Conditions: Hodgkin's Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This phase II trial studies how well umbralisib and pembrolizumab work in treating patients with classical Hodgkin lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving umbralisib and pembrolizumab may work better in treating classical Hodgkin lymphoma.

Detailed description:
OUTLINE:

Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 for up to 16 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive umbralisib orally (PO) daily on days 1-21 days. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days, then up to 1 year.

Arms:
arm 1: Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 for up to 16 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive umbralisib PO daily on days 1-21 days. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Pembrolizumab intervention 2: Umbralisib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol document:
ICF_000.pdf: 
 
 
Official Title: 
A Phase II Trial of Umbralisib and Pembrolizumab in 
Patients With Relapsed or Refractory Classical Hodgkin 
Lymphoma   
NCT number: 
NCT03776864 
Document Type:  
Informed Consent Form 
Date of the 
Document: 
January 28, 2021 
 
 


Version 4.0 dated  08 January 2021 
Page 1 of 15 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCHINSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
Consent to take part in a research study: 
CC10075
A Phase II Trial of Umbralisib and Pembrolizumab in Patients with Relapsed or Refractory 
Classical Hodgkin Lymphoma 
Sponsor-Investigator: 
Ryan Lynch, MD 
825 Eastlake Ave. East 
Seattle, WA 98109 
(206) 606-1739
Emergency number (24 hours):  206-598-6190 
University of Washington Medical Center paging operator.  Please ask the operator to page the 
hematology-oncology fellow on call. 
IRO received 01/08/21


 
Version 4.0 dated  08 January 2021 
 
 
Page 2 of 15 
We would like you to join this research study 
 
We are asking you to be in a research study.  Research is not the same as treatment or medical 
care.  The purpose of a research study is to answer scientific questions.  The purpose of this 
consent form is to give you the information you will need to help you decide if you want to be 
in the study.  Please read the form carefully.  You may ask questions about the purpose of the 
research, what we would ask you to do, the possible risks and benefits, your rights as a 
volunteer, and anything else about the research or this form that is not clear.  When we have 
answered all your questions, you can decide if you want to be in the study or not.  This process 
is called ‘informed consent.’  We will give you a copy of this form for your records. 
 
This consent form may contain words that you do not understand.  Please ask the researcher or 
the study staff to explain any words or information that you do not clearly understand.  You 
may take home an unsigned copy of this consent form to think about or discuss with family or 
friends before making your decision. 
 
You do not have to be in the study.  You are free to say “yes” or “no”, or to drop out after 
joining.  If you say “no,” you would have no penalty or loss of benefits.  Whatever you decide, 
your regular medical care would not change.  You could choose to receive standard methods to 
treat your cancer.  
 
We invite you to join this research study because you have relapsed or refractory Classical 
Hodgkin Lymphoma. Up to twenty (20) people will take part in this study.  
 
Please read this description carefully.  We will give you details about the purposes, procedures, 
risks and possible benefits related to this study.  We will explain other choices that you have.  
We will also give you any other information that you need in order to make an informed 
decision about joining this study.  Afterwards, you can ask questions that will help you decide 
whether to join the study.  If you join this study, we would give you a signed copy of this form 
to keep for future reference.  
 
PURPOSE OF THE STUDY 
The purpose of this study is to study the effects (both good and bad) of using Umbralisib in 
combination with Pembrolizumab to treat patients with relapsed or refractory Classical Hodgkin 
Lymphoma. If you join this study, we would give you umbralisib and pembrolizumab and watch 
carefully for any side effects. 
 
Classical Hodgkin Lymphoma is a type of cancer that affects the lymphatic system.  The 
lymphatic system helps to fight infections and disease.   
 
Pembrolizumab (MK-3475, Keytruda ®) is a type of drug that targets cancer cells.  It is approved 
by the U.S. Food and Drug Administration (FDA) has recently been approved to treat individuals 
who have refractory Classical Hodgkin Lymphoma or those who have relapsed after 3 or more 
prior treatments. 


 
Version 4.0 dated  08 January 2021 
 
 
Page 3 of 15 
 
Umbralisib belongs to a new class of drugs called “PI3K delta inhibitors”. Umbralisib stops 
affected lymphocytes from increasing in numbers and shortens their life time. 
 
Your study doctor can give you more information about the use of this medication. 
 
PROCEDURES 
If you join this study, we would do these tests and procedures.  Most of these procedures are 
considered standard care for patients with relapsed or refractory Classical Hodgkin Lymphoma.  
The tests and procedures which are done only for research purposes are marked clearly below. 
 
Screening/Baseline (within 4 weeks of starting treatment unless otherwise indicated): 
• 
Medical history - You will be asked questions about your medical history.  This includes 
ongoing medical conditions you have and drugs you are taking. 
• 
Physical exam - Physical exams will assess your overall health status and include 
measuring your vital signs.  This includes blood pressure, heart rate, temperature, and 
breathing rate.  Your weight and height will also be recorded.  You will also be asked 
how easily you perform daily activities. 
• 
Routine laboratory tests - Blood samples will be taken for routine tests.  About 2 - 3 
teaspoons of blood will be taken and your blood will be tested for levels for certain 
components to see if it is safe for you to receive treatment.  A little over a teaspoon of 
blood will be taken to test for hepatitis and HIV.   
• 
Pregnancy test - If you are a female who could become pregnant, you will have a 
pregnancy test.  A blood sample will be taken for this test. 
• 
Electrocardiogram (ECG/EKG) - Sticky patches are placed on your chest, arms and legs.  
These patches are connected to a machine which shows the electrical activity of your 
heart.  Radiation is not used to obtain an ECG.  If you’re sensitive to the adhesive on the 
sticky patches, you may have a little redness where the patch was attached to your skin.   
• 
PET Positron Emission Tomography (PET) scans: PET scans use x-rays or radiation to 
allow doctors to see images of the part(s) of your body affected by cancer. 
• 
Optional research lab testing: We will request up to 4 teaspoons of blood will be taken 
for research tests.  The results will not be reported in your medical record. 
• 
Optional diagnostic tissue: We will request 10 slides of your diagnostic tissue, if 
available. 
 
Cycles 1 –16, Day 1 (+/- 3 days):  
• 
Physical exam - Physical exams will assess your overall health status and include 
measuring your vital signs.  This includes blood pressure, heart rate, temperature, and 
breathing rate.  Your weight will also be recorded.  You will also be asked how easily you 
perform daily activities and what drugs you are taking. 
• 
Routine laboratory tests - Blood samples will be taken for routine tests.  About a 
teaspoon of blood will be taken and your blood will be tested for levels for certain 
components to see if it is safe for you to receive treatment.  
• 
Side effects assessment (adverse events) – Questions about symptoms and side effects 


 
Version 4.0 dated  08 January 2021 
 
 
Page 4 of 15 
will be part of each visit, to determine what side effects that you are experiencing 
during treatment.  
• 
Research lab testing: Up to 4 teaspoons of blood will be taken for research tests at day 
1 of every cycle.  The results will not be reported in your medical record. 
 
Umbralisib alone - Every 4th cycle starting with Cycle 17 (e.g. 17, 21, 25, etc) until the end of 
treatment, Day 1 (+/- 3 days):  
 
• 
Physical exam - Physical exams will assess your overall health status and include 
measuring your vital signs.  This includes blood pressure, heart rate, temperature, and 
breathing rate.  Your weight will also be recorded.  You will also be asked how easily you 
perform daily activities and what drugs you are taking. 
• 
Routine laboratory tests - Blood samples will be taken for routine tests.  About a 
teaspoon of blood will be taken and your blood will be tested for levels for certain 
components to see if it is safe for you to receive treatment.  
• 
Side effects assessment (adverse events) – Questions about symptoms and side effects 
will be part of each visit, to determine what side effects that you are experiencing 
during treatment. 
 
Off-study visit (end of treatment visit): 
• 
Physical exam - Physical exams will assess your overall health status and include 
measuring your vital signs.  This includes blood pressure, heart rate, temperature, and 
breathing rate.  Your weight will also be recorded.  You will also be asked how easily you 
perform daily activities. 
• 
Routine laboratory tests - Blood samples will be taken for routine tests.  About a 
teaspoon of blood will be taken and your blood will be tested for levels for certain 
components to see if it is safe for you to receive treatment.  
• 
Side effects assessment (adverse events) – Questions about symptoms and side effects 
will be part of each visit, to determine what side effects that you are experiencing 
during treatment. 
• 
PET Positron Emission Tomography (PET) scans: PET scans use x-rays or radiation to 
allow doctors to see images of the part(s) of your body affected by cancer. 
 
Long Term Follow-Up: 
• 
Long term follow-up means keeping track of your medical condition. Your medical 
condition will be followed for one (1) year after your end of treatment. In order to do 
this, we will obtain the following information regarding your medical condition: 
o Physical exam - Physical exams will assess your overall health status and 
include measuring your vital signs.  This includes blood pressure, heart rate, 
temperature, and breathing rate.  Your weight will also be recorded.  You will 
also be asked how easily you perform daily activities 


 
Version 4.0 dated  08 January 2021 
 
 
Page 5 of 15 
 
 
RISKS AND DISCOMFORTS  
 
Required 
Studies 
Pre-Entry 
(within 4 weeks 
of cycle 1 day 1 
unless indicated 
otherwise) 
Within 3 
days prior 
to each 
cycle (cycle 
1-16) 
Restaging 
Within 3 days prior to 
every 4th cycle starting 
with cycle 17 while on 
umbralisib alone 
EOT 
Follow-
up 
Physical 
 
 
 
 
 
 
History and 
Physical 
X 
X 
 
X 
X 
 
Performance 
Status 
X 
X 
 
X 
X 
 
Clinical Disease 
Assessment 
X 
X 
 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
 
X 
X 
 
Concomitant 
Medication 
Assessment 
X 
X 
 
X 
X 
 
Lab 
 
 
 
 
 
 
 
TSH, T3, T4, 
LDH, ESR 
X 
 
X 
X 
X 
 
CBC with 
differential 
X 
X 
X 
X 
X 
 
Comprehensive 
metabolic panel 
X 
X 
X 
X 
X 
 
Serum 
Pregnancy test  
X 
 
 
 
 
 
Hepatitis B/C 
serology, , 
direct and 
indirect 
coombs, CMV 
X 
 
 
 
 
 
Radiology 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
PET/CT 
X 
 
X 
 
X 
 
CT 
 
 
X 
 
X 
 
Correlative 
Studies 
X 
X 
X 
 
X 
 


 
Version 4.0 dated  08 January 2021 
 
 
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Risks of Pembrolizumab 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your type of 
cancer.  
 
Pembrolizumab works by helping your immune system to fight your cancer.  
 
However, pembrolizumab can also cause your immune system to attack normal organs and 
tissues in your body and can affect the way they work, which can result in side effects that may 
become serious or life-threatening, and in some cases, may lead to death. 
 
