheral Blood 
(SST Clot Tube) 
 
5 mL 
 
Humoral Response 
Serum Anti-Drug 
Antibodies 
Pre-treatment initiation 
Day 0 
 
Post-treatment 
initiation 
Day 6 
(just prior to 4th infusion) 
 
Days 14, 28, 90, and 180 
Collect the blood sample 
and place into an SST 
Vacutainer tube containing 
clot activator. Allow blood 
samples to clot upright for 
30-60 minutes in a tube rack 
prior to centrifugation. 
 
In Europe: Samples should 
be aliquoted and stored at -
80⁰C. 
US: Centrifuged blood 
sample tube will be shipped 
at 2-8⁰Conthedayof
collection, to the BMT CTN 
Biorepository, aliquoted, 
and stored at -80⁰C. The 
sample aliquots will be 
batch-shipped to Ardena 
for analysis. 
 
Europe: Frozen serum 
aliquots will be periodically 
batched-shipped to Ardena 
for analysis. 
T-Guard 
Participants 
Only 
Peripheral Blood1 
(SST Clot Tube) 
 
5 mL 
 
Serum 
Pharmacokinetic 
Testing (2 aliquots) 
Cytokines testing 
during safety run-in 
and for patients 
experiencing an 
infusion reaction (1 
aliquot) 
Free-RTA + free-mAb 
testing on selected 
left-over PK samples 
(1 aliquot) 
Day 0 
(1st infusion) 
Prior to study drug 
infusion and 4, 5, 6, 8, 
and 24 hours after start 
of infusion 
 
Days 2 & 4 
(2nd & 3rd infusions) 
Prior to study drug 
infusion and 4 and 24 
hours after start of 
infusion 
 
Day 6 
(4th infusion) 
Prior to study drug 
infusion and 4, 6, 24, 
and 48 hours after start 
of infusion 
 
Notably no PK 
sampling is required on 
Weekend Days 
Collect the blood sample 
and place into an SST 
Vacutainer tube containing 
clot activator. Allow blood 
samples to clot upright for 
30-60 minutes in a tube rack 
prior to centrifugation, serum 
removal, and serum aliquot 
equally in 4 aliquots of 0.5 
mL; storage at -80⁰C. 
Frozen serum aliquots will 
be periodically batched-
shipped to the BMT CTN 
Biorepository (US) or 
Ardena (Europe). 
 
One aliquot will be shipped 
from BMT CTN/Ardena to 
MyriadRBM for cytokine 
testing for the first 12 T-
Guard patients, and in 
cases where patients 
experience a T-Guard 
infusion reaction. All other 
sample aliquots wil be PK 
tested at Ardena. 
 
Remaining PK samples 
may be selected for free-
RTA + free-mAb testing. 
All Study 
Participants 
Peripheral Blood 
(SST Clot Tube) 
 
5 mL 
 
Serum 
GVHD Biomarkers 
REG3αandST2 
Pre-treatment initiation 
Day 0 
 
Post-treatment 
initiation 
Day 6 
(just prior to 4th infusion 
for T-Guard arm) 
 
Days 14 and 28 
Collect the blood sample 
and place 5 mL SST 
Vacutainer tube containing 
clot activator. Allow blood 
samples to clot upright for 
30-60 minutes in a tube rack 
prior to centrifugation. 
 
In Europe: Samples should 
be aliquoted and stored at -
80⁰C. 
US: Centrifuged blood 
sample tube will be shipped 
at 2-8⁰Conthedayof
collection, to the BMT CTN 
Biorepository and stored at 
-80⁰C. Serum aliquots will 
be batch-shipped to Dr. 
Ferrara’s lab at Mt. Sinai 
for analysis. 
 
Europe: Frozen serum 
aliquots will be batched-
shipped to Ardena, and 
forwarded Dr. Holler’s lab 
in Regensburg, Germany 
for analysis. 


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Subjects 
Sample Type 
Sample Collection Time 
Points 
Sample Collection and 
Sample Processing 
Summary 
Shipping Specifications 
All Study 
Participants 
Urine 
 
6 mL 
 
GVHD Related 3IS 
Biomarkers 
Pre-treatment initiation 
Day 0 
 
Post- treatment 
initiation 
Day 6 
(just prior to 4th infusion 
for T-Guard arm) 
 
Days 14 and 28 
In the US: Place urine in 
sterile transport tube for 
same-day shipping. 
 
In Europe: Aliquote urine 
and place in ultra-freezer 
temperature cryovials and 
stored at -80⁰C. 
US: Urine sample tube will 
be shipped at 2-8⁰Conthe
day of collection to the 
BMT CTN Biorepository, 
aliquoted, and stored at -
80⁰C. 
 
