Clinical trial NCT04209621
Conditions: Small Lymphocytic Leukemia (SLL) Chronic Lymphocytic Leukemia (CLL)
Keywords: P13K Inhibitor PLCG2 Mutations BTK Mutations Myeloid Cells and Myeloid Derived Suppressor Cells (MDSCs) T and Leukemic B Cells Aggregate
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2020-07-31; Completion date: 2021-01-22
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers often treated with the drug ibrutinib. For some people, ibrutinib stops working. Researchers want to see if adding another drug can help.

Objective:

To test how people with ibrutinib-resistant CLL respond to duvelisib.

Eligibility:

People ages 18 and older with CLL or SLL that is no longer responding to ibrutinib or has developed mutations that could stop it from working

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Heart tests
* Blood and urine tests
* CT scan. For this, participants will have a dye injected into a vein. They will lie in a machine that takes pictures of the body.
* Bone marrow biopsy. For this, a needle injected into the participant s bone will remove marrow.
* Optional lymph node biopsy. For this, the participants whole lymph node or part of it will be removed through the skin.
* Optional lymphapheresis. For this, the participants blood is removed through a vein in one arm, the white blood cells separated out, and the blood returned through a vein in the other arm.

Participants will take duvelisib twice daily by mouth. They will continue ibrutinib at their current dose for the first 6 months. They will continue to take duvelisib until their CLL/SLL stops responding or they develop intolerable side effects.

Participants will take an antibiotic and antiviral medication. They may take steroids.

Participants will have blood tests every 2 weeks during the first 2 months.

Participants will have monthly follow-up visits during the first 6 months and every 3 months thereafter. These will include repeats of some of the screening tests.

Detailed description:
Background:

* In chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib resistance is predominantly caused by somatic mutations in BTK and PLCG2. Virtually all patients with detectable mutations eventually develop progressive disease. Patients who discontinue ibrutinib often have rapidly progressive disease that can be difficult to control. These observations suggest that BTK inhibitors still exert at least a partial anti-tumor effect. Outcomes after ibrutinib discontinuation are poor. Early detection of BTK and PLCG2 mutations represents an opportunity for preemptive intervention to eliminate the resistant clone.
* Duvelisib is a dual PI3K-gamma and delta inhibitor. Duvelisib monotherapy improved progression-free survival and overall response rate compared to ofatumumab and had a manageable safety profile in subjects with previously treated CLL/SLL. Based on these results, duvelisib received US approval for CLL/SLL after at least 2 prior therapies.
* This study will assess duvelisib in patients who develop disease progression or BTK and/or PLCG2 mutations on ibrutinib. Duvelisib will overlap with ibrutinib for the first six 28-day cycles to prevent disease acceleration often seen in patients who discontinue ibrutinib.

Primary Objective:

-To investigate the rate of overall response to duvelisib in patients with ibrutinib-resistant CLL.

Key Eligibility Criteria:

* Patients on current treatment for CLL/SLL with ibrutinib and at least one of the following:

  * BTK and/or PLCG2 mutations
  * Progressive CLL per CLL guidelines
* Patients with known Richter transformation will be excluded.

Design:

* This is a single-center, single-arm, open-label phase 2 study with a safety lead-in cohort.
* Treatment plan: Duvelisib will be administered with ibrutinib for the first six 28-day cycles then duvelisib monotherapy will be administered continuously until disease progression or intolerance.

Study Duration: 5 years.

Participant Duration: until disease progression or intolerance.

Arms: arm 1: Duvelisib with ibrutinib will be administered for the first six 28-day (± 7) cycles followed by duvelisib alone until disease progression or intolerance. Duvelisib is an orally administered at 15 mg twice a day (dose level 1) or 25 mg twice day (dose level 2). Subjects will continue the same dose of ibrutinib prior to study enrollment for the first six 28-day cycles. Ibrutinib is an orally administered and provided as 140 mg white opaque capsules or tablets in 4 strengths: 140 mg, 280 mg, 420 mg, and 560 mg.
Interventions: intervention 1: Duvelisib intervention 2: Ibrutinib
Intervention descriptions: intervention 1: twice daily as tolerated until disease progression intervention 2: daily for the first six 28-day cycles

Protocol documents:
ICF_000.pdf: 
Title: Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
(CLL/SLL) 
NCT: 04209621 
Document Date: 11/13/2019 
 
 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PRINCIPAL INVESTIGATOR: Clare Sun, MD  
STUDY TITLE: Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma (CLL/SLL) 
 
STUDY SITE: National Heart, Lung, and Blood Institute 
 
Cohort: Affected patient    
Consent Version:  Consents should be versioned using the date of the last revision. Each time 
the consent is revised, you must update the version date. Use this space to specify the version 
date.  
 
 
WHO DO YOU CONTACT ABOUT THIS STUDY?  
Principal Investigator: 
 
 
 
Research Nurse: 
Clare Sun 
 
 
 
 
 
Pia Nierman 
clare.sun@nih.gov 
 
 
 
 
pia.nierman@nih.gov  
301-402-1806  
 
 
 
 
301-827-1094 
 
KEY INFORMATION ABOUT THIS RESEARCH  
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.   
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you make 
a decision can be found in other sections of the document. Taking part in research at the NIH is 
your choice. 
You are being asked to be in this research study because you have a form of cancer called chronic 
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). You have been receiving 
ibrutinib to treat CLL/SLL, but your CLL/SLL is no longer responding to ibrutinib or has 
developed mutations in certain genes that would eventually stop ibrutinib from working.  We 
want to find out if adding another drug called duvelisib to your treatment will help your cancer. 
Duvelisib is a type of drug that blocks proteins inside CLL/SLL cells. The specific protein 
blocked by duvelisib helps CLL/SLL cells live and grow.  Laboratory studies have shown that 
duvelisib can kill CLL/SLL cells obtained from patients who no longer respond to ibrutinib. 
Drugs similar to duvelisib can control CLL/SLL in some patients who no longer respond to 
ibrutinib and we want to know if duvelisib has the same effect. 
You will take duvelisib by mouth twice daily. Your CLL/SLL might get worse if ibrutinib is 
suddenly stopped. To prevent this from happening, you will continue ibrutinib at your current 
dose with duvelisib for the first 6 months. You will then continue duvelisib alone until your 