The study doctor believes that the following side effects may be caused by pembrolizumab 
 
Common (greater than 20% of people)  
• Itching of the skin 
• Cough 
• Loose or watery stools 
 
Less Common (greater than or equal to 10% to less than or equal to 20% of people)  
• Joint pain 
• Fever 
• Back pain 
• Rash 
• Low level of salt in the blood that may cause you to feel tired, confused, have a 
headache, muscle cramps, and/or feel sick to your stomach 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have 
infrequent or hard stools 
 
Uncommon (greater than or equal to 1% to less than 10% of people)  
• Inflammation of the lungs so you may feel short of breath and cough. Sometimes this 
condition might lead to death  
• Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools  
• Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, 
feel short of breath at the time of receiving your infusion (IV) or just after, or pain at the 
site of infusion  
• Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus  
• Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (i.e. peeling, itching and redness) could also be 
widespread throughout your body. More severe skin reactions may involve the inside of 


 
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your mouth, the surface of your eye and genital areas, and/or may cause the top layer 
of your skin to peel from all over your body which can cause severe infection. These 
severe conditions can sometimes lead to death  
 
Rare (less than to 1% of people) 
• 
Immune-mediated Inflammation of the nerves that may cause pain, weakness or tingling in 
your hands and feet, and may spread to your legs, arms and upper body leading to severe 
muscle weakness and possible temporary paralysis  
• 
Inflammation of the muscles so you may feel weak or have pain in your muscles  
• 
Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe pain in the top part of your belly that may move to your back, feel sick to 
your stomach, and vomiting that gets worse when you eat  
• 
Inflammation of the eye so you may have redness, blurred vision, sensitivity to light, eye 
pain, see floaters or have headaches  
• 
Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, have a pain in the right side of your belly, yellow 
eyes and skin, and dark urine  
• 
Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick 
to your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness or fainting  
• 
Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which 
could cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and belly 
aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan  
• 
Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination and weight loss. You are likely to need regular insulin shots.  
• 
Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain  
• 
Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath and swelling of the legs. You may experience a fast or irregular heartbeat that may 
cause dizziness or fainting. Sometimes this condition can lead to death  
• 
Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy.  
• 
A condition that may make you feel weak and tired and might have drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing  
• 
The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs  
• 
Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness 
 


 
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Risks of Umbralisib 
 
The following side effects have been reported as at least possibly related to umbralisib in other 
studies:  
Common (greater than or equal to 10%) 
• Anemia (decrease in the number of red blood cells) 
• ALT increase 
• AST increase 
• Blood creatinine increase 
• Diarrhea 
• Fatigue/tiredness 
• Low levels of lymphocytes 
• Low platelet levels 
• Fever 
• Nausea 
• Decrease in number of white blood cells 
• Vomiting  
• Decreased appetite 
• Rash  
 
Uncommon (greater than or equal to 1% to less than 10% of people)  
• Fever with decrease in white blood cells, white blood cells above normal range, 
decreased number of platelets  
• Vision blurred  
• Abdominal bloating, abdominal pain, constipation, dry mouth, indigestion, inflammation 
of the bowel that can cause, severe diarrhea which may require hospitalization  
• Fever, weakness, chills, general discomfort, swelling of hands, arms, legs, ankles, and/or 
feet  
• Yeast infection in the mouth, pneumonia, infection of the mouth or throat  
• Increase in liver enzymes, increase in levels of creatinine in blood which can indicate 
decreased kidney function, increase in lymphocyte count (type of white blood cell), 
weight loss 
• Dehydration, increase in blood sugar levels, decrease in levels of potassium in blood, 
decrease in levels of phosphate in blood which can lead to bone weakness  
• Pain in joints, muscle spasms, pain in arms and/or legs  
• Dizziness, change in taste, headache, numbness and/or tingling of the hands and/or 
feet, involuntary shaking or trembling  
• Difficulty sleeping  
• Cough  
• Hair loss, night sweats, itching  
• Damage to multiple organs (sepsis) 
• Inflammation of the colon (colitis) 


 
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• Edema (swollen limbs) 
• Sepsis including septic shock 
• Maculo-papular rash 
 
Rare (less than to 1% of people) 
• Blood disorders  
• Ringing in the ears 
• Problems with eyesight 
• Gas (flatulence) 
• Stomach pains 
• Mouth sores 
• Pancreas inflammation (Pancreatitis) 
• Fungal skin infections and eczema 
• Tingling in arms, legs and mouth 
• Anxiety, hallucinations or poor memory 
• Erectile Dysfunction  
• Hot flashes 
 
Women who are pregnant or nursing a child may not take part in this study.  Before entering 
the study, you and your study doctor must agree on the method of birth control you will use 
during the entire study.  If you think that you have become pregnant during the study, you 
must tell your study doctor immediately.  Pregnant women will be taken out of the study. 
 
Men who are in this study should not get a sexual partner pregnant while taking the study drug 
and for 4 months after the last dose of study drug.  The effect of the study drug on sperm is not 
known. 
 
Electrocardiogram (ECG/EKG) 
Electrocardiogram (ECG) is a recording of the heart’s beats. An ECG shows the electrical activity 
of the heart. You may have mild irritation, slight redness, or itching at the sites on your skin 
where the recording patches are placed. 
 
Blood Draws 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or get an infection.  
Infection rarely happens.  There may be redness and irritation at the place where the needle 
enters your vein. 
 
Intravenous Line (IV Line) 
Infusion of the Pembrolizumab may cause discomfort, irritation, mild bruising, bleeding, 
leakage of the drug solution, and rarely infection, nausea and lightheadedness. 
 
Radiation risks 
 


 
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Some of the tests that you will have in this research study will expose you to radiation. Everyone 
receives a small amount of radiation every day called “background radiation”. This radiation is 
natural and comes from space, air, water, soil, and the food you eat. Each year you are exposed 
to about 3 milliSieverts (mSv) of this background radiation. A milliSievert is a unit of radiation 
dose. For comparison, the estimated radiation dose from each of these tests is listed below. The 
risk to your health from this level of radiation exposure is too low to be detectable and may be 
nonexistent. 
 
18-FDG PET/CT Scan: 19 mSv 
CT-chest: 7 mSv 
CT-abdomen: 8 mSv 
CT-pelvis: 6 mSv 
CT-head: 2 mSv 
CT-neck: 3 mSv 
 
NEW INFORMATION  
You will be told about any new information that might change your decision to be in this study.  
You may be asked to sign a new consent form if this occurs. 
 
BENEFITS 
 
We do not know if this study would help you. We are testing umbralisib in combination with 
pembrolizumab to see its effects on people with relapsed or refractory Classical Hodgkin 
Lymphoma.  You might get better if you receive umbralisib and pembrolizumab, but your 
condition could stay the same or even get worse. We hope the information from this study will 
help other people with relapsed or refractory Classical Hodgkin Lymphoma in the future. 
 
COSTS 
TG Therapeutics, Inc. will provide the study drug (umbralisib) free of charge during this study. 
The cost of Pembrolizumab will be billed to you or your insurance company. Tests and 
procedures that are done only for the study will not be billed to you or your insurance 
company. 
 
You or your insurance company may be billed for any standard medical care given during this 
research study. 
 
You may want to talk with your insurance company about its payment policy for standard 
medical care given during a research study.  If your insurance company does not pay, you may 
be billed for those charges. 
 
You might have unexpected expenses from being in this study.  Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor.  This discussion should include who 
will pay the costs of treating possible side effects. 
 


 
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Page 11 of 15 
PAYMENT FOR PARTICIPATION  
You will not be paid for taking part in this study. You might have unexpected expenses from 
being in this study. You may want to talk with your insurance company about its payment policy 
for standard medical care given during a research study. If your insurance company does not 
pay, you may be billed for those charges. If you have any questions about what is billed to you 
or your insurance company, you may call a study staff member.  
 
Reimbursement for travel expenses may be available.  Please talk with the Principal Investigator 
or study staff about this option. 
 
ALTERNATIVE TREATMENT  
If you decide not to enter this study, there are other choices available.  Ask the study doctor to 
discuss these alternatives with you.  You do not need to be in this study to receive treatment 
for your cancer. The other choices include: 
 
• Standard treatment 
• Another research study 
• No treatment 
• Comfort care 
 
The study team strongly suggests that you do not take any type of “alternative” or 
“naturopathic” medications because they may interfere with the study medications. 
 
CONFIDENTIALITY 
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. 
 
Your participation in this study will be noted in your UW medical record.  
 
The information may also be given to the U.S. Food and Drug Administration (FDA).  It may be 
given to governmental agencies in other countries where the study drug may be considered for 
approval.  Medical records which identify you and the consent form signed by you will be looked at 
and/or copied for research or regulatory purposes by: 
 
• the sponsor, TG Therapeutics, Inc., and any agent for the sponsor 
• Seattle Cancer Care Alliance, University of Washington and Fred Hutchinson Cancer 
Research Center 
• Fred Hutchinson Cancer Research Center Institutional Review Board (an IRB is a group that 
reviews the study to protect the right and welfare of research participants).  
• Food and Drug Administration (FDA) 
• Office for Human Research Protections (OHRP) 
• Department of Health and Human Services (DHHS) agencies, 


 
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We will do our best to keep personal information confidential. Absolute confidentiality cannot be 
guaranteed because of the need to give information to these parties.  The results of this research 
study may be presented at meetings or in publications.  Your identity will not be disclosed in those 
presentations. Personal information may be given out if required by law. For example, workplace 
safety rules may require health workers to contact you about lab tests. Or a court may order study 
information to be disclosed. Such cases are rare. 
 
If you join this study, information about your participation would be made part of your permanent 
medical record. This information would include a copy of this consent form. If an insurance 
company or employer or anyone else were authorized to see your medical record, they would see a 
copy of this consent form.  
 
COMPENSATION FOR INJURY 
In the event of injury to a research participant, resulting from research procedures, appropriate medical 
treatment will be available at the University of Washington to the injured research participant; however, 
financial compensation will not be offered. 
 
No money has been set aside to pay for things like lost wages, lost time, or pain.  However, you do not 
waive any rights by signing this consent form. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Your participation in this study is voluntary.  You may decide not to participate, or you may 
leave the study at any time.  Your decision will not result in any penalty or loss of benefits to 
which you are entitled. 
 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent for any reason, including: 
• if it is in your best interest, 
• you do not consent to continue in the study after being told of changes in the research that 
may affect you 
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures done so that you leave the study safely. 
 
SOURCE OF FUNDING FOR THE STUDY 
The sponsor TG Therapeutics, Inc. is paying for this research study. 
QUESTIONS 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE RESEARCH STUDY? 
If you have questions about: 
 
Call: 
This study (including complaints 
and requests for information) 
 
206-606-1739 
(Ryan Lynch, MD, Principal Investigator) 
If you get sick or hurt in this study 
 
206-606-1739 (Dr. Ryan Lynch) 
 


 
Version 4.0 dated  08 January 2021 
 
 
Page 13 of 15 
Your 
rights 
as 
a 
research 
participant 
 
206-667-5900 
or 
email 
irodirector@fredhutch.org 
(Director of Institutional Review Office, Fred Hutchinson 
Cancer Research Center) 
 
206-543-0098 (Human Subjects Division, University of 
Washington) 
Your bills and health insurance 
coverage 
 
206-606-1377 (Patient Financial Services, Seattle Cancer 
Care Alliance) 
24-hour emergency number 
 
(206) 598-6190 (UWMC Paging Operator) 
 
Contact Ryan Lynch, MD at (206) 606-1739 for any of the following reasons: 
• if you have any questions about your participation in this study,   
• if you feel you have had a research-related injury or a reaction to the study drug, or 
• if you have questions, concerns or complaints about the research 
 
You may also contact: 
Human Subjects Division 
University of Washington 
Box 359470 
Seattle, Washington  98195-9470 
Telephone:  206-543-0098 
(You may also call collect at 206-221-5940 if you do not otherwise have access to a 
telephone) 
Email:  hsdinfo@uw.edu  
 
Do not sign this consent form unless you have had a chance to ask questions and have gotten 
satisfactory answers. 
 