Europe: Frozen aliquots will 
be periodically batched-
shipped to Ardena, and 
forwarded to Dr. Holler’s 
lab in Regensburg, 
Germany for analysis. 
50 Study 
Participants 
in selected 
centers (25 
on T-Guard 
and 25 on 
ruxolitinib) 
Peripheral Blood 
(Sodium Heparin 
Vacutainer Tubes) 
 
30 mL 
 
Peripheral blood 
mononuclear cells 
(PBMC) viably frozen 
Pre-treatment initiation 
Day 0 
 
Post-treatment 
initiation 
Days 14, 28, 56, and 180 
Collect the blood sample 
and place 10 mL into each 
of three Vacutainer tubes 
containing sodium heparin 
anticoagulant. Gently mix 
sample by inversion 8-10 
times to mix sample well 
with anticoagulant. 
 
In Europe: Samples will be 
viably frozen at site. 
US: Blood sample tubes 
will be shipped at 2-8⁰Con
the day of collection, to the 
BMT CTN Biorepository for 
viably freezing. 
 
Europe: Samples should be 
viably frozen at site and 
batch-shipped to Ardena. 
 
Samples will be banked for 
later analysis (e.g. 
CMV/EBV Alloreactive T- 
Cells). 
50 Study 
Participants 
in selected 
centers (25 
on T-Guard 
and 25 on 
ruxolitinib) 
Peripheral Blood 
(Cyto-Chex BCT) 
 
10 mL 
 
Flow Cytometry 
Immune Profiling 
Pre-treatment initiation 
Day 0 
 
Post-treatment 
initiation 
Days 14, 28, 56, and 180 
Collect the blood sample 
and place 5 mL into each of 
two Cyto-Chex tubes 
containing EDTA 
anticoagulant and cell 
fixative. Gently mix sample 
by inversion 8-10 times to 
mix sample well with 
anticoagulant and cell 
fixative reagent. 
Cyto-Chex blood tubes will 
be shipped at 2-8⁰Conthe
day of collection to the 
RPCI project laboratory 
(US) or Ardena (Europe). 
1Pharmacokinetic blood samples directly at pre-infusion and at 4, 5, 6, 8, and 24 hours after start of 1st infusion; pre-infusion and at 4 and 24 hours 
after the 2nd and 3rd infusion; and pre-infusion and at 4, 6, 24 and 48 hours after the 4th T-Guard infusion. Pre-infusion samples should be drawn 
prior to T-Guard administration. A window of +/- 15 minutes is allowed for samples drawn at 4 hours, a window of +/- 30 minutes for samples 
drawn at 5, 6 or 8 hours after the start of infusion, and a window of +/- 60 minutes for the sample drawn at 24 and 48 hours after the start of 
infusion. Every effort should be made to collect PK samples at all timepoints; however, no PK sampling is required on weekend days. 
 


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APPENDIX C: STAGING AND GRADING OF ACUTE GVHD (HARRIS, YOUNG ET 
AL. 2016) 
 
 
 
 


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APPENDIX D: GRADING OF CHRONIC GVHD (NIH CRITERIA), (JAGASIA, 
GREINIX ET AL. 2015) 
 
 
Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; 
LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, 
alkaline phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit. *Weight loss within 90 days. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists 
between the percentage of total BSA score and the skin feature score, OR if superficial sclerotic features are present (Score 
2), but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. To be 
completed by specialist or trained medical providers. **Lung scoring should be performed using both the symptoms and FEV1 
scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and 
FEV1 scores. 


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APPENDIX E: PATIENT REPORTED OUTCOMES 
 
In general, would you say your health is…. 
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
In general, would you say your quality of life is…. 
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
In general, how would you rate your physical health?  
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
In general, how would you rate your mental health, including your mood and your ability to 
think?  
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
In general, how would you rate your satisfaction with your social activites and 
relationships?  
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
In general, please rate how well you carry out your usual social activities and roles. (This 
includes activities at home, at work and in your community, and responsibilities as a 
parent, child, spouse, employee, friend, etc.)  
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 


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To what extent are you able to carry out your everyday physical activities such as walking, 
climbing stairs, carrying groceries ro moving a chair?  
1. Not at all 
2. A little 
3. Moderately 
4. Mostly 
5. Completely 
How often have you been bothered by emotional problems such as feeling anxious, 
depressed or irritable?  
1. Always 
2. Often 
3. Sometimes 
4. Rarely 
5. Never 
How would you rate your fatigue on average?  
1. Very severe 
2. Severe 
3. Moderate 
4. Mild 
5. None 
In the past 7 days, how would you rate your pain on average? 
0. No pain 0 
1. 1 
2. 2 
3. 3 
4. 4 
5. 5 
6. 6 
7. 7 
8. 8 
9. 9 
10. Worst imaginable pain, 10 
In the past 7 days, how often did you have nausea – that is, a feeling like you could vomit? 
1. Never (skip next question) 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
 