 
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CLL/SLL no longer responds to duvelisib or you experience intolerable side effects from 
duvelisib. 
You must return to the NIH monthly during the first 6 months of this study then every 3 months 
thereafter. Blood tests, bone marrow biopsies and CT scans will be performed periodically to 
see how your CLL/SLL is responding. Blood tests will also be used to monitor the safety of 
duvelisib. Visits will take place at the NIH Clinical Center. Most visits, including tests, will take 
less than a day. The study staff will provide specific dates and times for your study visits and 
tests. 
You may continue taking most medications that were prescribed before you started the study. 
Because these other medicines might interact with the study drugs, we ask that you tell us about 
all of your medications or changes in the medications you take, including prescription drugs, 
over-the-counter products, vitamins, and herbal supplements. 
Patients treated with duvelisb may be at an increased risk of developing certain infections. You 
will take an antibiotic and an antiviral medication to prevent such infections. You may also 
require steroids if you experience side effects related to a heightened immune system or 
granulocyte-colony stimulating factor if your white blood cell count decreases below normal. 
Side effects occurring in more than 25 out of 100 patients treated with duvelisib for blood cancer 
were: 
• Infections that could be caused by a bacteria, virus, or fungus. 
• Frequent loose watery stools (diarrhea) and/or inflammation of the intestines (colitis).  
• Decrease in number of white blood cells that helps fight infection with or without fever. 
• Rash which may be itchy or may cause blisters.  
• Feeling tired or weak. 
• Fever. 
• Cough. 
• Feeling sick to your stomach 
Side effects occurring in more than 10 but less than 25 out of 100 subjects treated with duvelisib 
for blood cancer were: 
• Abnormally high level of enzymes produced by the liver meaning that it could affect how 
your liver functions.  
• Pain in your muscles and/or joints.  
• Decrease in red blood cells and decrease in cells in the blood that help the blood to clot. 
• Swelling which may be in a specific location or may be more generalized. 
• Decreased appetite 
In addition, a small number of subjects experienced severe inflammation of the lungs which can 
be serious and can lead to death in rare cases (<1%). 
 
If you have any new and concerning systemic symptoms (e.g. fevers, rigors, severe fatigue), 
respiratory symptoms (e.g. shortness of breath, persistent cough, chest pain), or gastrointestinal 


 
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symptoms (e.g. diarrhea or blood in your stool), you should immediately notify your doctor for 
further evaluation. 
Your participation will continue as long as you continue to respond to and tolerate duvelisib, as 
long as the duvelisib remains available, until you decide that you no longer want to be in this 
study, or the Sponsor decides to stop or interrupt the study. 
The possible benefit from this study is that duvelisib will help treat your CLL/SLL. If you decide 
to participate in this study, your health will be monitored very closely which may provide a 
benefit to you.  By being in this study, you will give doctors more information about how well 
duvelisib works.  It may help doctors understand your condition better and may help future 
patients with CLL/SLL. 
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could choose to be treated by your home 
health care provider. Venetoclax (Venclexta®) is a Bcl-2 inhibitor approved for previously 
treated CLL/SLL. Idelalisib (Zydelig®), a PI3Kδ inhibitor, combined with rituximab 
(Rituxan®), a monoclonal antibody, is approved for CLL/SLL after 2 prior therapies. If you 
received ibrutinib as the first treatment for your CLL/SLL, chemotherapy combined with 
monoclonal antibody is also an option. Other experimental treatments may be available at other 
research centers. 
 
 
The remaining document will now describe more about the research study.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers. 
 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY 
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.   
WHY IS THIS STUDY BEING DONE? 
This is a research study. The purpose of this research study is to evaluate the safety and efficacy 
of duvelisib for CLL/SLL no longer responding to ibrutinib or CLL/SLL with mutations in certain 
genes that would eventually prevent ibrutinib from working. Duvelisib is approved by the U.S. 
Food and Drug Administration (FDA) to treat CLL/SLL after 2 prior therapies, but has not been 
specifically tested after treatment with ibrutinib. 


 
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WHAT WILL HAPPEN DURING THE STUDY? 
If you decide to take part in this study, you will be asked to: 
• Complete physical exam, laboratory tests, CT scan, bone marrow biopsy, and possibly 
lymph node biopsy and/or lymphapheresis before starting duvelisib. 
• Take duvelisib twice daily and continue ibrutinib at your current dose for the first 6 months 
to prevent your CLL/SLL from worsening if ibrutinib is suddenly stopped. Ibrutinib will 
be supplied from the NIH Clinical Center Pharmacy. Continue to take duvelisib until your 
CLL/SLL stops responding or you develop intolerable side effects. 
• Obtain laboratory tests every 2 weeks during the first 2 months to monitor the safety of 
duvelisib. These tests can be performed at an outside laboratory provided you share the 
results with us. 
• Return to the NIH Clinical Center every month for follow-up during the first 6 months and 
every 3 months thereafter. We will perform a physical exam and laboratory tests at these 
visits and CT scans and procedures described below. You may be asked to come more 
frequently if your CLL/SLL does not respond to treatment or you develop side effects. 
• Undergo a CT scan to see  how your CLL/SLL is responding to treatment after 3 months, 
6 months, 12 months on duvelisib, and annually thereafter. 
• Undergo a bone marrow biopsy after 3 months and 6 months on duvelisib and when you 
achieve complete remission. 
Some of your blood samples obtained during this study may be stored for the duration of the study. 
Your identity will be protected by using a code, such as a number, to label these samples.  These 
blood samples may be used for the following: 
• Research associated with this study.  
• Future research or be given to another investigator for future research without consent. 
Any such research would either protect or remove any personally identifiable information 
about you. 
• Development of medical products or processes. You will not gain financially from any 
products or processes that may result from this research even if your blood is used. 
• DNA sequencing, including whole exome sequencing. 
HOW LONG WILL THE STUDY TAKE? 
If you agree to take part in this study, your involvement is expected to last as long as your 
CLL/SLL is responding to treatment and you do not experience intolerable side effects. Most 
visits will range from 4-8 hours in length and will occur every month during the first 6 months 
and every 3 months thereafter. If you discontinue duvelisib, then for your safety you will be 
asked to return approximately 30 days after your last dose of duvelisib. If you discontinue 
duvelisib for reasons other than disease progression or to start new anti-CLL therapy, you will 
also be asked to return every 6 months to monitor your CLL/SLL. After your CLL/SLL 
progresses or you start new anti-CLL therapy, you will be asked to return or be contacted by 
telephone yearly to see how you are doing. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY? 
We plan to have approximately 36 people participate in this study at the NIH Clinical Center.  