If you agree to be in this study, you will receive a signed and dated copy of this consent form for 
your records 
 
CONSENT 
 
I have read this consent form (or it has been read to me).  All my questions about the study and 
my part in it have been answered.  I freely consent to be in this research study. 
 
By signing this consent form, I have not given up any of my legal rights. 
 
 I agree to have the optional blood draws collected as part of this Study. 
 
 I do NOT agree to have the optional blood draws collected as part of this Study. 
 
 I agree to allow the collection of my tissue from my diagnosis, if available.  


 
Version 4.0 dated  08 January 2021 
 
 
Page 14 of 15 
 
 I do NOT agree to allow the collection of my tissue from my diagnosis, if available.  
 
 
 
________________________________________ 
Subject Name (printed) 
 
 
 
________________________________________ 
 
__________________ 
Signature of Subject 
 
 
Date 
 
 
 
________________________________________ 
Person Conducting Informed Consent (printed) 
 
 
 
________________________________________ 
 
 
__________________ 
Signature of Person Conducting Informed 
 
 
 
 
Date 
Consent Discussion 
 
 
 
---------------------------- Use this section only if applicable ------------------------- 
 
If this consent form is read to the subject because the subject is unable to read the form, an 
impartial witness not affiliated with the research or investigator must be present for the 
consent and sign the following statement: 
 
I confirm that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the subject.  The subject freely 
consented to be in the research study. 
 
 
________________________________________ 
Printed Name of the Impartial Witness 
 
 
_______________________________________ 
_______________________________ 
Signature of the Impartial Witness                                                                               Date 
FHCRC IRB Approval  
JAN 28 2021 
Document Released Date


 
Version 4.0 dated  08 January 2021 
 
 
Page 15 of 15 
 
If you served as an interpreter or witness during the consent process, sign below to indicate you 
attest to the accuracy of the presentation to the participant and the apparent understanding of 
the research by the participant.  
 
 
________________________________________ 
Printed Name of Interpreter 
 
 
_________________________________________ 
______________________________ 
Signature of Interpreter 
                               Date 
 
Copies to: 
Researcher’s file 
 
 
Subject 
 
 
Subject’s medical record (if applicable) 
 

Prot_SAP_002.pdf: 
 
 
Official Title: 
A Phase II Trial of Umbralisib and Pembrolizumab in 
Patients With Relapsed or Refractory Classical Hodgkin 
Lymphoma   
NCT Number: 
NCT03776864 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
10/29/2021 
 
 


Protocol version 4.0 dated 12 November 2020 
 
Page 1 of 37 
 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCHINSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
 
A Phase II Trial of Umbralisib and Pembrolizumab in Patients with Relapsed or 
Refractory Classical Hodgkin Lymphoma 
 
Protocol Version 4.0 Dated 12 November 2020 
 
Sponsor/Principal Investigator:   
 
 
 
 
 
  
Ryan Lynch, MD 
Assistant Professor, University of Washington 
Assistant Member, Fred Hutchinson Cancer Research Center 
Seattle Cancer Care Alliance 
825 Eastlake Ave. E, CE3-300 
Seattle, WA  98109 
Telephone: (206) 606-1739 
 
 
Statistical Consultant 
Qian (Vicky) Wu, PhD- Assistant Member, FHCRC  
 
This trial is supported by a grant from TG Therapeutics, Inc.  
Tracking Number:  TGR-NTG-001 
 
 
Previous Protocol Version (Dates): 
1.0 dated 01 March 2019 
2.0 dated 07 October 2019 
3.0 dated 20 August 2020 
 
 
IRO received 10/06/21
FHCRC IRB Approval  
10/29/2021 
Document Released Date


 Protocol version 4.0 dated 11 November 2020 
 
Page 2 of 37 
 
SCHEMA 
 
Registration 
 
Cycles 1-16 
Umbralisib 800 mg PO daily day 1-21 
Pembrolizumab 200 mg IV day 1 
Cycle length: 21 days 
 
 
 
Continue therapy until disease progression, unacceptable toxicity or the discretion of 
subject/investigator 
 
 
 
Cycle 17 and beyond 
Umbralisib 800 mg PO daily day 1-21 
 
 
 
Continue therapy until disease progression, unacceptable toxicity or the discretion of 
subject/clinician  
 
 
 
Follow up for 1 year after enrollment for survival and remission status for subjects on study 
for < 1 year 
 
 
 


 Protocol version 4.0 dated 11 November 2020 
 
Page 3 of 37 
 
 
 
TABLE OF CONTENTS: 
1.0 
Objectives  ................................................................................................................. 4 
2.0 
Background and Rationale ........................................................................................ 4 
3.0 
Drug Information ....................................................................................................... 6 
4.0 
Staging Criteria .......................................................................................................... 9 
5.0 
Eligibility Criteria  ..................................................................................................... 9 
6.0 
Registration  ............................................................................................................... 11 
7.0 
Treatment Plan  .......................................................................................................... 11 
8.0 
Dosage Modifications  ............................................................................................... 14 
9.0 
Study Calendar  ......................................................................................................... 19 
10.0 
Criteria for Evaluation and Endpoint Definitions ..................................................... 21 
11.0 
Statistical Considerations .......................................................................................... 21 
12.0 
Study Monitoring and Reporting Procedures ............................................................ 21 
13.0 
Elements of Informed Consent  ................................................................................. 26 
14.0 
Administrative and Regulatory Considerations  ........................................................ 26 
15.0 
References ................................................................................................................. 27 
16.0 
Appendices ................................................................................................................ 27 
 
  
 


 Protocol version 4.0 dated 11 November 2020 
 
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1.0 
OBJECTIVES 
 
1.1 
Primary objective: To estimate the proportion of subjects with relapsed/ 
refractory classical Hodgkin Lymphoma (CHL) who achieve a complete 
response (CR) with a regimen of umbralisib (oral, daily) and pembrolizumab 
(IV, day 1 of 21-day cycles).  
 
1.2 
Secondary objective: Overall response rate (ORR) and safety of this regimen.  
 
1.3 
Exploratory objective: 1-year overall survival (OS) and progression free survival 
(PFS), association of biomarkers with response.  
 
2.0 
BACKGROUND  
 
Main Scientific Question: 
 
The fundamental scientific question of this proposal is to evaluate the efficacy and 
safety profile of dual targeting of the immune microenvironment by means of PD1 
blockade and PI3Kδ inhibition as well as direct targeting of the tumor cell by blocking 
PI3Kδ in patients with relapsed/ refractory classical Hodgkin Lymphoma (CHL). 
Single agent anti-PD1 therapy can induce high overall response rates in CHL, but few 
patients achieve complete remissions1,2. Likewise, single agent PI3Kδ inhibition can 
induce responses in about 20% of patients with relapsed/refractory CHL3. Preclinical 
data indicate that inhibiting PI3Kδ inactivates regulatory T-cells (Tregs) and 
potentially myeloid-derived suppressor cells (MDSCs)4, which may further contribute 
to the antitumor effect of PD1-inhibition. This trial will build on this work by testing 
the safety of dual targeting of the immune microenvironment by means of combining 
the anti-PD1 agent pembrolizumab (approved for relapsed CHL) and a novel PI3Kδ 
inhibitor, umbralisib. This question will be addressed by means of a clinical trial to 
assess the CR rate of this combination in relapsed/refractory CHL. Secondary and 
exploratory endpoints include safety with attention paid to immune-related toxicities 
as well as additional efficacy endpoints of this combination in patients who are anti-
PD1 naïve and anti-PD1-refractory. Correlative endpoints may include assessment of 
PD1 and PDL1 by IHC, del 9p24.1 by FISH, and monocytic MDSC 
(CD11b+CD14+CD33+) and granulocytic MDSC (CD11b+CD66b+) by flow 
cytometry, cytokine profiles, and circulating tumor DNA. 
 
Rationale and background for scientific question: 
Unmet Medical Need:  
 
Relapsed CHL remains an area of unmet medical need despite the approval of three 
novel agents in the last 7 years (brentuximab vedotin [BV] – 2011, nivolumab- 2016, 
pembrolizumab- 2017). Only about 1/3 of patients with relapsed CHL will achieve a 
CR following BV and ~10% will attain long term remissions3. Likewise, 
pembrolizumab and nivolumab induce complete remissions in ~15% of patients and 
the long-term durability is unknown1,2. Despite the clear benefit of these agents, most 


 Protocol version 4.0 dated 11 November 2020 
 
Page 5 of 37 
 
patients will not achieve complete remission or be cured, and improved options are 
needed for relapsed or refractory CHL.  
 
CHL as an immune responsive malignancy: 
CHL represents the prototype of tumor immune evasion with often <1% of the 
involved node representing malignant Reed-Sternberg cells. The majority of the tissue 
is made of an ineffective inflammatory infiltrate predominantly composed of T-cells. 
Early data indicated that expression of PDL1 in tumor cells was associated with poor 
outcome5, leading to evaluation of PD1 blockade in this setting (as described above). 
However, methods to safely augment the anti-tumor immune response to improve on 
the low complete remission rates observed with single agent PD1 blockade have yet to 
be demonstrated. This proposal will evaluate a novel method of augmenting the 
immune response via concurrently targeting the PI3Kδ pathway along with PD1 
blockade.  
PI3K inhibition in CHL: 
 
PI3K is known to mediate key components of cellular signaling. PI3K isoforms in 
CHL patient samples demonstrated expression of the δ isoform in 81% of Reed-
Sternberg cells, suggesting that this isoform may serve as a viable target in this 
disease6. Importantly, treatment of CHL cell lines with the PI3Kδ inhibitor idelalisib 
in a stromal cell co-culture resulted in a decrease in stroma-produced pAKT (thought 
to support CHL survival) and CHL derived CCL-5 (thought to promote stromal cell 
function). In addition to the tumor-microenvironment effects, PI3Kδ inhibition also 
directly induced cell cycle arrest and apoptosis within the CHL cells. We carried out a 
pilot trial evaluating PI3Kδ inhibition with idelalisib in 25 patients with relapsed/ 
refractory CHL7. These patients had received a median of 5 prior therapies and 92% 
had disease progression following brentuximab vedotin. Responses were initially 
observed in 3 of 24 response-evaluable patients (12.5%) and 17/24 (71%) showed 
decrease in disease burden. Longer follow up demonstrated an overall response rate of 
20%7. These data indicate that single agent PI3Kδ targeting was tolerable and yields 
real, though modest response rates in CHL and sets the stage for further improvements 
of PI3K targeting in CHL. Since this trial was completed, additional data indicate that 
blockade of PI3Kδ directly inhibits MDSCs and Tregs, potentially further augmenting 
the immune response4. 
 