 


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In the past 7 days, how often did you know that you would have nausea before it 
happened? 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, how often did you have a poor appetite? 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, how often did you throw up or vomit? 
1. Never 
2. One day 
3. 2-6 days 
4. Once a day 
5. More than once a day 
In the past 7 days, how often did you have belly pain? 
1. Never 
2. One day 
3. 2-6 days 
4. Once a day 
5. More than once a day 
In the past 7 days, how many days did you have loose or watery stools? 
1. No days 
2. One day 
3. Two days 
4. 3-5 days 
5. 6-7 days 
In the past 7 days, how often did you feel like you needed to empty your bowels right away 
or else you would have an accident? 
1. Never 
2. One time during the past 7 days 
3. 2-6 days during the past 7 days 
4. Often once a day 
5. More than once a day 
 
 
 


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In the past 7 days, how often did you have bowel incontinence – that is, have an accident 
because you could not make it to the bathroom in time? 
1. No days 
2. One day 
3. 2-3 days 
4. 4-5days 
5. 6-7 days 
Are you able to dress yourself, including tying shoelaces and buttoning your clothes? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to get out of bed into a chair? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to go for a walk of at least 15 minutes? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to go up and down stairs at a normal pace? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
In the past 7 days, I feel fatigued 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
 
 
 


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In the past 7 days, I have trouble starting things because I am tired 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how run-down did you feel on average? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how fatigued were you on average? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how much did pain interfere with your day to day activities? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how much did pain interfere with your enjoyment of life? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I felt worthless 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, I felt helpless 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 


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In the past 7 days, I felt depressed 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, I felt hopeless 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, my sleep quality was… 
1. Very poor 
2. Poor 
3. Fair 
4. Good 
5. Very good 
In the past 7 days, my sleep was refreshing 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I had a problem with my sleep 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I had difficulty falling asleep 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
 
 


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APPENDIX F: DERIVATION OF A SEQUENTIAL TEST FOR COMPARING 
BINOMIAL PROPORTIONS BETWEEN TWO STUDY ARMS 
Background – The Sequential Probability Ratio Test 
Let (. , ) be the density function for a random variable X. According to Neyman and 
Pearson, the most powerful test of 0:  =  versus 1:  = 1 decides in favor of 1 or 0 if 
 > 	
 or  < 	
, respectively, where  = ∏(; 1)/(; 0)


 is the likelihood ratio, and 
	
 is the critical value determine so that the test will have size . When the sample size is 
not fixed in advance, further improvement is possible by using Wald’s Sequential Probability 
Ratio Test (SPRT). The SPRT continues to sample as long as  <  <  for some 
constants ,  with  < 1 < , stops sampling and decides in favor of 1 as soon as  > , 
and stops sampling and decides in favor of 0 as soon as  < . 
The usual measures of performance of such a procedure are the error probabilities  and  
of rejecting 0 when  = 0 and of accepting 0 when  = 1, respectively, and the expected 
sample size  = (). Wald and Wolfowitz showed that among all tests, sequential 
or not, for which ( reject 0| = 0) ≤, ( accept 0| = 1) ≤, and the () are finite 
for  = 0,1, the SPRT with error probabilities  and  minimizes 0() and 1(). If, in 
addition, the  are independent and identically distributed (i.i.d.) with density function 
(, ), with monotone likelihood ratio in (), then any SPRT for testing 0 against 1(> 0) 
has a non-decreasing power function. 
For the SPRT with error probabilities  and , the SPRT boundaries are given approximately 
by  = (1  )/ and  = /(1  ). The operating characteristics of the SPRT are given by 
(, , , 0, 1) = (()  1)/(()  ()) where ℎ() is the non-trivial solution to the 
equation ∫[(; 1)/(, 2)]()(; )# = 1. 
The formula (; ) = {[(1{()] $%&  + () $%& }/('; ) provides the average sample 
number for an arbitrary . The sample size distribution is highly skewed with ()*() ≈
[()]2. Thus, we consider a truncated test with maximum sample size of 0 and simulate to 
obtain the operating characteristics of the test. 
Derivation of the SPRT for Comparing Binomial Proportions Between Two 
Arms 
Suppose that we wish to construct a sequential test that compares the proportions of 
participants experiencing an event of interest between two treatment arms, Arm 1 and Arm 
2, with interest lying in detecting excess event risk in Arm 1 if it exists. This is equivalent to 
comparing the composite null hypothesis that the odds ratio  of Arm 1 to Arm 2 equals 1 
versus the alternative hypothesis that  > 1. 
At a given point during the study, let , denote the current number of participants who are 
evaluable for the event’s occurrence, , be the current number of evaluable participants on 
treatment arm -,  be a binary indicator of whether the . participant on treatment arm - 
had an event, and / = ∑