 
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WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY? 
Duvelisib 
All the side effects of duvelisib are not known. The effects of duvelisib when combined with 
other medications or substances such as alcohol are not known and might result in serious or 
even life-threatening reactions. Therefore, you should always discuss the use of any drugs (over-
the-counter, prescription, herbal, recreational) or substances such as alcohol, with your study 
doctor prior to taking duvelisib, and while you are participating in this study. 
Side effects can go away while continuing to take the drug, or shortly after you stop taking the 
drug, but some side effects could be long-lasting, permanent, serious, life threatening, or even 
cause death. Everyone taking part in the study will be watched carefully for any side effects, and 
the drug may be stopped if intolerable or concerning side effects develop. You should talk to 
your study doctor about any side effects that you have while taking part in the study. 
Approximately 700 subjects with blood cancers have received study treatment (either duvelisib 
and/or another treatment for their cancer) on studies of duvelisib. Based on available information 
from subjects who received duvelisib on these studies, a list of potential side effects has been 
identified. These potential side effects may or may not be caused by duvelisib (for example, they 
may be due to underlying blood cancer or other medical conditions the subjects had before the 
study). 
Should information become available that might change your decision to participate in this study, 
you will be informed immediately. You can always decide whether or not to continue 
participating in this study. As new risks are identified, you will also be informed of these risks. 
You will be asked to sign a new consent form that confirms you have been made aware of the 
new risks and agree to continue participating in this study. 
As of 19 July 2018, the side effects seen in subjects with blood cancer who have taken duvelisib 
alone as a single anti-cancer treatment (total daily doses range from 16 mg to 200 mg), with most 
subjects with blood cancer having received a total daily dose of 50 mg (25 mg 2 times a day) are 
listed below. Most side effects seen were mild and subjects recovered with or without holding 
treatment with duvelisib. However, some side effects were severe, led to hospitalization, were 
life-threatening, or caused death. 
The most common side effects are described in the table below.  
Side effects occurring in more than 25 out of 100 subjects treated with duvelisib for blood 
cancer were 
• Infections that could be caused by a bacteria, virus, or fungus. This includes infections that 
affect the throat, lungs and sinuses such as the common cold or pneumonia. The most 
frequent infections occurred in the lungs. Infection can spread to vital organs causing the 
organs to not function properly (sepsis). In some cases, infections can be life-threatening 
and may cause death (4% fatal), such as lung infections or sepsis. In rare instances (<1%), 
more specific infections that would typically not occur in people with normal immunity 
can occur in people with decreased immune systems (such as people with cancer). Such 
infections may include infections with viruses such as Herpes simplex virus, 


 
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Cytomegalovirus or Epstein-Barr virus (a virus that can cause mononucleosis otherwise 
known as “mono”); and infections with fungus such as Aspergillus, Candida, or 
Pneumocystis. Report any new or worsening signs and symptoms of infections such as 
fever and chills or any other sign of infection. You may require medical attention and 
should immediately notify your doctor for further evaluation. Your doctor may prescribe 
medications such as antibiotics or antivirals to help prevent some of these infections. 
• Frequent loose watery stools (diarrhea) and/or inflammation of the intestines (colitis). This 
can be life-threatening and may cause death in rare cases (<1%). Tell your doctor right 
away if you have any new or worsening diarrhea, stool with mucus or blood, or if you have 
severe stomach-area (abdominal) pain. You may require medical attention and should 
immediately notify your doctor for further evaluation.  
• Decrease in number of white blood cells that helps fight infection with or without fever. 
• Rash which may be itchy or may cause blisters.  In rare cases (<1%), you could have 
peeling of the skin which could be serious, life-threatening or may cause death. Tell your 
doctor right away if you get a new or worsening skin rash or other skin reaction including 
painful sores or ulcers on your skin, lips, or in your mouth, severe rash with blisters or 
peeling skin, rash with itching or rash with fever.  
• Feeling tired or weak. 
• Fever. 
• Cough. 
• Feeling sick to your stomach 
Side effects occurring in more than 10 but less than 25 out of 100 subjects treated with 
duvelisib for blood cancer were: 
• Abnormally high level of enzymes produced by the liver meaning that it could affect how 
your liver functions. Tell your doctor right away if you get any symptoms of liver 
problems, including yellowing of your skin or the white part of your eyes (jaundice), pain 
in the stomach-area (abdominal) region, bruising or bleeding more easily than normal.  
• Pain in your muscles and/or joints.  
• Decrease in red blood cells which can cause tiredness and shortness of breath and decrease 
in cells in the blood that help the blood to clot. 
• Swelling which may be in a specific location or may be more generalized. 
• Decreased appetite 
• Sores in your digestive tract (nose, mouth, stomach, etc.) which can lead to not wanting to 
eat. 
• Throwing up or vomiting 
• Shortness of breath. 
• Headache. 
• Difficulty having a bowel movement or constipation. 
• Abdominal pain  
• Decrease in potassium in your blood which can cause muscle weakness or cramps, or 
changes in heart rhythms. 


 
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In addition, a small number of subjects experienced severe inflammation of the lungs which can 
be serious and can lead to death in rare cases (<1%). Tell your doctor right away if you get new 
or worsening cough or difficulty breathing. Your doctor may do tests to check your lungs if you 
have breathing problems during treatment. Your doctor may treat you with a steroid medicine if 
you develop inflammation of the lungs that is not due to an infection. 
If you have any new and concerning systemic symptoms (e.g. fevers, rigors, severe fatigue), 
respiratory symptoms (e.g. shortness of breath, persistent cough, chest pain), or gastrointestinal 
symptoms (e.g. diarrhea or blood in your stool), you should immediately notify your doctor for 
further evaluation. 
Additional Potential Effects While on Treatment with duvelisib 
Exposure to Sun: The effect of duvelisib on the skin, especially when in direct sunlight or with 
artificial UV light (e.g. tanning booths), is not known. As a general precaution, it is advised to 
use appropriate protective measures (e.g. long sleeve shirts and pants, hat, umbrella) to minimize 
exposure to direct sunlight during the treatment period and for at least 30 days after the last dose 
of duvelisib. 
Vaccinations: Tell your study doctor if you have had a recent vaccination or are scheduled to 
receive vaccinations. You should not receive certain vaccines after starting duvelisib. 
Vaccinations while on duvelisib may not work or could result in infection. Tell your doctor if 
anyone in your household is scheduled to receive a vaccination. 
Drug-drug interactions: If you start any new medications (prescriptions, herbal and/or over the 
counter), inform your doctor. Drug-drug interactions can decrease how well your medications 
work, may increase minor or serious unexpected side effects, or even increase the blood level 
and possible toxicity of a certain drug.  
 