Combinations of PI3Kδ inhibition and PD1 blockade: 
 
Umbralisib is a highly specific and orally available PI3Kδ inhibitor with nanomolar 
inhibitory potency, and high selectivity over the alpha, beta, and gamma isoforms8. 
The PI3Ks are a family of enzymes involved in various cellular functions, including 
cell proliferation. survival, and differentiation, as well as intracellular trafficking and 
immunity4,9. The delta isoform of PI3K is highly expressed in cells of hematopoietic 
origin, and is strongly upregulated and often mutated in various hematologic 
malignancies10. Inhibition of PI3Kδ signaling with umbralisib has demonstrated robust 
activity in both CLL and B cell lymphoproliferative disorders with a toxicity profile 


 Protocol version 4.0 dated 11 November 2020 
 
Page 6 of 37 
 
that appears to be superior to idelalisib11.  
 
Importantly, a multi-center phase I/II trial evaluating umbralisib in combination with 
pembrolizumab (and anti-CD20 antibody ublituximab) for patients with 
relapsed/refractory CLL has been initiated. This study, which is open at our center  has 
completed the dose escalation phase and has shown that full dose checkpoint 
inhibition (pembrolizumab 200 mg) can be safely combined with full dose umbralisib 
at 800mg/day12. The dose escalation portion tested two different doses of 
pembrolizumab (100 mg and 200 mg every 3 weeks). A dose limiting toxicity (DLT) 
was reached with pembrolizumab 200 mg dosing of elevated liver function tests. 
Therapy was interrupted, and the patient was re-challenged without re-occurrence of 
the abnormality. No maximum tolerate dose was reached, therefore pembrolizumab 
200 mg was chosen as the dose to proceed in phase II studies.  
 
Updated toxicity was presented in 201913. Grade 3-4 transaminitis occurred in 4/20 
(20%) of subjects. Other grade 3-4 non-immune related adverse events include 
neutropenia (40%), thrombocytopenia (15%), nausea (5%), and anemia (5%). Earlier 
data presented12 showed other grade 3-4 events included rash, back pain, asthenia, 
elevated triglycerides, and hypophosphatemia. 
 
 
  
Summary of Rationale and Background: 
 
Treatment for relapsed CHL remains an unmet need. Targeting the microenvironment 
with PD1 blockade can yield responses in CHL, but the vast majority are partial 
responses and methods to augment the activity of anti-PD1 therapy are needed, but not 
known. PI3K isoforms including δ are overexpressed in CHL and preclinical data 
indicate that targeting these kinases can induce both direct antitumor effects as well as 
indirect efficacy via impacting the inflammatory microenvironment. Clinical data 
indicate that single agent targeting of PI3Kδ using idelalisib can yield tumor reduction 
in the majority of patients and objective responses in 20%. This study builds on both 
the data regarding PD1 and PI3K blockade in CHL to develop a safe combination 
regimen with these 2 classes of drugs.  
 
3.0 
DRUG INFORMATION 
 
3.1 
Pembrolizumab 
 
Pembrolizumab must be obtained from commercial sources.  Please refer to the 
current FDA-approved package inserts or prescribing information for 
information about possible side effects and instructions for preparation, 
handling, dosing and storage of pembrolizumab. 
 
3.1.1 Adverse Reactions in >10% of Patients with Hodgkin Lymphoma treated 
with pembrolizumab (Merck&Co. Inc., 2017)  


 Protocol version 4.0 dated 11 November 2020 
 
Page 7 of 37 
 
 
• General Disorders and Administration Site Conditions: Fatigue 
(26%; grade 3: 1%), pyrexia (24%; grade 3: 1%)  
• Respiratory, Thoracic and Mediastinal Disorders: Cough (24%; 
grade 3: 0.5%), dyspnea (11%; grade 3: 1.0%)  
• Musculoskeletal 
and 
Connective 
Tissue 
Disorders: 
Musculoskeletal pain (21%; grade 3: 1%), Arthralgia (10%; grade 3: 
0.5%)  
• Gastrointestinal Disorders: Nausea (13%; grade 3: 0%), diarrhea 
(20%; grade 3: 1.4%), vomiting (15%; grade 3: 0%)  
• Skin and Subcutaneous Tissue Disorders: Pruritus (11%; grade 3: 
0%), Rash (20%; grade 3: 0.5%) 
• Endocrine Disorders: Hypothyroidism (14%; grade 3: 0.5%)  
• Infections and Infestations: Upper respiratory tract infection (13%; 
grade 3: 0%)  
• Nervous System Disorders: Headache (11%; grade 3: 0.5%), 
Peripheral neuropathy (10%; grade 3: 0%) Selected Laboratory 
Abnormalities Worsened from Baseline Occurring in ≥ 15% of 
Patients with Hodgkin Lymphoma  
• Hypertransaminasemia (34%; Grade 3/4: 2%)  
• Alkaline phosphatase increased (17%; grade 3/4: 0%)  
• Creatinine increased (15%; grade 3/4: 0.5%)  
• Anemia (30%; grade 3/4: 6%) • Thrombocytopenia (27%; grade 
3/4:4%)  
• Neutropenia (24%; grade 3/4: 7%)  
 
Other clinically important adverse reactions that occurred in less than 
10% of patients with CHL included infusion reactions (9%), 
hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% 
each), myelitis and myocarditis (0.5% each). 
 
Please refer to the FDA approved prescribing information for the 
most up to date information including warning and precautions 
(Merck&Co Inc., Prescribing Information; 2017) 
  
3.2 
Umbralisib 
Classification: Dual inhibitor of Phosphatidylinositol-3-Kinase (PI3K) Delta 
and casein kinase 1 epsilon (CK1ε)  
Formulation: See Investigator Brochure 
Mode of Action: Irreversibly inhibits activity of the Class I Delta isoform of 
PI3K  
How Supplied: 200 mg tablets  


 Protocol version 4.0 dated 11 November 2020 
 
Page 8 of 37 
 
Storage: Store between 20°C and 25°C. Excursions permitted 15°C to 30°C.  
Do not freeze. 
The Investigator’s Brochure (IB) is the primary source for safety information. 
The umbralisib IB includes a summary of adverse event data and discussion on 
potential risks that have been observed or may be predicted to occur with this 
study drug. Refer to the most recent IB, which is updated periodically, for 
current information on umbralisib. 
 
4.0 
STAGING CRITERIA AND RISK STRATIFICATION 
 
4.1 
The Ann Arbor staging criteria will be utilized; Stage will be scored as maximal 
stage since diagnosis. This information will be reported with the results, but will 
not impact dosing or treatment duration. 
4.2 
Bulk will be defined as the long axis of the single largest nodal mass measuring 
> 10 cm. This information will be reported with the results, but will not impact 
dosing or treatment duration. 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Inclusion Criteria 
1. Relapsed or refractory CHL that has received at least 1 prior line of 
therapy. 
2. Measurable FDG-avid disease defined by standard criteria (Lugano 2014)14 
and a minimum of 1.0 cm in diameter. 
3. Prior treatment with anti-PD1 or anti-PDL1 therapy is allowed.  
a. Patients who are currently on anti-PD1 or anti-PDL1 therapy who have 
failed to achieve a CR after at least 18 weeks of treatment may enroll 
on study. For these patients, anti-PD1 or anti-PDL1 therapy may be 
delayed for screening and to align pembrolizumab dosing with the 
expected cycle 1 day 1. Patients with progressive disease after prior 
anti-PD1 or anti-PDL1 therapy do not have to be treated for 18 weeks. 
4. ECOG performance status ≤ 2 
5. Male or female ≥ 18 years of age 
6. Ability to swallow and retain oral medication  
7. Willingness and ability to comply with study and follow-up procedures, 
and give written informed consent 
8. Female subjects of childbearing potential must be surgically sterile, be 
post-menopausal (for at least 1 year prior to screening visit), or must have a 
negative serum pregnancy test within 3 days prior to Cycle 1 Day 1 and 
agree to use medically acceptable contraception throughout the study 
period and for 4 months after the last dose of either study drug. Men of 


 Protocol version 4.0 dated 11 November 2020 
 
Page 9 of 37 
 
reproductive potential may not participate unless they agree to use 
medically acceptable contraception throughout the study period and for 4 
months after the last dose of either study drug. (See appendix 3 for further 
detail) 
9. Patients must be expected to receive at least 2 cycles of therapy. 
10. Patients should have a life expectancy if untreated of ≥90 days in the 
opinion of the investigator.  
11. Patients must have a FDG-PET-CT of chest, abdomen, and pelvis within 
42 days of enrollment.  
12. Adequate organ system function, defined below:  
a. Absolute neutrophil count (ANC) > 750 / platelet count > 40,000  
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN)  
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 x ULN (if known liver involvement then ≤5 x ULN is allowed)  
d. Calculated creatinine clearance >30 mL/min (as calculated by the 
Cockcroft-Gault formula)  
5.2  
Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not to be enrolled 
to this study:  
1. Patients receiving cancer therapy (i.e., chemotherapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery and/or tumor embolization, 
prednisone > 10 mg or equivalent) or any investigational drug within 21 
days of Cycle 1 Day 1.  Patients receiving radiation therapy within 14 days 
from Cycle 1 Day 1.  Anti-PD1 or anti-PDL1 therapy in patients with less 
than a CR after 18 weeks of such therapy is permitted to continue on 
schedule. 
2. Discontinuation from prior anti-PD1 or anti-PDL1 therapy due to immune-
related adverse event or any other treatment-related adverse event. 
3. Autologous transplantation within 100 days.  
4. Prior allogeneic transplant within 12 months of initiation on study. 
5. Active GVHD within 90 days prior to Cycle 1 Day 1. 
6. Evidence of active central nervous system lymphoma. 
7. Pregnant or nursing women. 
8. Evidence of chronic active Hepatitis B or chronic active Hepatitis C 
infection (HCV), active cytomegalovirus (CMV), or known history of HIV.  
If HBc antibody, HCV antibody or CMV IgG or CMV IgM is positive, the 
patient should be correspondingly evaluated for the presence of HBV 
DNA, HCV RNA or CMV DNA by PCR to determine presence or absence 
of active infection.  If HBc antibody is positive, the subject must be 
evaluated for the presence of HBV DNA by PCR.  If HCV antibody is 
positive, the subject must be evaluated for the presence of HCV RNA by 


 Protocol version 4.0 dated 11 November 2020 
 
Page 10 of 37 
 
PCR.  Subjects with positive HBc antibody and negative HBV DNA by 
PCR are eligible.  Subjects with positive HCV antibody and negative HCV 
RNA by PCR are eligible.  Subjects who are CMV IgG or CMV IgM 
positive but who are CMV DNA negative by PCR are eligible. 
9. Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), or any drug 
that specifically inhibits phosphoinositide-3-kinase (PI3K)  
10. Evidence of ongoing active systemic bacterial, fungal or viral infection.  
11. Any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY 
Heart Association functional classification III-IV)  
b. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 
months of randomization 
c. Concomitant use of medication known to cause QT prolongation or 
torsades de pointes. Poorly controlled or clinically significant 
atherosclerotic vascular disease including cerebrovascular accident 
(CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular 
stenting within 3 months of randomization. 
12. Patients with other prior malignancies except for adequately treated basal 
cell carcinoma, squamous cell carcinoma of the skin, breast or cervical 
cancer in situ, or other cancer from which the patient has been disease-free 
for 5 years or greater, unless approved by the protocol principal 
investigator. 
13. Patients with an active autoimmune disorder (with the exception of 
autoimmune hemolytic anemia, ITP or vitiligo). 
14. History of non-infectious pneumonitis related to prior line of therapy. 
6.0 
REGISTRATION 
 
6.1 
Subjects must be registered prior to the start of protocol therapy. All of the 
eligibility requirements must have been met. 
 