1
=1
 be the total number of events observed in treatment arm -. If 
we condition on the total number of events / = /1 + /2, the distribution of /1 is known to 
follow Fisher’s noncentral hypergeometric distribution with probability mass function 
(/1|, /) =
345
657348
68765
∑
45
9 3 48
6−979
min (45,6)
9>max (A,6−48)
.  


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Then the conditional likelihood of  given / can be written as B() = (|/) = (/1|, /), 
which is a monotone function of /1. Thus, it is straightforward to apply the SPRT toward a 
sequential test comparing events rates. 
The SPRT can be derived with reference to point null and alternative hypotheses, 0: = 1 
and 1:  = 1 for some value 1 > 1 chosen to indicate unacceptably elevated risk in Arm 1 
compared to Arm 2. The sequential test that we employ modifies this SPRT in two ways: 
1) Only early stopping to reject 0 is included in order to exercise enhanced vigilance in 
safety monitoring 
2) The test is truncated at a prespecified number of evaluable participants 0 such that, if 
0 is not rejected after all 0 participants become evaluable, 0 will be accepted 
Therefore, our testing procedure will reject 0 after the ,. participant becomes evaluable if 
the likelihood ratio  =
CD()
CD(1) exceeds  = (1  )/ for , = 1, … , 0. Because this is a 
modification of the standard SPRT, operating characteristics should be simulated to assess 
its performance across a range of values for the true event probabilities ( = 1) for Arms 
1 and 2. 
 


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APPENDIX G: BMT CTN INFECTION GRADING TABLE AND RECURRENCE 
INTERVAL DEFINITIONS 
 
Type of Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
Bacterial 
infections 
Bacterial focus NOS 
requiring no more than 
14 days of therapy for 
treatment (e.g urinary 
tract infection) 
Bacteremia (except 
CoNS) without severe 
sepsis *** 
Bacteremia with deep 
organ involvement (e.g. 
with new or worsening 
pulmonary infiltrates; 
endocarditis) 
 
Coag Neg Staph (S. epi), 
Corynebacterium, or 
Proprioniobacterium 
bacteremia 
Bacterial focus with 
persistent signs, 
symptoms or persistent 
positive cultures requiring 
greater than 14 days of 
therapy 
Severe sepsis with 
bacteremia. 
 
Cellulitis responding to 
initial therapy within 14 
days 
Cellulitis requiring a 
change in therapy d/t 
progression 
Localized or diffuse 
infections requiring 
incision with or without 
drain placement 
Fasciitis requiring 
debridement  
 
 
Any pneumonia 
documented or presumed 
to be bacterial 
Pneumonia requiring 
intubation 
Brain abscess or 
meningitis without 
bacteremia 
 
C. Difficile toxin positive 
stool with diarrhea < 
1L without abdominal 
pain (child < 20 mL/kg) 
C. Difficile toxin positive 
stool with diarrhea > 1L 
(child > 20 mL/kg) or with 
abdominal pain 
C. Difficile toxin positive 
stool with toxic dilatation 
or renal insufficiency 
with/without diarrhea 
Fungal infections 
Superficial candida 
infection (e.g. oral thrush, 
vaginal candidiasis) 
 
Candida esophagitis 
(biopsy proven). 
Proven or probable fungal 
sinusistis confirmed 
radiologically without 
orbital, brain or bone 
involvement. 
Fungemia including 
Candidemia 
Proven or probable 
invasive fungal infections 
(e.g., Aspergillus, Mucor, 
Fusarium, Scedosporium). 
 
 


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Type of Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
Fungal infections 
continued 
 
 
Disseminated infections 
(defined as multifocal 
pneumonia, presence of 
urinary or blood antigen, 
and/or CNS involvement) 
with Histoplasmosis, 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus. 
Pneumocystis jiroveci 
pneumonia (regardless of 
PaO2 level) 
Viral infections 
Mucous HSV infection 
 
 
 
Dermatomal Zoster 
VZV infection with 3 or 
more dermatomes 
Severe VZV infection 
(coagulopathy or organ 
involvement) 
 
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 
2/3 of the baseline value 
after 2 weeks of therapy 
Clinically active CMV 
infection (e.g. symptoms, 
cytopenias) or CMV 
Viremia not decreasing by 
at least 2/3 of the baseline 
value after 2 weeks of 
therapy 
CMV end-organ 
involvement (pneumonitis, 
enteritis, retinitis) 
 