Ibrutinib 
To be eligible for this study, you must be currently taking ibrutinib. Ibrutinib is an U.S. FDA 
approved for treatment of CLL. The table below lists the most common side effects seen in 
patients who have taken ibrutinib. 
Most Common (≥ 20%) 
Very Common (≥ 10%) 
Less Common (≥ 1%) 
• Increase in frequency of 
loose or watery stools 
(diarrhea) 
• Bruises 
• Muscle and bone/joint 
pain (musculoskeletal 
pain) 
• Nausea 
• Rash 
• Swelling of the hands 
or feet (peripheral 
edema) 
• Sinus infection 
(sinusitis) 
• Common cold (upper 
respiratory infection) 
• Fever 
• Constipation 
• Joint aches (arthralgia) 
• Dizziness 
• Urinary tract infection 
• Low white blood cells 
with fever (febrile 
neutropenia) 
• Abnormal heart rhythm 
(atrial fibrillation) 
• Blurry vision 


 
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• Low white blood cell 
count, cells that help 
fight infection 
(neutropenia) 
• Mouth sores 
(stomatitis) 
• Headache 
• Pneumonia 
• Vomiting 
• Muscle spasms 
• Severe infection 
throughout the body 
• Low platelet count, 
cells that help blood to 
clot 
(thrombocytopenia) 
• High blood pressure 
(hypertension) 
• Skin infection 
• Increase in white blood 
cell counts 
(leukocytosis) 
• Breaking of the nails 
(onychoclasis) 
• Inflammation of the 
lungs that could lead to 
permanent damage 
(interstitial lung 
disease) 
• Nose bleed (epistaxis) 
• Non-melanoma skin 
cancer (basal cell and 
squamous cell 
carcinoma) 
• Severe infection 
throughout the body 
(sepsis) 
• Skin redness 
(erythema) 
• Increased level of uric 
acid in the blood 
(hyperuricemia) 
• Small purple or red 
spots caused by 
bleeding under the skin 
(petechiae) 
• Increase in lymphocyte 
count (lymphocytosis) 
 
Blood Sampling 
Risks associated with drawing blood or needle sticks include pain, bruising, bleeding, light-
headedness, inflammation, temporary redness of the skin at the place the needle is put into your 
arm, fainting, and, on rare occasions, infection and/or local clot formation.   
Bone Marrow Biopsy 
A local anesthetic will be injected at the site of bone marrow biopsy. There may be a stinging or 
burning sensation from the injection. The biopsy needle will be placed through the skin and into 
the bone and may produce a brief, dull pain. As the bone marrow liquid is withdrawn from the 
bone, there may be a brief, sharp pain. Since the interior of the bone cannot be anesthetized, this 
procedure may cause some discomfort, however not all patients experience these symptoms. In 
some cases, the doctor may prescribe some medication used as conscious sedation. This is given 
to you to help you relax if the doctor feels it is necessary. 


 
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Some risks associated with this procedure include persistent bleeding and infection, pain after 
the procedure at the site where the bone marrow biopsy is done, and sometimes very infrequently 
a nerve may be injured during the procedure causing pain. 
Lymph Node Biopsy (Optional) 
There are several ways to do a lymph node biopsy.  
In a fine-needle or core needle aspiration biopsy, a thin needle is used to remove cells from the 
lymph node. Patients will feel only a quick sting from the local anesthesia used to numb the skin 
and may feel some pressure from the biopsy needle. After a fine-needle aspiration biopsy or core 
needle biopsy, the site may be tender for 2 to 3 days. 
In an open biopsy, the lymph node is removed through a cut in the skin. This can be done under 
local anesthesia. After the open biopsy, the biopsy site may feel tender, firm, swollen, and/or 
bruised. Subjects may be advised to not do any heavy lifting or other activities that stretch or 
pull the muscles around the area. 
As patients are at risk of infection at the biopsy site, we will ask you to report any swelling, 
redness or discharge to the research team so that appropriate antibiotics can be started if 
necessary. 
I give my permission for my lymph node biopsy: 
 
_____ Yes 
_____ No 
Initials  
Initials 
CT Scans 
Before the CT scan a contrast dye (iodine dye) may be injected into your vein.  These injections 
may cause a slight discomfort, bruising, swelling and sometimes an allergic reaction, although 
this is rare. If an allergic reaction occurs, it can range from being mild (itching, rash) to severe 
(difficulty breathing, shock, or rarely, death).  In addition, contrast material may also cause 
kidney problems, especially if you are dehydrated or have poor kidney function.  The study 
doctors will ask you about any allergies, kidney problems, or related conditions before the 
procedure.  If you have any of these problems, you may not be allowed to have a CT scan. 
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when you are inside the scanner, or by lying in one position for a 
long time.  The contrast material may make you feel discomfort when it is injected/given by 
mouth.  You may feel warm and flushed and get a metallic taste in your mouth.  Rarely, the 
contrast material may cause nausea, vomiting, or a headache.  
Lymphapheresis (Optional)   
Blood will be taken from your body (from an IV in your arm) and sent through a machine to 
remove white blood cells. Blood without white blood cells will be returned to you (through an 
IV in your other arm). 