7.0 
TREATMENT PLAN 
 
7.1 
For treatment or dose modification related questions, please contact Dr. Lynch 
(MedCon may also be used to contact MDs at 206-543-5300). 
 
7.2 
Administration of therapeutic agents:  Each cycle of therapy is given every 21 
days. Pembrolizumab is given on day 1 at a fixed dose of 200 mg IV per standard 
of care. Cycle start date may be +/-3 days from the prior cycle. Infusion details 
should be as per institutional standard of care.  
 
All subjects will start umbralisib at 800 mg daily and this will be given 
continuously throughout the cycle on days 1-21 (see 7.2.1 for more information).   
Pembrolizumab will be continued for a total of 16 cycles on this study, 


 Protocol version 4.0 dated 11 November 2020 
 
Page 11 of 37 
 
regardless of the number of cycles of previous treatment with pembrolizumab 
before entering the study. Patients may discontinue pembrolizumab early based 
on criteria listed in 7.4.5. Umbralisib will be continued indefinitely until disease 
progression or unacceptable toxicity.  The order of administration is not 
specified in this trial.  Further recommendations are listed in section 8. 
 
7.2.1 Guidelines for administration of umbralisib 
 
• Method of Administration: umbralisib will be administered orally once daily 
within 30 minutes of a meal 
• Potential Drug Interactions: No drug Interactions have been reported to date.  
• Prophylaxis: Subjects are required to start prophylaxis treatment with 
Pneumocystis jiroveci pneumonia (PCP) and antiviral therapy prior to cycle 
1 day 1. Prophylaxis should continue throughout the duration of the subject’s 
enrollment on study: 
o Anti-viral Prophylaxis: Valtrex 500 mg daily or Acyclovir 400 mg BID 
or equivalent  
o PCP Prophylaxis: Trimethoprim/Sulfamethoxazole 160 mg/800 mg BID 
on Mondays/Tuesdays (or equivalent) or Dapsone 100 mg daily. 
o Final choice of PCP and antiviral prophylactic therapy is per investigator 
discretion  
o NOTE:  If PCP or anti-viral therapy is not tolerated, alternate to a 
different PCP or anti-viral therapy, discontinue, or reduce dose/schedule 
as per investigator discretion. 
 
7.2.2 Ordering umbralisib (TGR-1202):  Umbralisib is available from TG 
Therapeutics.  Please direct drug orders to 
ISTdrugorder@tgtxinc.com.  The email should include the following:  
Requested quantity of TG Therapeutics study drug (umbralisib), date 
needed, Principal Investigator name, Study title, TG Therapeutics, Inc. 
tracking number (TGR-NTG-001), and Investigational drug pharmacy 
shipping address.  Please allow 5 to 7 business days between drug 
ordering and drug arrival.   
 
7.2.3 Dispensing of umbralisib: If any abnormality on the supplied bottles 
(umbralisib) is observed, the Pharmacist or the appropriate person must 
document that on the acknowledgement of receipt and contact TG 
Therapeutics at productquality@tgtxinc.com. 
 


 Protocol version 4.0 dated 11 November 2020 
 
Page 12 of 37 
 
Before dispensing, the site pharmacist must check that the umbralisib is 
in accordance with the product specifications and the validity is within 
the re-test date.  
 
Subjects must be provided drug in its original container. Subjects 
should be instructed to return all empty bottles and any unused tablets 
when they return to the site. Study drug compliance should be reviewed 
with the patient at clinic visit and as needed. Missed doses will be 
documented in the subject’s research record.  
 
The exact dose and the date of missed doses of umbralisib must be 
recorded within the eCRF, subject’s medical records, and/or in the drug 
accountability records. For the purpose of drug accountability and 
dosing, subjects should record the doses of umbralisib missed on a drug 
diary. Any error in drug administration should be recorded (e.g., missed 
dose). The pharmacist should follow the institution’s SOP regarding 
drug accountability concerning the dispensation of umbralisib.   
 
Umbralisib will be self-administered (by the patient). Tablets should be 
taken at approximately the same time each day within 30 minutes of a 
meal. Subjects should be instructed to swallow the tablets as a whole 
and should not chew or crush them.  
 
If a dose of umbralisib is missed, it should be taken as soon as possible 
on the same day. If it is missed for at least 12 hours, it should not be 
replaced. If vomiting occurs, no attempt should be made to replace the 
vomited dose. 
 
7.3 
Growth factor support: will be at the discretion of the treating team. 
Growth factors should be avoided whenever possible within 10 days of 
FDG-PET imaging. Antibiotic and antiemetic prophylaxis will be per 
institutional standard of care however PJP and anti-viral prophylaxis is 
recommended per standard of care, and it is required during treatment 
with umbralisib (see Section 7.2.1). 
 
7.4 
Criteria for removal from protocol treatment 
 
7.4.1 Documented progression of disease by Lugano criteria (see 
appendix 3)14. Since anti-PD1 agents can be associated with 
tumor flare and mixed responses that may meet Lugano criteria 
for progression15, subjects may continue treatment on protocol 


 Protocol version 4.0 dated 11 November 2020 
 
Page 13 of 37 
 
beyond progression at the discretion of the investigator 
provided that the subject is clinically benefiting from the 
treatment. Examples of clinical benefit include but are not 
limited to overall decrease in tumor burden and improvement in 
symptoms. 
 
7.4.2 If at any time the constraints of this protocol are detrimental to 
the subject’s health and/or the subject no longer wishes to 
continue protocol therapy, protocol therapy shall be 
discontinued, the principal investigator shall be notified, and the 
reason for discontinuation shall be documented. 
 
7.4.3 Delay of treatment for more than 8 weeks for either 
pembrolizumab or umbralisib due to related adverse events 
unless prophylactic measures can be taken for subsequent 
cycles.  Treatment delays of greater than 8 weeks are permitted 
at investigator discretion and with notification of TG 
Therapeutics.  If only one agent is discontinued, the other agent 
should be continued provided that at least one of the following 
criteria is met. 
• The subject has received at least 6 cycles of therapy. 
• Achieved a FDG-PET-defined CR 
  
7.4.4 
The subject may withdraw from the treatment at any time for 
any reason. 
 
7.4.5 Subjects may opt to discontinue pembrolizumab prior to 
completing 16 cycles of treatment and continue receiving 
umbralisib if they have one of following 
• Achieved a FDG-PET-defined CR 
• Received a minimum of 6 additional doses of 
pembrolizumab after achieving a PR. 
7.5       Study stopping rules for immune-related toxicity 
 
There is the potential for increased immune-related adverse events with 
combination of umbralisib and pembrolizumab. The study will be 
suspended and an ad hoc safety committee will be convened with 
individuals with appropriate expertise (majority of whom are no 
directly affiliated with the study) for consideration of results and 
appropriate modification or termination of the study if there is 


 Protocol version 4.0 dated 11 November 2020 
 
Page 14 of 37 
 
sufficient evidence that the probability of Grade 3 or 4 immune-related 
adverse events that do not resolve to Grade ≤ 2 within 72 hours exceeds 
20%. This will be deemed to occur if the lower level of a one-sided 
80% confidence interval for this proportion exceeds 20%.  
 
The protocol was originally written to determine if there was sufficient 
evidence that the probability of grade 3-4 immune-related adverse 
events exceeded 10%. This was based on earlier data, though follow up 
data from a study that combined umbralisib with pembrolizumab and a 
CD20 monoclonal antibody found 4/20 (20%) subjects had grade 3-4 
transaminitis. This protocol hit the suspension rule when 2 out of the 
first 5 subjects met this (grade 3 rash and grade 3 ALT elevation).  
 
An ad hoc safety committee was convened. Since there are no standard 
therapies beyond PD1 inhibitors in the treatment of classical Hodgkin 
lymphoma, it was felt that a higher threshold for toxicity was 
warranted. Therefore, the threshold was increased to suspend again if 
the lower level of a one-sided 80% confidence interval for this 
proportion exceeds 20% (increased from 10%) 
  
In addition, a change was recommended to allow for prednisone 
treatment that exceeds 10 mg for 6 weeks before requiring 
discontinuation of the protocol.  
 
There are 15 subjects remaining in the study to be enrolled. The study 
operation rules will include the first two subjects as meeting this 
criteria, and will mandate another suspension in the following 
circumstances 
 
• If 4 out of the first 11 or fewer patients, or 5 out of the first 15 
or fewer, or 6 out of 20 or fewer patients experience Grade 3 or 
4 immune-related adverse events that do not resolve to Grade ≤ 
2 within 72 hours. 
 
8.0 
DOSAGE MODIFICATION, DELAY, OR DISCONTINUATION 
 
8.1 
Dose modification of pembrolizumab 
 
8.1.1 Withholding pembrolizumab: Adverse events (both non-serious and 
serious) associated with pembrolizumab exposure may represent an 
immunologic etiology.  These adverse events may occur shortly after the 
first dose or several months after the last dose of treatment (see below). 
The use of corticosteroids should be considered for management of 
immune-related adverse events (irAEs). Please refer to prescriber 


 Protocol version 4.0 dated 11 November 2020 
 
Page 15 of 37 
 
manual for further detail on dosing of corticosteroids for 
pembrolizumab-related toxicity. If the drug-related toxicity does not 
resolve to Grade 0-1 within 4 weeks after onset of toxicity, 
discontinuation is recommended. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per the 
below criteria (may resume upon recovery to grade 0 or 1 toxicity unless 
otherwise noted below).  
 
• Hematological toxicity- Grade 4; Pembrolizumab should be held 
until resolved to Grade ≤ 3. 
• Colitis, any Grade– Grade 2-3; also administer high-dose systemic 
corticosteroids (followed by a taper). 
• Hyperthyroidism– Grade 3; administer high-dose systemic 
corticosteroids (followed by a taper).  
• Hypophysitis– 
Grade 
2-4; 
administer 
high-dose 
systemic 
corticosteroids (followed by a taper).  
• Nephritis– Grade 2; consider administration high-dose systemic 
corticosteroids (followed by a taper).  
• Pneumonitis– Grade 1-2; administer high-dose systemic 
corticosteroids (followed by a taper).  Pembrolizumab may be 
resumed after resolution.   
• Hepatitis- Grade 2-3. Pembrolizumab should be held until 
resolution to Grade ≤ 1. If the subject has baseline liver 
involvement and Grade 2 abnormalities at baseline, treatment may 
continue unless it worsens to Grade 3. 
• Other treatment-related toxicity, severe or Grade 3; may require 
high-dose systemic corticosteroids (based on severity). Upon 
improvement to grade 0 or 1, initiate corticosteroid taper and 
continue to taper over at least 1 month. Restart pembrolizumab if the 
adverse reaction remains at grade 0 or 1 and steroid dose is ≤ 10 mg. 
Please refer to the FDA approved pembrolizumab prescribing 
information for more information. 
 