EBV reactivation not 
treated with rituximab 
EBV reactivation requiring 
institution of therapy with 
rituximab 
EBV PTLD 
 
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia not 
requiring treatment 
Adenoviral upper 
respiratory infection, 
viremia, or symptomatic 
viruria requiring treatment 
Adenovirus with end-
organ involvement (except 
conjunctivitis and upper 
respiratory tract) 
 
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a 
viral load decline by at 
least 0.5 log after 2 
weeks of therapy 
Clinically active HHV-6 
infection (e.g. symptoms, 
cytopenias) or HHV-6 
viremia without viral load 
decline 0.5 log after 2 
weeks of therapy 
 
 
BK viremia or viruria with 
cystitis not requiring 
intervention 
BK viremia or viruia with 
clinical consequence  
requiring prolonged 
therapy and/or surgical 
intervention 
 
 
 
Enterocolitis with enteric 
viruses 
 


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Type of Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
Viral infections 
continued 
 
Symptomatic upper tract 
respiratory virus 
Lower tract respiratory 
viruses 
 
Viremia (virus not 
otherwise specified) not 
requiring therapy 
Any viremia (virus not 
otherwise specified) 
requiring therapy 
 
 
 
 
Any viral encephalitis or 
meningitis 
Parasitic 
infections 
 
 
CNS or other organ 
toxoplasmosis 
Strongyloides 
hyperinfection 
Nonmicrobiologic
ally defined 
infections 
Uncomplicated fever with 
negative cultures 
responding within 14 
days 
 
Clinically documented 
infection not requiring 
inpatient management 
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation 
Any acute pneumonia 
requiring mechanical 
ventilation 
 
 
Typhlitis 
 
 
 
 
Severe sepsis*** without 
an identified organism 
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the higher grade of 
severity. 
**Therapy includes both PO and IV formulations 
***Severe Sepsis: 
 
Adults: 
Hypotension 
-A systolic blood pressure of <90 mm Hg or a reduction of >40 mm hg from baseline in 
the absence of other causes for hypotension 
Multiple Organ Dysfunction Syndrome 
-2 or more of the following: Renal failure requiring dialysis, respiratory failure requiring 
bipap or intubation, heart failure requiring pressors, liver failure 
 
Disseminated Infections: 
1. Two or more non-contiguous sites with the SAME organism 
2. A disseminated infection can occur at any level of severity, but most will be grade 2 
or 3. 


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Recurrence Intervals to Determine Whether an Infection is the Same or New: 
1. CMV, HSV, EBV, HHV6: 2 months (< 60 days) 
2. VZV, HZV: 2 weeks (< 14 days) 
3. Bacterial, non-C. difficile: 1 week (< 7 days) 
4. Bacterial, C. difficile: 1 month (< 30 days) 
5. Yeast: 2 weeks (< 14 days) 
6. Molds: 3 months (< 90 days) 
7. Helicobacter: 1 year (< 365 days) 
8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 
days) 
9. Polyomavirus (BK virus): 2 months (< 60 days) 
 
For infections coded as “Disseminated” per the Infection Form, any previous infection with 
the same organism but different site within the recurrence interval for that organism will be 
counted as part of the disseminated infection. 
 


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APPENDIX H: LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AAT 
Alpha-1 Antitrypsin 
ABW 
Actual Body Weight 
ADA 
Anti-Drug-Antibody 
AE 
Adverse Event 
AIBW 
Adjusted Ideal Body Weight 
Allo-HSCT 
Allogeneic Hematopoietic Stem Cell Transplantation 
ATG 
Anti-Thymocyte Globulin 
AUC 
Areas Under the Time-Concentration Curves 
B-cells 
B Lymphocytes 
BAT 
Best Available Therapy 
BSA 
Body Surface Area 
BMI 
Body Mass Index 
Cmax 
Peak Concentration 
CBC 
Complete Blood Count 
CD3/TCR 
CD3 T-Cell Receptor 
CI 
Confidence Interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CK 
Creatine Kinase 
CLL 
Chronic Lymphocytic Leukemia 
CLS 
Capillary Leak Syndrome 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitor 
CR 
Complete Response, the disappearance of symptoms in all organ 
systems 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRFs 
electronic Case Report Forms 
CTCAE 
Common Terminology Criteria for Adverse Events 
DoCR 
Duration of Complete Response 
DRI 
Disease Risk Index 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr Virus 
EDC 
Electronic Data Capture 
ERC 
Endpoint Review Committee 
FDG 
Fluoro-deoxyglucose 
GCP 
Good Clinical Practice 
GI 
Gastro-intestinal 
GVHD 
Graft-Versus-Host Disease 
aGVHD 
(acute) Graft-Versus-Host Disease 
cGVHD 
(chronic) Graft-Versus-Host Disease 