 
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If you choose to have lymphapheresis, you might feel lightheadedness or have bleeding from the 
sites where blood is taken or returned.  Low blood pressure and muscle cramps can occur during 
the procedure.  If you feel uncomfortable, you should tell the study team. There is also the chance 
for infection after the procedure. 
I give my permission for my blood to be taken for lymphapheresis: 
 
_____ Yes 
_____ No 
Initials  
Initials 
  
What are the risks related to pregnancy?  
Duvelisib has not been tested to determine whether it may have an effect on pregnancy or a 
developing baby. 
All patients enrolled in the study and their partners should agree to take effective measures in 
order to prevent a pregnancy from the screening visit up to 30 days after the last dose of duvelisib. 
You must also agree not to donate sperm during this period. 
If you are pregnant or plan to become pregnant, you will not be allowed to participate in this 
study because of possible harm to you or your baby. Females who are capable of bearing children 
will be required to take a pregnancy test prior to entry into this study and during the study. If at 
any time during the study and up to 30 days after you take the last dose of duvelisib you suspect 
that you have become pregnant, please notify the study doctor immediately. 
If you become pregnant, you will be permanently taken off study drug(s), but we will continue 
to follow you at regular intervals. 
If you are a male study participant, you should agree to protect your partner from becoming 
pregnant before and during the study and for up to 30 days after your last dose of duvelisib. If 
your partner becomes pregnant while you are on study and for up to 30 days after discontinuing 
the study, you must immediately notify the research study staff. We can provide counseling about 
preventing pregnancy for either male or female study participants. 
To participate in this study, you should agree to use an effective method of birth control to 
prevent pregnancy. Acceptable methods to prevent pregnancy during participation in this study 
and for 30 days after the last dose of duvelisib are: 
• Total abstinence (no sexual intercourse). 
• Surgical sterilization including tubal ligation (tubes tied) or hysterectomy (removal of 
uterus or womb) in women or a vasectomy in men. 
• Oral contraceptives (birth control pills), intrauterine devices (IUD), implantable or 
injectable contraceptives in combination with barrier methods (such as a condom or 
diaphragm) used with a spermicide. 
• Barrier methods (such as a condom or diaphragm) used with a spermicide.  


 
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The contraception methods described above may not protect against HIV infection (AIDS) and 
other sexually transmitted diseases. If you need more information about this, please ask your 
study doctor. 
You should not nurse (breastfeed) a baby while on this study because duvelisib may enter breast 
milk and possibly harm your child. 
What are the risks of radiation from being in the study?  
You may have up to 4 CT scans during the first year of the study, one of which you may have 
already had as part of your screening visit. The CT scan done after completion of 3 month and 6 
months of duvelisib is medically indicated. The other CT scans (at the completion of one year 
on duvelisib and once a year for as long as you remain on treatment), will be done for research 
purposes if not required for your medical care. The amount of radiation you will receive in this 
study is 1.3 rem per year for annual research scans, which is below the guideline of 5 rem (or 0.5 
rem in children) per year allowed for research subjects by the NIH Radiation Safety Committee. 
The average person in the United States receives a radiation exposure of 0.3 rem per year from 
natural sources, such as the sun, outer space, and the earth's air and soil. Although it is important 
for this research, you may choose not to undergo the CT scans that are scheduled for research 
purposes. If you would like more information about radiation, please ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.  
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe. There may be a very 
slight increase in the risk of cancer. Please tell your doctor if you have had any radiation exposure 
in the past year, either from other research studies or from medical tests or care, so we can make 
sure that you will not receive too much radiation. Radiation exposure includes x-rays taken in 
radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine 
scans in which radioactive materials were injected into your body. If you are pregnant you will 
not be permitted to participate in this research study. It is best to avoid radiation exposure to 
unborn or nursing infants since they are more sensitive to radiation than adults. 
WHAT ARE THE BENEFITS OF BEING IN THE STUDY? 
You will not benefit from being in this study.     
However, the potential benefit to you might be that duvelisib will help treat your CLL/SLL. If you 
decide to participate in this study, your health will be monitored very closely which may provide 
a benefit to you. 
In the future, other people might benefit from this study because you will give doctors more 
information about how well duvelisib works.  It may help doctors understand your condition better 
and may help future patients with CLL/SLL.  
Are there any potential benefits to others that might result from the study? 
In the future, other people might benefit from this study because we will have better understanding 
how this medication can help other patients.  


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
WHAT OTHER OPTIONS ARE THERE FOR YOU? 
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could choose to be treated by your home 
health care provider. Venetoclax (Venclexta®) is a Bcl-2 inhibitor approved for previously 
treated CLL/SLL. Idelalisib (Zydelig®), a PI3Kδ inhibitor, combined with rituximab 
(Rituxan®), a monoclonal antibody, and duvelisib (Copiktra®) is approved for CLL/SLL after 
2 prior therapies. If you received ibrutinib as the first treatment for your CLL/SLL, chemotherapy 
combined with monoclonal antibody is also an option. Other experimental treatments may be 
available at other research centers.  
DISCUSSION OF FINDINGS 
New information about the study 
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places. 
Return of research results 
Clinically relevant research results will not be shared with you. 
EARLY WITHDRAWAL FROM THE STUDY  
Your participation is entirely voluntary. You may choose to stop at any time. If you stop because 
of side effects, you might be asked to return for additional tests until the side effects resolve. New 
information regarding safety and effectiveness of duvelisib may become available. Following 
discussion of that new information with the research team: 
• You may decide to discontinue participation 
• You may decide to continue in the study, if so we will ask you to sign an updated consent 
form 
• The research team may decide it is not in your best interest to continue in the study 
The principal investigator of this study (Clare Sun, MD), the Institutional Review Board (IRB), 
and Verastem, Inc. may stop this study at any time, for any reason, without your consent. For 
safety reasons, the Data Safety Monitoring Board may also recommend stopping this study without 
your consent. 
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA 
Will your specimens or data be saved for use in other research studies? 
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 


 
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additional information that will be helpful in understanding Lymphoma, or other diseases or 
conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you. 
I give permission for my coded specimens and data to be stored and used for future research as 
described above. 
 
_____ Yes 
_____ No 
Initials  
Initials 
 
Will your specimens or data be shared for use in other research studies? 
We may share your coded specimens and data with other researchers.  If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you.  They may be doing research in areas similar to this research or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above. 
 
_____ Yes  
_____ No 
Initials  
Initials 
 
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them.  
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data. 


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not.  If you do not wish to have your data placed in this 
database, you should not enroll in this study.   
How long will your specimens and data be stored by the NIH? 
Your specimens and data may be stored by the NIH until they are no longer of a scientific value, 
at which time they will be destroyed.  
Risks of storage and sharing of specimens and data 
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data. 
COMPENSATION, REIMBURSEMENT, AND PAYMENT 
Will you receive compensation for participation in the study? 
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines. 
You will not receive compensation for participation in this study.  
Will you receive reimbursement or direct payment by NIH as part of your participation? 
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines. 
This study will offer reimbursement for, or payment of, travel, lodging or meals according to 
NIH and NHLBI policies and guidelines.  
Will taking part in this research study cost you anything?  
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center.  
CONFLICT OF INTEREST (COI)  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH. 
 