8.1.2 Discontinuing Pembrolizumab: If any of the following criteria are met, 
pembrolizumab should be permanently discontinued 
 
• Confirmed radiographic disease progression per the appropriate 
tumor evaluation criteria.  
• Immune-mediated Pneumonitis – discontinue for Grade 3-4 or 
recurrent Grade 1-2 pneumonitis  


 Protocol version 4.0 dated 11 November 2020 
 
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• Colitis – Grade 4  
• Immune-mediated Hepatitis – Grade 4 
• Immune-mediated Endocrinopathies – (excluding endocrinopathies 
controlled with hormone replacement therapy)  
 Hyperthyroidism – Grade 4 
• Immune-mediated Nephritis – Grade 3-4  
• Infusion-related reaction – Grade 3 or 4 
• Inability to reduce corticosteroid dose to 10mg or less of prednisone 
or equivalent per day within 6 weeks  
• Persistent 
Grade 
2 
or 
3 
adverse 
reactions 
(excluding 
endocrinopathies controlled with hormone replacement therapy) that 
do not recover to Grade 0-1 within 4 weeks after last dose of 
pembrolizumab  
• Any Grade 3-4 treatment-related adverse reaction that recurs 
• Please refer to the FDA approved pembrolizumab prescribing 
information for more information. 
• For treatment or dose modification related questions, please contact 
Dr. Lynch (MedCon may also be used to contact MDs at 206-543-
5300). 
 
8.2 
Umbralisib dose reduction steps: If a subject undergoes a dose reduction, it 
should not be subsequently increased, even if the toxicity resolves to Grade 0.  
However, if further evaluation of the toxicity reveals the event was not related 
to umbralisib, this should be recorded in the medical record and dose re-
escalation to the previous dose may be considered at the discretion of the 
investigator.     
 
Drug 
Starting Dose 
1st Dose Reduction 
2nd Dose 
Reduction 
Umbralisib 
800mg daily 
600mg daily 
400mg daily 
 
Supportive care should be considered for any subject who experiences Grade ≥ 
2 cytopenias, or Grade ≥ 1 non-hematologic toxicities.   


 Protocol version 4.0 dated 11 November 2020 
 
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NCI-CTCAE Grade 
Umbralisib Dose Delay or modification 
Hematologic Adverse Event 
Neutropenia 
Grade ≤ 2 neutropenia 
Maintain current umbralisib dose. Consider supportive care 
as warranted. 
Grade 3 neutropenia 
Maintain current umbralisib dose for first occurrence, 
consider supportive care. If recurrence or persistent Grade 3 
after re-challenge, resume umbralisib at next lower dose 
level at discretion of the principal investigator/sub-
investigator. 
Grade 4 neutropenia or occurrence of 
neutropenic fever/infection 
Delay umbralisib until Grade ≤ 3 and/or neutropenic fever or 
infection is resolved; thereafter, resume at current dose. 
Consider supportive care. If recurrence after re-challenge, 
resume umbralisib at next lower dose level at discretion of 
the principal investigator/sub-investigator. 
Thrombocytopenia 
Grade ≤ 3 thrombocytopenia 
Maintain current umbralisib dose level and provide 
supportive care as clinically warranted. 
Grade 4 thrombocytopenia 
Delay umbralisib until Grade ≤ 3; thereafter, resume at 
current dose. Consider supportive care intervention as 
warranted. If recurrence after re-challenge, resume 
umbralisib at next lower dose level at discretion of the 
principal investigator/sub-investigator. 
Hepatitis 
Grade 2-3 AST/ALT or total bilirubin 
increase  
Delay umbralisib until resolution to Grade ≤ 1. If the subject 
has baseline liver involvement and grade 2 abnormalities at 
baseline, treatment may continue unless it worsens to grade 
3.  For grade 3 toxicity, reduce the umbralisib dose to the 
next lower dose level upon resolution to Grade ≤ 1. 
Grade 4 AST/ALT or total bilirubin increase 
Permanently discontinue umbralisib. 
Immune related pneumonitis* 
Grade 1-2 
Stop all therapy (umbralisib and pembrolizumab) and hold 
until complete resolution. Restart umbralisib at one lower 
dose level. Restart pembrolizumab at current dose. If 
recurrence after re-challenge, discontinue all treatment 
therapy. 
Grade ≥ 3 
Discontinue all therapy (umbralisib and pembrolizumab). 
* For sinopulmonary infections clearly not related to immune-mediated pneumonitis, umbralisib  may be 
continued at investigator’s discretion.  While pneumonitis has been minimal with umbralisib, it is a reported 
adverse event associated with other PI3K delta inhibitors. Pneumocystis jiroveci pneumonia (PCP) and anti-
herpetic viral prophylaxis must be instituted as outlined in 7.2.1. 


 Protocol version 4.0 dated 11 November 2020 
 
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Diarrhea and/or colitis 
Diarrhea grade ≤ 2 
Maintain current umbralisib dose level if tolerable or hold 
and then resume at current dose level once has resolved. 
NOTE: If persistent grade 2 diarrhea, despite supportive 
care, delay umbralisib until ≤ grade 1. If recurrence after re-
challenge, resume umbralisib at current dose or next lower 
dose level at discretion of the principal investigator/sub-
investigator. 
Diarrhea ≥ 3 
Withhold umbralisib until Grade ≤ 1. Resume umbralisib at 
current dose or next lower dose level as per discretion of 
principal investigator/sub-investigator.  If recurrence after 
rechallenge, resume umbralisib at next lower dose level at 
discretion of the principal investigator/sub-investigator. 
Colitis (all grades) 
Hold umbralisib. Treat with supportive care and after 
resolution of colitis, resume umbralisib at next lower dose 
level 
All other non-hematological events 
Grade ≤ 2 
Maintain current umbralisib dose level. 
Grade ≥ 3 
Withhold umbralisib until Grade ≤ 1. If recurrence after re-
challenge, resume umbralisib at current dose or next lower 
dose level at the discretion of the principal investigator/sub-
investigator. 
 
 
8.3 
Concomitant Therapy 
Medications used during the course of the study will be documented. 
 
8.3.1 
Prohibited Concomitant Therapy: The administration of concurrent 
medications intended to treat the primary cancer are not allowed during 
protocol therapy.  This includes any chemotherapy, investigational 
agent, biologic agent or other anti-tumor agents.  Radiation therapy is 
also prohibited. 
 
8.3.2 
Subjects should be strongly discouraged from taking any “alternative” 
or “naturopathic” medications since these agents may interfere with 
metabolism of study medications. 
 


Protocol version 4.0 dated 12 November 2020 
 
Page 19 of 37 
9.0 
STUDY CALENDAR  
 
Required Studies 
Screening  
Cycle 1-4 
Day 1 
Cycle 1-4 
Day 8 
Restaging5 
Cycle 5-16  
day 1 
Within 3 days 
prior to every 4th 
cycle starting 
with cycle 17 
while on 
umbralisib alone 
End of 
treatment7 
Follow-up6 
Scheduling window (days) 
-42 to -19 
+/- 3 days 
+/- 2 days 
 
+/- 3 days 
 
 
 
Physical 
 
 
 
 
 
 
 
 
History and Physical 
X 
X1 
 
 
X3 
X 
X 
 
Performance Status 
X 
X1 
 
 
X3 
X 
X 
 
Clinical Disease Assessment 
X 
X1 
 
 
X3 
X 
X7 
X 
Adverse Event Assessment 
X 
X1 
 
 
X3 
X 
X 
 
Concomitant Medication 
Assessment 
X 
X 
 
 
X 
X 
X 
 
Lab2 
 
 
 
 
 
 
 
 
 
TSH, T3, T4, LDH, ESR2 
X 
 
 
X 
 
X 
X 
 
CBC with differential 
X 
X1 
X 
X 
X 
X 
X 
 
Comprehensive metabolic 
panel 
X 
X1 
X 
X 
X 
X 
X 
 
Serum pregnancy test4 
X4 
 
 
 
 
 
 
 
Hepatitis B/C serology, direct 
and indirect coombs, CMV 
X 
 
 
 
 
 
 
 
CMV surveillance by PCR10 
 
X10 
 
 
X10 
X10 
X10 
 
Radiology 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
PET/CT5 
X 
 
 
X 
 
 
X7 
 
CT5 
 
 
 
X 
 
 
 
 
Correlative Studies8 
X 
X 
 
X 
X 
 
 
 


 Protocol version 4.0 dated 11 November 2020 
 
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1. For Cycle 1 Day 1, pre-entry H&P, performance status, disease assessment and adverse event assessment may be used (these do not need to be repeated 
within 3 days) and labs done within 14 days of cycle 1 day 1 are acceptable. 
2. LDH and ESR must be done within 14 days prior to study entry.  
3. Between cycles 6-16 history, physical, performance status, and AE assessment by the investigator/sub-investigator may be performed every 2 cycles at 
investigator discretion. 
4. Serum pregnancy test in women of childbearing potential should be performed with screening and repeated within 3 days of cycle 1 day 1. 
5. FDG-PET-CT should be performed at baseline within 42 days prior to first dose of cycle 1. Diagnostic quality CT is not required at baseline for subjects 
who have CT measurable lesions from CT component of FDG-PET-CT. Follow up CT-scans should be performed after day 1 of cycle 3, 6, 9, 12 and 16, 
but prior to day 1 of the next cycle. PET-CT should be performed on the next imaging assessment for: 1) subjects meeting CR criteria by CT, 2) subjects 
meeting criteria for PR on 2 consecutive images, 3) subjects being removed from protocol for reasons other than progressive disease (including end of 
treatment), and 4) at the discretion of the investigator. For patients continuing on umbralisib for cycle 17 and beyond, imaging should be performed at the 
discretion of the investigator and upon clinical suspicion of progression/relapse.  
6. Subjects continuing on umbralisib alone for cycle 17 and beyond should be seen in clinic every 4th cycle (Cycle 17, cycle 21, cycle 25 etc.).  
7. There should be an end of treatment visit within 28 days after completion of therapy. For patients ending treatment on study for reasons other than 
progression, end of treatment imaging is strongly recommended within 28 days of completion of therapy. Imaging within this window can be recorded for 
a final response assessment. All subjects will be followed for survival and remission status while on treatment and up to 1 year after end of treatment visit. 
8. Correlative studies will be carried out whenever possible and include PD1/PDL1/PDL2 expression, MRD (e.g. Adaptive Clonoseq or similar) and cytokine 
monitoring. This will include up to 10 unstained slides of diagnostic tissue block from most recent biopsy (additional biopsy not required for study entry),as 
well as whole blood for plasma (20 ml EDTA or equivalent) at baseline and after cycle 2, at end of 16 cycles or progression (whichever comes first), as 
well as any time point that a PET scan is being performed for response assessment 
9. Testing can be performed within 42 days of cycle 1 day 1 unless specifically indicated above.   
10. CMV screening by PCR within 3 days prior to cycles 4, 7, 10, 13 and 17, and then within 3 days prior to every 4th treatment cycle thereafter for all subjects 
receiving study treatment.  A final CMV test by PCR should be done upon treatment discontinuation. 
 