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List of Abbreviations and Definitions of Terms 
 
SR-aGVHD 
Steroid-refractory (acute) Graft-Versus-Host Disease 
HCT 
Hematopoietic Cell Transplantation 
IBW 
Ideal Body Weight 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
JAK 
Janus Kinase 
mAb 
Monoclonal Antibody 
MMF 
Mycophenolate Mofetil 
MOP 
Manual of Procedures 
MTX 
Methotrexate 
NIH 
National Institutes of Health (USA) 
NK cells 
Natural Killer Cells 
NR 
Non-Responder; No Response, Progression/Relapse of aGVHD or 
death by the end of Day 28 
NRM 
Non-Relapse Mortality 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease, progression in 1 or more organ-systems resulting 
in a worsening of overall at least one Grade, without improvement in any 
other organs 
PET 
Positron Emission Tomography 
PHA 
Phytohemagglutinin 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response, the improvement of 1 or more organs, with no 
worsening in other organs 
PRO 
Patient Reported Outcomes 
Progression/Malignancy 
Relapse 
The time from the date of the start of treatment to the date of 
hematologic malignancy relapse/progression. 
REG3α 
Regenerating Family Member 3 Alpha 
RFS 
Relapse Free Survival 
RTA 
Ricin Toxin A-chain 
SAE 
Serious Adverse Event 
SCTOD 
Stem Cell Transplant Outcomes Database 
SoC 
Standard of Care 
SOS/VOD 
Sinusoidal obstruction syndrome/veno-occlusive disease 


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List of Abbreviations and Definitions of Terms 
 
SPRT 
Sequential Probability Ratio Test 
SPV-T3a 
Anti-CD3, IgG2b 
SR 
Steroid-refractory 
ST2 
Interleukin 1 receptor-like 1 
t1/2 
Terminal-phase Elimination Half-life 
T cells 
T Lymphocytes 
TCR 
T-cell Receptor 
TEAE 
Treatment Emergent Adverse Event 
TMA 
Thrombotic Microangiopathy 
WT1 
Anti-CD7, IgG2a 
3-IS 
3-Indoxyl Sulfate 


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APPENDIX I: REFERENCES 
 
Aandahl, E. M., M. F. Quigley, W. J. Moretto, M. Moll, V. D. Gonzalez, A. Sonnerborg, S. Lindback,  
F. M. Hecht, S. G. Deeks, M. G. Rosenberg, D. F. Nixon and J. K. Sandberg (2004). "Expansion of 
CD7(low) and CD7(negative) CD8 T-cell effector subsets in HIV-1 infection: correlation with antigenic 
load and reversion by antiretroviral treatment." Blood 104(12): 3672-3678. 
Aandahl, E. M., J. K. Sandberg, K. P. Beckerman, K. Tasken, W. J. Moretto and D. F. Nixon (2003). 
"CD7 is a differentiation marker that identifies multiple CD8 T cell effector subsets." J Immunol 170(5): 
2349-2355. 
Akbar, A. N., P. L. Amlot, K. Ivory, A. Timms and G. Janossy (1990). "Inhibition of alloresponsive 
naive and memory T cells by CD7 and CD25 antibodies and by cyclosporine." Transplantation 50(5): 823-
829. 
Ali, H., Snyder, D., Stiller, T., Synold, T., Mokhtari, S., Palmer, J., Salhotra, A., Pullarkat, V. A., Cai, J., 
Forman, S. J., Mei, M., Nakamura, R., “Peri-Transplant Administration of Ruxolitinib Is Safe and 
Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib 
Administration in Combination with Reduced Intensity Conditioning.” Blood 2019; 134 
(Supplement_1): 669 
Alousi, A. M., D. J. Weisdorf, B. R. Logan, J. Bolanos-Meade, S. Carter, N. Difronzo, M. Pasquini,  
S. C. Goldstein, V. T. Ho, B. Hayes-Lattin, J. R. Wingard, M. M. Horowitz and J. E. Levine (2009). 
"Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host 
disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network." 
Blood 114(3): 511-517. 
Amlot, P. L., M. J. Stone, D. Cunningham, J. Fay, J. Newman, R. Collins, R. May, M. McCarthy,  
J. Richardson, V. Ghetie and et al. (1993). "A phase I study of an anti-CD22-deglycosylated ricin A 
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APPENDIX J: INVESTIGATOR’S SIGNATURE PAGE 
 