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
The NIH and the research team for this study are using duvelisib developed by Verastem, Inc.  
through a joint study with your study team and the company. The company also provides financial 
support for this study. 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING  
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. 
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY   
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 
• The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
• National Institutes of Health Intramural Institutional Review Board 
• The study Sponsor (NHLBI Division of Intramural Research) 
• Qualified representatives from Verastem, Inc., the pharmaceutical company who produces 
duvelisib. 
 
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.  
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.   
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.   
The Certificate does not protect your information when it:   


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or  
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);  
3. is for other research; 
4. is disclosed with your consent.  
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research.  
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent. 
Privacy Act 
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act.  In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act. 
POLICY REGARDING RESEARCH-RELATED INJURIES   
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action. 
PROBLEMS OR QUESTIONS 
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Clare Sun, 
clare.sun@nih.gov, 301-402-1806. Other researchers you may call are: Pia Nierman, 
pia.nierman@nih.gov, 301-827-1094. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern. 
CONSENT DOCUMENT  
Please keep a copy of this document in case you want to read it again. 


 
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MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
 
 
Signature of Research Participant 
 
Print Name of Research Participant 
 
Date 
 
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study. 
 
 
 
 
 
Signature of LAR 
 
Print Name of LAR 
 
Date 
 
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study. 
 
 
 
 
 
Signature of Parent/Guardian 
 
Print Name of Parent/Guardian 
 
Date 
 
 
 
 
 
 
Signature of Parent/Guardian (as applicable) 
 
Print Name of Parent/Guardian 
 
Date 
 
Assent: (Use this section only when this process is approved by an IRB for older minors. Do not use if an IRB 
requires a separate assent form for this population.) 
I have had this study explained to me in a way that I understand, I have been given the opportunity to discuss 
it, and I have had the chance to ask questions. I agree to take part in this study. 
Assent of Minor: (as applicable) 
 
 
 
 
 
Signature of Minor 
 
Print Name of Minor 
 
Date 
Investigator: 
 
 
 
 
 
Signature of Investigator 
 
Print Name of Investigator 
 
 
Date 
 


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
 
 
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process with a non-English speaking subject and this English consent form has been approved 
by the IRB for use as the basis of translation. 
 
Witness: 
 
 
 
 
 
Signature of Witness* 
 
Print Name of Witness 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness. 
 
 
 
 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent but did not serve as a witness. The name or ID code of the person  
providing interpretive support is: 
 
. 
 
 
 
 
 

Prot_SAP_002.pdf: 
19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
1 
CLINICAL RESEARCH PROJECT 
Protocol #: 19-H- 
Drug Names: Ibrutinib, Duvelisib 
IND: exempt 
 
Title: Duvelisib for Ibrutinib-Resistant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 
(CLL/SLL) 
 
Short Title: Duvelisib for Ibrutinib-Resistant CLL 
 
Keywords: Duvelisib, PI3K Inhibitor, Ibrutinib, BTK Inhibitor, CLL, SLL 
  
Principal Investigator: 
Clare Sun, M.D., HB, NHLBI (E)* 
301-402-1806  
 
Bldg 10, CRC 3-5132 
Subjects of Study: 
 
Number  
 
 
Sex  
 
Age-range  
33 evaluable 
 
 
M/F 
 
18 
(Accrual Ceiling 36, to account for ineligible subjects) 
 
 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
2 
PROTOCOL SUMMARY 
 
 SYNOPSIS 
 
Background: 
 
x 
In chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib resistance is 
predominantly caused by somatic mutations in BTK and PLCG2.1-3  Virtually all patients with 
detectable mutations eventually develop progressive disease.2,4 Patients who discontinue ibrutinib often 
have rapidly progressive disease that can be difficult to control.5 These observations suggest that BTK 
inhibitors still exert at least a partial anti-tumor effect. Outcomes after ibrutinib discontinuation are 
poor.2 Early detection of BTK and PLCG2 mutations represents an opportunity for preemptive 
intervention to eliminate the resistant clone.2 
x 
Duvelisib is a dual PI3K-ȖDQGįLnhibitor. Duvelisib monotherapy improved progression-free survival 
and overall response rate compared to ofatumumab and had a manageable safety profile in subjects 
with previously treated CLL/SLL.6 Based on these results, duvelisib received US approval for 
CLL/SLL after at least 2 prior therapies. 
x 
This study will assess duvelisib in patients who develop disease progression or BTK and/or PLCG2 
mutations on ibrutinib. Duvelisib will overlap with ibrutinib for the first six 28-day cycles to prevent 
disease acceleration often seen in patients who discontinue ibrutinib.  
 
Primary Objective: 
 
x 
To investigate the rate of overall response to duvelisib in patients with ibrutinib-resistant CLL. 
 
Key Eligibility Criteria: 
 
x 
Patients on current treatment for CLL/SLL with ibrutinib and at least one of the following: 
o BTK and/or PLCG2 mutations  
o Progressive CLL per iwCLL guidelines7 
x 
Patients with known Richter transformation will be excluded. 
 
Design: 
 
x 
This is a single-center, single-arm, open-label phase 2 study with a safety lead-in cohort.  
x 
Treatment plan: Duvelisib will be administered with ibrutinib for the first six28-day cycles then 
duvelisib monotherapy will be administered continuously until disease progression or intolerance. 
 