Protocol version 4.0 dated 12 November 2020 
 
Page 21 of 37 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will 
be defined by standard NCI criteria (Lugano 2014) for lymphoid malignancies.   
 
11.0  STATISTICAL CONSIDERATIONS 
 
11.1 
The primary objective of this study is to estimate the CR rate of this regimen. In 
a population of CHL patients who have failed after autologous transplant, the 
CR rate of single agent pembrolizumab is 16%2. Targeted accrual is 20 subjects.  
If the assumed-true CR is 40%, we will have 88% power to observe a statistically 
significantly higher CR than the fixed rate of 16% with 20 subjects (at the one-
sided significance level of 0.1). The 95% confidence interval (CI) by exact 
Clopper Pearson for the proposed 40% CR is from 19% to 64%, which will 
reasonable exclude a response rate of < 16%.  With 20 subjects, CI will change 
to 27% to 73% with estimated CR 50%, and 36% to 81% with estimated CR 
60% 
11.2 
Anticipated accrual: We anticipate accrual of 20 subjects over 2 years.   
11.3 
Descriptive summary statistics for continuous variables will include sample 
size, mean, standard deviation (SD), median, minimum and maximum for both 
baseline and post-baseline measurements (if applicable).  Summary statistics for 
categorical variables will include sample size, frequency and percentages. 
11.4 
Estimated distribution of study population by gender and race and ethnicity: 
 
 
Ethnic Category 
Females 
Males 
Total 
American Indian/Alaska Native 
 
 
 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
Black or African American 
0 
1 
1 
White 
7 
10 
17 
More than one race 
0 
0 
0 
Unknown or not reported 
0 
0 
0 
Racial 
Categories: 
Total 
of 
all 
subjects 
8 
12 
20 
 
 
12.0  STUDY MONITORING AND REPORTING PROCEDURES 
 
 
12.1 
Adverse Event Reporting  
 
Reporting of AEs and SAEs should commence after first administration of 
either umbralisib or pembrolizumab, and should continue for up to 30 days after 


 Protocol version 4.0 dated 11 November 2020 
 
Page 22 of 37 
 
last dose of study treatment (pembrolizumab or umbralisib, whichever is given 
last). 
Complete and timely reporting of adverse events (AEs) is required to ensure the 
safety of subjects.  Reporting requirements are determined by the characteristics 
of the adverse event including the grade (severity), the relationship to the study 
therapy (attribution), and the prior experience (expectedness) of the adverse 
event.  The guidelines outlined in this section, as well as the specific direction 
on each report form must be followed.  The NCI Common Terminology Criteria 
for Adverse Events v5.0 (CTCAE) will be used to classify and grade toxicities.  
The CTC can be found on the Cancer Therapy Evaluation Program (CTEP) 
homepage at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTC
AE_v5_Quick_Reference_8.5x11.pdf 
 
12.2  Definitions and descriptions of terms used in adverse event reporting. 
 
Adverse Event (AE) 
An adverse event (AE) is defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure. The investigator 
should log AEs that are deemed to be clinically significant and assess their 
attribution to either or both of the study medications. 
 
Serious Adverse Event or Adverse Drug Reaction 
A Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR) means any 
AE/ADR occurring at any dose that results in: 
 
• Death; 
• A life-threatening AE/ADR (i.e, the patient/subject was, in the view of 
the initial reporter/investigator, at immediate risk of death from the AE 
as it occurred. It does not refer to an AE that hypothetically might have 
caused death if more severe); 
• Inpatient hospitalization or prolongation of existing hospitalization (i.e, 
hospitalization was required to treat or diagnose the AE/ADR: excludes 
hospitalization for unrelated reasons); 
• A persistent or significant disability or incapacity (disability here 
means that there is a substantial disruption of a person's ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; 
• An important medical event (i.e., AEs/ADRs that might not be 
immediately life-threatening, or result in death or hospitalization might 
be considered serious when, based upon appropriate medical and 
scientific judgment, they might jeopardize the patient/subject or might 
require medical or surgical intervention to prevent one of the other 
serious outcomes listed above); 


 Protocol version 4.0 dated 11 November 2020 
 
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• Any suspected transmission via a medicinal product of an infectious 
agent. 
 
Grade 
Grade is defined as the severity of the adverse event.  The CTCAE Version 5.0 
must be used to determine the grade of the adverse event. If toxicity is not listed 
in the CTCAE use the following general criteria for grading.   
 
0 – No adverse event or within normal limits 
1 – Mild adverse event 
2 – Moderate adverse event 
3 – Severe adverse event 
4 – Life-threatening or disabling adverse event 
5 – Fatal adverse event 
 
Attribution 
Attribution is defined as the determination of whether an adverse event is related 
to a medical treatment or procedure.  The investigator or authorized sub-
investigator will assess attribution according to the following categories: 
 
• Unrelated: the adverse event is clearly NOT related to therapy 
• Unlikely: the adverse event is doubtfully related to therapy 
• Possible: the adverse event may be related to therapy 
• Probable: the adverse event is likely related to therapy 
• Definite: the adverse event is clearly related to therapy 
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse event that is not listed in the current 
Investigator’s Brochure, package insert, protocol, or associated documents; or 
the specificity or severity of which is not consistent with these documents.   
 
 
12.3 
Routine Reporting 
 
Routine reporting is required for all grade adverse events.  Routine reports 
include data after each cycle of therapy and 30 days after the last dose of study 
drugs, or until the patient receives an alternative anti-cancer therapy, whichever 
date comes first.    
 
12.4  Expedited Reporting –  
 
SAE Reporting to TG Therapeutics  
 
SAEs require expeditious handling and reporting to TG Therapeutics in order to 
comply with regulatory requirements.  All SAEs (regardless of causality 
assessment) occurring on study or within 30 days of last study treatment should 
be immediately reported to TG Therapeutics at safety@tgtxinc.com (copy 


 Protocol version 4.0 dated 11 November 2020 
 
Page 24 of 37 
 
mcoon@tgtxinc.com and donna.gesumaria@tgtxinc.com) within 24 hours of the 
first knowledge of the event by physician member of the research team or 
research personnel on an SAE Form (MedWatch FORM FDA 3500 or 
equivalent) and followed until resolution (with autopsy report if applicable).  
Include the TG Therapeutics, Inc. tracking number (TGR-NTG-001) on the SAE 
report. 
 
SAE Reporting to Regulatory Agencies  
 
Sponsor-Investigator is responsible for reporting serious, unexpected, suspected 
adverse reactions (SUSARs) to the FDA in accordance with regulations under 
21 CFR 312.32.  Sponsor-Investigator is responsible for reporting unexpected 
fatal or life-threatening events associated with the use of the study drugs to the 
FDA within 7 calendar days after being notified of the event.  Sponsor-
Investigator will report other SUSARs to the FDA by a written safety report 
within 15 calendar days of notification. Other SAEs will be reported to the FDA 
on an annual basis.  
 
The investigator must report SAEs and follow-up information to the responsible 
Institutional Review Board (IRB) according to the policies of the IRB.  
 
The following are events of special interest, and will need to be reported within 
2 business days of awareness by a member of the study team with exceptions as 
indicated below for reporting these events to TG Therapeutics within 24 hours 
of awareness: 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
 
During the course of the study, all female subjects of childbearing potential must 
contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating 
investigator).   
 
If an investigator suspects that a subject may be pregnant prior to administration 
of study drug(s), the study drug(s) must be withheld until the result of the 
pregnancy test is confirmed.  If a pregnancy is confirmed, the patient must not 
receive any study drug(s), and must be discontinued from the study.   
 
If an investigator suspects that a subject may be pregnant after the subject has 
been receiving study drug(s), the study drug(s) must immediately be withheld 
until the result of the pregnancy test is confirmed.  If a pregnancy is confirmed, 
the study drug(s) must be immediately and permanently stopped, the patient 
must be discontinued from the study, and the investigator must submit a 
Pregnancy Report Form to TG Therapeutics within 24 hours of the first 
knowledge of the event by the treating physician or research personnel.  
Abortions (spontaneous, accidental, or therapeutic) must also be reported to TG 


 Protocol version 4.0 dated 11 November 2020 
 
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Therapeutics within 24 hours of awareness using the Pregnancy Report Form.  
Submit Pregnancy Report Forms to TG Therapeutics, Inc. following the same 
process described for reporting SAEs to TG Therapeutics, Inc. (to 
safety@tgtxinc.com, mcoon@tgtxinc.com and donna.gesumaria@tgtxinc.com, 
and including the TG Therapeutics, Inc. tracking number (TGR-NTG-001) on 
the Pregnancy Report Form).  
 
Congenital anomalies/birth defects always meet SAE criteria, and should 
therefore be expeditiously reported as an SAE to TG Therapeutics within 24 
hours of the first knowledge of the event by the treating physician or research 
personnel following the same process described for reporting SAEs to TG 
Therapeutics, Inc. 
 
In the event a subject’s partner becomes pregnant, a Pregnancy Report Form 
should be completed and submitted to TG Therapeutics following the same 
process described for reporting SAEs to TG Therapeutics, Inc., and the partner 
will be requested to consent to access to medical records.  After the subject’s 
partner provides consent, the pregnant partner and baby will be followed to see 
what effect the drug(s) under study may have on the outcome of the pregnancy 
or the health of the newborn.  
 
See APPENDIX 3:  CONTRACEPTIVE GUIDELINES AND PREGNANCY 
for additional information. 
 
Study Drug Overdose 
 
Any accidental or intentional overdose with the study treatment (either 
umbralisib or pembrolizumab) that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to TG Therapeutics immediately (within 
24 hours of awareness) on an SAE form and following the same process 
described for SAEs.  If a study drug overdose occurs, subjects should stop study 
drug dosing and be clinically monitored as appropriate, managing 
symptoms/side effects that may occur. 
 
   
 
 
12.5 
Data Safety and Monitoring Plan-  
 
Institutional support of trial monitoring will be in accordance with the 
FHCRC/University of Washington Cancer Consortium Institutional Data and 
Safety Monitoring Plan.  Under the provisions of this plan, FHCRC Clinical 
Research Support coordinates data and compliance monitoring conducted by 
consultants, contract research organizations, or FHCRC employees unaffiliated 
with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP.  


 Protocol version 4.0 dated 11 November 2020 
 
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In addition, protocols are reviewed at least annually and as needed by the 
Consortium Data and Safety Monitoring Committee (DSMC), Fred 
Hutchinson Cancer Research Center (FHCRC) Scientific Review Committee 
(SRC) and the FHCRC Institutional Review Board (IRB).  The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to 
the applicable data and safety monitoring plan for studies actively enrolling or 
treating subjects.  The IRB reviews the study progress and safety information 
to assess continued acceptability of the risk-benefit ratio for human subjects.  
Approval of committees as applicable is necessary to continue the study. 
   