A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY, TO COMPARE  
T-GUARD TO RUXOLITINIB FOR THE TREATMENT OF PATIENTS WITH GRADE III 
OR IV STEROID-REFRACTORY ACUTE GRAFT-VERSUS-HOST DISEASE  
(SR-AGVHD) 
 
BMT CTN PROTOCOL 2002 
Version 1.0 
 
 
Protocol History: 
Version 1.0 ; 21May2021 
 
 
I have read all pages of this clinical study protocol. I agree to conduct the study as outlined in the 
protocol and to comply with all the terms and conditions set out therein. I confirm that I will conduct the 
study in accordance with ICH GCP guidelines and applicable local regulations. I will also ensure that 
other relevant members of my study staff have the appropriate training and access to copies of this 
protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions of these 
documents. 
Principal Investigator: 
 
 
Signature: 
 
 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Site Name: 
 
 
 
 
 
 
 
 


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APPENDIX K: SCHEDULE OF ASSESSMENTS 
Table K-1: Required Assessments for T-Guard Arm 
Assessment 
Prior to 
Random-
ization 
Day of 
Randomization 
and Prior to 
Treatment 
First 
Infusion 
Second 
Infusion 
Third 
Infusion 
Fourth 
Infusion 
Follow-up 
Target study day 
-1 
0 
0 
2 
4 
6 
14 
21 
28* 
35 
42 
49 
56 
70 
90 
1801 
Window (days) 
-3 to -1 
0 
0 to 3 
2 post-
previous 
infusion 
2 post-
previous 
infusion 
2 post-
previous 
infusion 
+/-3 +/-3 +/-2 +/-3 +/-3 +/-3 +/-3 +/-7 +/-7 +/-7 
Study drug administration 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Acute GVHD evaluation, including 
bilirubin 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
X3 
X3 
Chronic GVHD evaluation 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (weight and height) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (temperature, pulse, 
respiratory rate)4 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential and platelet 
count 
X 
X 
X2 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
Albumin 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Renal function (blood urea and/or 
blood urea nitrogen, Creatinine) 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Schistocytes, haptoglobin and 
LDH 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
CK levels5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for CMV and 
EBV viral load 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy test (if applicable)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky performance status 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Pharmacokinetics7, 8 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for Anti-Drug 
Antibody7, 9 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 


BMT CTN 2002/SR aGVHD 
 
Version 1.0 
Protocol 
 
21May2021 
 
NCT# 04934670 
 
 
EudraCT# 2021-000343-53 
CONFIDENTIAL 
Page K-2 
Assessment 
Prior to 
Random-
ization 
Day of 
Randomization 
and Prior to 
Treatment 
First 
Infusion 
Second 
Infusion 
Third 
Infusion 
Fourth 
Infusion 
Follow-up 
Target study day 
-1 
0 
0 
2 
4 
6 
14 
21 
28* 
35 
42 
49 
56 
70 
90 
1801 
Window (days) 
-3 to -1 
0 
0 to 3 
2 post-
previous 
infusion 
2 post-
previous 
infusion 
2 post-
previous 
infusion 
+/-3 +/-3 +/-2 +/-3 +/-3 +/-3 +/-3 +/-7 +/-7 +/-7 
Peripheral blood for GVHD 
biomarkersREG3αandST27 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Peripheral blood mononuclear 
cells (PBMC)7 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Peripheral blood for 
immunophenotyping7 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Urine sample for GVHD biomarker 
3-IS7 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Concomitant medication review10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessment11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Patient-reported outcomes: 
PROMIS 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Infection monitoring 
Reporting of infections at time of occurrence from time of enrollment through Day 180 
Primary disease relapse reporting 
Reporting of relapse at time of occurrence from time of enrollment through Day 180 
1Participants will be followed for survival post Day 180 
2Assessment does not need to be repeated if treatment starts on same day as randomization 
3Patients will be instructed to contact the site when their aGVHD symptoms worsen in between visits Day 70, 90 and 180 
4Vital signs should be taken directly pre-infusion, 15 minutes after the start of the infusion, 30 minutes after the start of the infusion, then every 30 minutes during the infusion, and at 1-hour 
post-infusion. Deviation of +/- 5 minutes may occur for all vital sign collection timepoints. 
5If patients experience muscle pain, then a serum CK should be performed 
6May be performed within 30 days of enrollment 
7Research-specific samples must be drawn after participant signs consent, see APPENDIX B for more details 
8Pharmacokinetic blood samples for T-Guard participants only. Samples directly at pre-infusion and at 4, 5, 6, 8, and 24 hours after start of 1st infusion; pre-infusion and at 4 and 24 
hours after the 2nd and 3rd infusion; and pre-infusion and at 4, 6, 24 and 48 hours after the 4th T-Guard infusion. A window of +/- 15 minutes is allowed for samples drawn at 4 hours after 
the start of infusion, a window of +/-30 minutes for the sample drawn 5, 6, and 8 hours after the start of infusion, and a window of +/- 1 hour for samples drawn 24 and 48 hours after the 
start of infusion. Every effort should be made to collect PK samples at all timepoints; however, no PK sampling is required on weekend days. 
9Blood sample for ADA assessment should be collected for participants in the T-Guard treatment arm only. Day 6 sample should be collected just prior to the 4th dose infusion. 
10All concomitant medications other than immunosuppressant agents will be collected starting at 7 days prior to randomization through 30 days after last dose of T-Guard. For all 
immunosuppressant agents, the overall start and stop date will be captured. For agents where dosing is tapered in response to drug levels, the medication dosing will not require 
reporting. Dosing for corticosteroids will be captured for all dosing changes. 
11AEs and SAEs will be reported as described in Section 4.4 Adverse Event Reporting 
*In the case where T-Guard was started 2 or 3 days after randomization, the Day 28 visit should be scheduled on either Day 29 or 30. If this scheduling is not possible, the Day 28 post-
randomization visit should still be completed within the allotted window and a separate visit should be arranged at Day 28 +/- 2days post T-Guard initiation to collect aGVHD and systemic 
immunosuppression assessments. 
 