Study Duration: 5 years.  
Participant Duration: until disease progression or intolerance. 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
3 
STATEMENT OF COMPLIANCE ....................................................................................................................... 6 
1.0 
OBJECTIVES............................................................................................................................................... 7 
1.1 
PRIMARY OBJECTIVE ................................................................................................................................................ 7 
1.2 
SECONDARY OBJECTIVES ........................................................................................................................................... 7 
1.3 
EXPLORATORY OBJECTIVES ........................................................................................................................................ 7 
2.0 
BACKGROUND & RATIONALE ............................................................................................................... 7 
2.1 
CHRONIC LYMPHOCYTIC LEUKEMIA AND/OR SMALL LYMPHOCYTIC LYMPHOMA ................................................................... 7 
2.2 
PATHOPHYSIOLOGY .................................................................................................................................................. 7 
2.3 
EPIDEMIOLOGY AND CLINICAL COURSE OF CHRONIC LYMPHOCYTIC LEUKEMIA ..................................................................... 8 
2.4 
TREATMENT OPTIONS FOR IBRUTINIB-RESISTANT CLL/SLL .............................................................................................. 8 
2.4.2 
Stem Cell Transplantation .............................................................................................................................. 9 
2.4.3 
Chimeric Antigen Receptor-Modified T cells ................................................................................................... 9 
2.4.4 
Targeted Agents ............................................................................................................................................. 9 
2.5 
DUVELISIB ............................................................................................................................................................ 10 
2.5.1 
Mechanism of Action .................................................................................................................................... 10 
2.5.2 
Absorption, Distribution, Metabolism, and Excretion .................................................................................. 10 
2.5.4 
Clinical Experience in CLL .............................................................................................................................. 11 
2.6 
CLINICAL AND SCIENTIFIC JUSTIFICATION FOR PROTOCOL DESIGN .................................................................................... 12 
2.7 
RISK/BENEFIT ASSESSMENT ..................................................................................................................................... 13 
2.7.1 
 Identified and Potential Risks Related to Duvelisib ..................................................................................... 13 
2.7.2 
Identified and Potential Risks Related to Ibrutinib ....................................................................................... 16 
2.7.3 
RISKS RELATED TO BLOOD DRAWS ............................................................................................................................ 17 
2.7.4 
RISKS RELATED TO CT SCANS ................................................................................................................................... 18 
2.7.5 
RISKS RELATED TO BONE MARROW BIOPSY ................................................................................................................ 18 
2.7.6 
RISKS RELATED TO LYMPH NODE BIOPSY .................................................................................................................... 18 
2.7.7 
RISKS RELATED TO LYMPHAPHERESIS ......................................................................................................................... 18 
Known Potential Benefits .......................................................................................................................................... 18 
Assessment of Potential Risks and Benefits ............................................................................................................... 19 
3.0 
STUDY DESIGN ........................................................................................................................................ 19 
TABLE 1. DOSE DE-ESCALATION RULES BASED ON NUMBER OF SUBJECTS WITH DLTS ...................................................................... 19 
4.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .............................................................................. 19 
4.1 
INCLUSION CRITERIA ............................................................................................................................................... 19 
Table 2. Summary of adequate organ function for eligibility .................................................................................... 20 
4.2 
EXCLUSION CRITERIA .............................................................................................................................................. 20 
5.0 
TREATMENT PLAN ................................................................................................................................. 22 
5.1 
DRUG ADMINISTRATION ......................................................................................................................................... 22 
5.2 
TREATMENT SCHEDULE ........................................................................................................................................... 22 
5.3 
DOSE LIMITING TOXICITIES ...................................................................................................................................... 22 
5.4 
DOSE MODIFICATION GUIDELINES ............................................................................................................................ 22 
5.4.1 
Dose Modification of Duvelisib ..................................................................................................................... 22 
5.4.2 
Dose Modification of Ibrutinib...................................................................................................................... 24 
5.5 
PERMANENT DISCONTINUATION OF STUDY DRUG ADMINISTRATION ................................................................................ 24 
5.5.1 
Permanent Discontinuation of Duveslisib..................................................................................................... 24 
5.5.2 
Permanent Discontinuation of Ibrutinib ....................................................................................................... 25 


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Clare Sun, M.D. 
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4 
5.6 
CONCOMITANT MEDICATIONS AND THERAPIES ............................................................................................................ 25 
5.6.1 
Supportive Medications and Care ................................................................................................................ 25 
5.6.2 
Medications that Inhibit or Induce CYP3A .................................................................................................... 25 
5.6.3 
QT Prolonging Agents ................................................................................................................................... 25 
5.6.4 
Antiplatelet Agents and Anticoagulants ...................................................................................................... 25 
5.6.5 
Lifestyle Considerations ................................................................................................................................ 26 
5.6.6 
Prohibited Concomitant Medications and Therapy ...................................................................................... 26 
6.0 
CLINICAL EVALUATIONS ..................................................................................................................... 27 
6.1 
SCREENING AND BASELINE ASSESSMENTS ................................................................................................................... 28 
6.2 
ON THERAPY ASSESSMENTS ..................................................................................................................................... 28 
6.2.1 
Cycles 1-6 ...................................................................................................................................................... 29 
6.2.2 
Cycle 7 Onwards ........................................................................................................................................... 29 
6.2.3 
Time of Progressive Disease or Suspicion of Progressive Disease ................................................................ 30 
6.3 
SAFETY ASSESSMENT AFTER PERMANENT DISCONTINUATION OF DUVELISIB ...................................................................... 30 
6.4 
FOLLOW-UP ASSESSMENTS ..................................................................................................................................... 31 
7.0 
CRITERIA FOR RESPONSE .................................................................................................................... 31 
TABLE 4. RESPONSE DEFINITION ............................................................................................................................................ 31 
8.0 
ANCILLARY LABORATORY RESEARCH STUDIES ............................................................................ 32 
8.1 
COLLECTION OF SAMPLES ........................................................................................................................................ 32 
8.2 
INTENDED USE ...................................................................................................................................................... 32 
8.3 
STORAGE, TRACKING AND DISPOSITION OF SAMPLES AND DATA ..................................................................................... 32 
9.0 
BIOSTATISTICAL CONSIDERATIONS .................................................................................................. 33 
9.1 
PRIMARY ENDPOINT ............................................................................................................................................... 33 
9.2 
SECONDARY ENDPOINTS ......................................................................................................................................... 33 
9.3 
EXPLORATORY ENDPOINTS....................................................................................................................................... 33 
9.4 
SAMPLE SIZE ......................................................................................................................................................... 34 
9.5 
STATISTICAL METHODS ........................................................................................................................................... 34 
9.6 
STUDY STOPPING RULES ......................................................................................................................................... 34 
9.7 
OFF STUDY CRITERIA .............................................................................................................................................. 35 
10.0 SAFETY ASSESSMENT AND MONITORING ......................................................................................... 36 
10.1 
ASSESSMENT OF SAFETY .......................................................................................................................................... 36 
10.1.1 
Severity .................................................................................................................................................... 36 
10.1.2 
Causality Assessments ............................................................................................................................. 36 
10.1.3 
Pregnancy ................................................................................................................................................ 37 
10.2 
DOCUMENTATION, DATA COLLECTION, AND REPORTING ............................................................................................... 37 
10.3 
REPORTING PERIOD FOR AES ................................................................................................................................... 38 
10.4 
FDA, NIH IRB, AND CD REPORTING ........................................................................................................................ 38 
10.4.1 
NIH Intramural IRB reporting ................................................................................................................... 38 
10.5 
SAFETY REPORTING TO THE PHARMACEUTICAL COLLABORATOR ...................................................................................... 38 
10.6 
FDA REGULATORY REQUIREMENTS (WAIVED) ............................................................................................................ 39 
10.7 
CONSIDERATIONS FOR OTHER REPORTABLE EVENTS ..................................................................................................... 39 
11.0 BIOSPECIMEN AND DATA MANAGEMENT PLAN ............................................................................. 40 
11.1 
DATA MANAGEMENT ............................................................................................................................................. 40 