The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
 
12.6  
Required Records and Materials 
12.6.1 Original signed informed consent form will be kept with the study 
coordinating office. A copy will be kept in the patient’s clinical chart..   
12.6.2 Data will be collected on patient characteristics, disease characteristics, 
protocol therapy, response to treatment, adverse events and follow-up for 
relapse and survival.  Source documentation may include the subject’s 
medical record from SCCA/UWMC and/or outside providers which 
would include history and physical exams, documentation of protocol 
therapy, labs, scans, x-rays, hospitalizations, operative reports, 
pathology reports etc.  
 
 
 
 
 
13.0 
ELEMENTS OF INFORMED CONSENT 
 
All Institutional, NCI, State and Federal regulations concerning informed consent and 
peer judgment will be fulfilled.  Written consent will be obtained from all subjects 
entering the study. 
 
14.0 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
 
14.1 Study Site Training 
 
Before initiation of the study, the PI, or its designated representatives will review and 
discuss the following items with the Investigator and clinic staff: the protocol, study 
procedures, record keeping and administrative requirements, drug accountability, AE 
reporting, Good Clinical Practice guidelines, and the ability of the site to satisfactorily 
complete the protocol.  
 
14.2 Informed Consent 
 


 Protocol version 4.0 dated 11 November 2020 
 
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The PI/sub-investigator assumes the responsibility of obtaining written Informed 
Consent for each subject or the subject’s legally authorized representative before any 
study-specific procedures are performed. 
 
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to 
participate in the study. To avoid introduction of bias, the Investigator must exercise 
no selectivity with regard to offering eligible subjects the opportunity to participate in 
the study. Subjects or parents/legal guardians of all candidate subjects will receive a 
comprehensive explanation of the proposed treatment, including the nature of the 
therapy, alternative therapies available, any known previously experienced adverse 
reactions, the investigational status of the study drug, and other factors that are part of 
obtaining a proper Informed Consent. Subjects will be given the opportunity to ask 
questions concerning the study, and adequate time to consider their decision to or not 
to participate. 
 
Informed Consent will be documented by the use of a written Consent Form that 
includes all the elements required by FDA regulations and ICH guidelines. A copy of 
the signed form will be given to the person who signed it, the original signed Consent 
Form will be filed with the subject’s medical records, and copy maintained with the 
subject’s study records. The date and time of time of the Informed Consent must be 
recorded in the source documents. 
 
If an amendment to the protocol changes the subject participation schedule in scope or 
activity, or increases the potential risk to the subject, the Informed Consent Form must 
be amended. Any amended Informed Consent must be reviewed by the Sponsor or 
designee and approved by the IRB prior to use. The revised Informed Consent Form 
must be used to obtain re-consent from any subjects currently enrolled in the study if 
the subject is affected by the amendment, and must be used to document consent from 
any new subjects enrolled after the approval date of the amendment. 
 
14.3 Institutional Review Board 
 
The PI will assure that an appropriately constituted IRB that complies with the 
requirements of 21 CFR Section 56 or written assurance of compliance with ICH (E6) 
guidelines will be responsible for the initial and continuing review and approval of the 
clinical study. Before initiation of the study, the PI or designee will forward copies of 
the protocol and Consent Form to be used for the study to the IRB for its review and 
approval. A photocopy of the IRB notification of approval must be forwarded to the 
Sponsor or its designee before any investigational supplies will be shipped to the PI. 
 
The PI or designee will also assure that all changes in the research activity and all 
unanticipated problems involving risks to human subjects or others will be reported 
promptly to the IRB, and that no changes will be made to the protocol without IRB 
approval, except where necessary to eliminate apparent immediate hazards to human 
subjects. 
 


 Protocol version 4.0 dated 11 November 2020 
 
Page 28 of 37 
 
The Investigator or designee will be responsible for submitting periodic progress 
reports to the IRB at intervals appropriate to the degree of subject risk involved in the 
study, but not less than once per year and at the completion or termination of the 
study. 
 
14.4 Subject Privacy 
 
The investigators affirm and uphold the principle of the subject's right to privacy. The 
investigator shall comply with applicable national and local privacy laws. 
 
15.0 
REFERENCES:  
 
 
1. 
Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in 
relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372:311-9, 2015 
 
2. 
Armand P, Shipp MA, Ribrag V, et al: Programmed Death-1 Blockade With 
Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin 
Failure. J Clin Oncol, 2016 
 
3. 
Gopal AK, Chen R, Smith SE, et al: Durable remissions in a pivotal phase 2 
study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood 125:1236-
43, 2015 
 
4. 
Ali K, Soond DR, Pineiro R, et al: Inactivation of PI(3)K p110delta breaks 
regulatory T-cell-mediated immune tolerance to cancer. Nature 510:407-11, 2014 
 
5. 
Greaves P, Clear A, Owen A, et al: Defining characteristics of classical 
Hodgkin lymphoma microenvironment T-helper cells. Blood 122:2856-63, 2013 
 
6. 
Meadows SA, Vega F, Kashishian A, et al: PI3Kdelta inhibitor, GS-1101 
(CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the 
microenvironment in cellular models of Hodgkin lymphoma. Blood 119:1897-900, 2012 
 
7. 
Gopal AK, Fanale MA, Moskowitz CH, et al: Phase II study of idelalisib, a 
selective inhibitor of PI3Kdelta, for relapsed/refractory classical Hodgkin lymphoma. Ann 
Oncol 28:1057-1063, 2017 
 
8. 
Burris HA, Patel MR, Brander DM, et al: TGR-1202, a Novel Once Daily 
PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking 
Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma. 
Blood 124:1984-1984, 2014 
 
9. 
Brown JR: The PI3K pathway: clinical inhibition in chronic lymphocytic 
leukemia. Semin Oncol 43:260-4, 2016 
 
10. 
Burris HA, Patel MR, Fenske TS, et al: Clinical activity and safety profile of 
TGR-1202, a novel once daily PI3Kδ inhibitor, in patients with CLL and B-cell lymphoma. 
Journal of Clinical Oncology 33:7069-7069, 2015 
 
11. 
Davids MS, Flinn IW, Mato AR, et al: An Integrated Safety Analysis of the 
Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with 
Relapsed/Refractory Lymphoid Malignancies. Blood 130:4037-4037, 2017 
 
12. 
Mato AR, Dorsey C, Chatburn ET, et al: Phase I/II Study of Pembrolizumab in 
Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with 
Relapsed/Refractory CLL. Blood 130:3010-3010, 2017 


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13. 
Mato AR, Svoboda J, Luning Prak ET, et al: PHASE I/II STUDY OF 
UMBRALISIB (TGR-1202) IN COMBINATION WITH UBLITUXIMAB (TG-1101) AND 
PEMBROLIZUMAB IN PATIENTS WITH REL/REF CLL AND RICHTER'S 
TRANSFORMATION. Hematological Oncology 37:119-120, 2019 
 
14. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. J Clin Oncol 32:3059-68, 2014 
 
15. 
Cheson BD, Ansell S, Schwartz L, et al: Refinement of the Lugano 
classification response criteria for lymphoma in the era of immunomodulatory therapy. Blood, 
2016 
 
 
 


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16.0 
Appendices 
Appendix 1: ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2:  Response Criteria: “The Lugano Classification”14 
Response 
and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi 
It is recognized that in Waldeyer's ring 
or 
extranodal 
sites 
with 
high 
physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, complete 
metabolic response may be inferred if 
uptake at sites of initial involvement is 
no greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake 
No 
extralymphatic 
sites 
of 
disease 
    
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
 New lesions 
None 
None 
 Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal 
by 
morphology; 
if 
indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial remission (all of the 
following) 
    Lymph 
nodes 
and 
extralymphatic 
sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 


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Response 
and 
Site 
PET-CT–Based Response 
CT-Based Response 
At interim, these findings suggest 
responding disease 
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value 
At end of treatment, these findings 
indicate residual disease 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
    
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
 New lesions 
None 
None 
 Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with 
baseline 
(diffuse 
uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan 
Not applicable 
No response or 
stable disease 
No metabolic response 
Stable disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Score 4 or 5 with no significant change 
in FDG uptake from baseline at interim 
or end of treatment 
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met 


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Response 
and 
Site 
PET-CT–Based Response 
CT-Based Response 
    
Nonmeasured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
disease 
Progressive metabolic disease 
Progressive disease requires at 
least 1 of the following 
    
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity 
of uptake from baseline and/or 
PPD progression: 
    
Extranodal 
lesions 
New FDG-avid foci consistent with 
lymphoma 
at 
interim 
or 
end-of-
treatment assessment 
An individual node/lesion must 
be 
abnormal 
with: 
LDi 
> 
1.5 
cm 
and 
Increase by ≥ 50% from PPD 
nadir 
and 
An increase in LDi or SDi from 
nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, 
the splenic length must increase 
by > 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to > 
16 cm). If no prior splenomegaly, 
must increase by at least 2 cm 
from 
baseline 
New or recurrent splenomegaly 
    
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured lesions 


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Response 
and 
Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, 
infection, 
inflammation). 
If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, 
its presence must be unequivocal 
and must be attributable to 
lymphoma 
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma 
 Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
• 
Abbreviations: 
5PS, 
5-point 
scale; 
CT, 
computed 
tomography; 
FDG, 
fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of 
a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, 
cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular 
to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
• 
↵* A score of 3 in many patients indicates a good prognosis with standard treatment, 
especially if at the time of an interim scan. However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider a score of 3 as inadequate 
response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable 
in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal 
lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not 
selected as measured, dominant disease and truly assessable disease should be 
considered not measured. These sites include any nodes, nodal masses, and extranodal 
sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, 
which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), 
FDG uptake may be greater than in the mediastinum with complete metabolic response, 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow 
activation as a result of chemotherapy or myeloid growth factors). 


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• 
↵† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > 
mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than 
liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
 
 


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Appendix 3: Contraceptive Guidelines and Pregnancy 
 
Women Not of Childbearing Potential are Defined as Follows:  
 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential.  
 
Contraceptive Guidelines for Women of Child-Bearing Potential:  
 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 4 months after 
stopping treatment. The highly effective contraception is defined as either:  
 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  
2. Sterilization: have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment.  
3. Male partner sterilization (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate). For female patients on the study, the 
vasectomised male partner should be the sole partner for that patient.  
4. Oral contraception, injected or implanted hormonal methods.  
5. Use of a combination of any two of the following (a+b):  
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.  
 
The following are unacceptable forms of contraception for women of childbearing 
potential:  
• Female condom  
• Natural family planning (rhythm method) or breastfeeding  
• Fertility awareness  
• Withdrawal  
• Cervical shield 
 
Women of child-bearing potential must have a negative serum pregnancy test ≤ 3 days prior 
to initiating treatment.  
 
Fertile Males:  


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Fertile males, defined as all males physiologically capable of conceiving offspring must use 
condom during treatment and for 4 months after study drug discontinuation and should not 
father a child in this period. Sperm donation is also prohibited until 4 months after study 
discontinuation. 
 
If a partner of a participant were to become pregnant, a pregnant partner consent will be 
created and the partner’s and/or child’s medical records will be followed for 3 months after 
the termination of the pregnancy to determine outcome including voluntary or spontaneous 
termination, details of the birth and the presence or absence of any birth defects, congenital 
abnormalities or maternal and/or newborn complications.  
 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.