BMT CTN 2002/SR aGVHD 
 
Version 1.0 
Protocol 
 
21May2021 
 
NCT# 04934670 
 
 
EudraCT# 2021-000343-53 
CONFIDENTIAL 
Page K-3 
Table K-2: Required Assessments for Ruxolitinib Arm 
Assessment 
Prior to 
Random-
ization 
Day of 
Randomization 
and Prior to 
Treatment 
Treatment and Follow-up 
Target study day 
-1 
0 
0 
6 
14 
21 
28 
35 
42 
49 
56 
70 
90 
1801 
Window (days) 
-3 to -1 
0 
0 to 3 
+/-3 
+/-3 
+/-3 
+/-2 
+/-3 
+/-3 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
Study drug initiation2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Acute GVHD evaluation, including bilirubin 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
X4 
X4 
Chronic GVHD evaluation 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (weight and height) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential and platelet count 
X 
X 
X3 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
Albumin 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Renal function (blood urea and/or blood 
urea nitrogen, Creatinine) 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Schistocytes, haptoglobin and LDH 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
CK levels5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for CMV and EBV viral load 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Pregnancy test (if applicable)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky performance status 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Peripheral blood for GVHD biomarkers 
REG3αandST27 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Peripheral blood mononuclear cells 
(PBMC)7 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Peripheral blood for immunophenotyping7 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
Urine sample for GVHD biomarker 3-IS7 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Concomitant medication review8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessment9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Patient-reported outcomes: PROMIS 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 


BMT CTN 2002/SR aGVHD 
 
Version 1.0 
Protocol 
 
21May2021 
 
NCT# 04934670 
 
 
EudraCT# 2021-000343-53 
CONFIDENTIAL 
Page K-4 
Assessment 
Prior to 
Random-
ization 
Day of 
Randomization 
and Prior to 
Treatment 
Treatment and Follow-up 
Target study day 
-1 
0 
0 
6 
14 
21 
28 
35 
42 
49 
56 
70 
90 
1801 
Window (days) 
-3 to -1 
0 
0 to 3 
+/-3 
+/-3 
+/-3 
+/-2 
+/-3 
+/-3 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
Infection monitoring 
Reporting of infections at time of occurrence from time of enrollment through Day 180 
Primary disease relapse reporting 
Reporting of relapse at time of occurrence from time of enrollment through Day 180 
1Participants will be followed for survival post Day 180 
2Refer to the pharmacy manual for details of ruxolitinib schedule 
3Assessment does not need to be repeated if treatment starts on same day as randomization 
4Patients will be instructed to contact the site when their aGVHD symptoms worsen in between visits Day 70, 90 and 180 
5If patients experience muscle pain, then a serum CK should be performed 
6May be performed within 30 days of enrollment 
7Research-specific samples must be drawn after participant signs consent, see APPENDIX B for more details 
8All concomitant medications other than immunosuppressant agents will be collected starting at 7 days prior to randomization through Day 44. For all immunosuppressant agents, the 
overall start and stop date will be captured. For agents where dosing is tapered in response to drug levels, the medication dosing will not require reporting. Dosing for corticosteroids will 
be captured for all dosing changes. 
9AEs and SAEs will be reported as described in Section 4.4 Adverse Event Reporting