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Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
5 
11.2 
DATA SHARING AND FUTURE USE OF DATA ................................................................................................................ 40 
11.3 
FUTURE USE OF BIOSPECIMENS ................................................................................................................................ 41 
11.4  
CLINICAL MONITORING ........................................................................................................................................... 41 
12.0 HUMAN SUBJECT PROTECTION .......................................................................................................... 41 
12.1 
RATIONALE FOR SUBJECT SELECTION ......................................................................................................................... 41 
12.1.1  
Predicted Distribution by Gender, Age and Race ..................................................................................... 41 
12.1.2  
Special Populations: ................................................................................................................................. 42 
12.2 
RISKS IN RELATION TO BENEFIT ................................................................................................................................. 43 
12.3 
INFORMED CONSENT PROCESS AND PROCEDURES ........................................................................................................ 43 
12.4 
CONFLICT OF INTEREST ........................................................................................................................................... 43 
12.5 
TECHNICAL TRANSFER AGREEMENTS ......................................................................................................................... 43 
12.6 
PROTOCOL AMENDMENTS ....................................................................................................................................... 43 
12.7 
PUBLICATION POLICY .............................................................................................................................................. 43 
13.0 PHARMACEUTICALS .............................................................................................................................. 44 
13.1 
DUVELISIB ............................................................................................................................................................ 44 
13.2 
IBRUTINIB............................................................................................................................................................. 44 
13.3 
ACCOUNTABILITY PROCEDURES ................................................................................................................................ 45 
14.0 REFERENCES ........................................................................................................................................... 45 
APPENDIX A:  SCHEDULE OF EVENTS ......................................................................................................... 50 
APPENDIX B: CYP3A INHIBITORS, INDUCERS, AND SUBSTRATES ......................................................... 52 
MEDICATIONS OR FOODS KNOWN TO INHIBIT CYP3A ............................................................................................................... 52 
Table 7. Classification of In Vivo Inhibitors of CYP3A ................................................................................................ 52 
MEDICATIONS KNOWN TO INDUCE CYP3A .............................................................................................................................. 52 
Table 8. Classification of In Vivo Inducers of CYP3A .................................................................................................. 52 
MEDICATIONS KNOWN TO BE CYP3A SUBSTRATES ................................................................................................................... 53 
Table 9. Cytochrome P450 3A (CYP3A) Substrates .................................................................................................... 53 
 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
6 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
x United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the 
conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection 
and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study.  In addition, all changes to 
the consent form will be IRB-approved; a determination will be made regarding whether a new consent needs 
to be obtained from participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
7 
 
 
1.0 
OBJECTIVES 
 
1.1 
  Primary Objective 
 
x 
To investigate the rate of overall response to duvelisib in patients with ibrutinib-resistant CLL 
 
1.2 
 Secondary Objectives  
 
x 
Progression-free survival (time from treatment initiation to progression of disease or death from any cause) 
x 
Overall survival (time from treatment initiation to death from any cause) 
x 
Duration of response (time from initial response to progression of disease) 
x 
Best response 
x 
Safety of duvelisib plus ibrutinib combination 
x 
Safety of duvelisib monotherapy 
 
1.3 
Exploratory Objectives 
 
x 
Immune cell profiling at baseline, during combination treatment with ibrutinib plus duvelisib, and during 
duvelisib monotherapy 
x 
Minimal residual disease by flow cytometry in peripheral blood and/or bone marrow 
x 
Quantification of allele frequency of BTK and PLCG2 mutations (if present at baseline) during treatment 
x 
Targeted or whole exome sequencing of sequential tumor samples to assess clonal evolution. 
 
2.0 
BACKGROUND & RATIONALE 
 
2.1 
Chronic Lymphocytic Leukemia and/or Small Lymphocytic Lymphoma 
 
The World Health Organization classification of hematopoietic neoplasias describes CLL as a leukemic, 
lymphocytic lymphoma, being only distinguishable from SLL by its leukemic appearance.8  In the National 
Cancer Institute (NCI)-Working Group (WG) guidelines, the diagnosis of CLL requires the presence of at least 
5 x 109 clonal B lymphocytes/L (5000/μL) in the peripheral blood. The definition of SLL requires the presence 
of lymphadenopathy and/or splenomegaly. Clonal B lymphocytes in the peripheral blood should not exceed 5 
x 109/L and the diagnosis should be confirmed by histopathologic evaluation of a lymph node biopsy when 
possible.9 
 
Chronic lymphocytic leukemia/small lymphocytic lymphoma cells co-express the T-cell antigen CD5 and B-
cell surface antigens CD19, CD20, and CD23. The levels of surface immunoglobulin, CD20, and CD79b are 
characteristically low compared with those found on normal B cells. Each clone of leukemia cells is restricted 
to expression of either kappa or lambda immunoglobulin light chains.9  
For the purposes of this study, the term “CLL” will encompass both CLL and SLL. 
 
2.2 
Pathophysiology  
 
CLL is characterized by a progressive accumulation of functionally incompetent lymphocytes. It is believed 
that antigenic stimulation, along with interactions of accessory cells, cytokines, and tumor microenvironment 
are promoting factors that stimulate proliferation of CLL cells and allows them to avoid apoptosis. These effects 
may differ in distinct CLL subgroups and thereby lead to the heterogeneity seen in clinical outcomes among 
individual cases.  
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
8 
The tumor microenvironment is known to play an important role in the development and maintenance of CLL. 
Important contributors to this permissive microenvironment include cellular components such as macrophages, 
T cells, or stromal follicular dendritic cells, and essential proteins (chemokines, cytokines, and angiogenic 
factors) which exert their oncogenic support via interactions with membrane receptors on the malignant cells. 
CLL cultured in vitro undergo apoptosis, but they can be rescued by coculturing with stromal cells or in 
presence of soluble factors.10  
 
In human, T and leukemic B cells aggregate to form ‘proliferation centers’ within bone marrow (BM) and 
lymphoid tissues, where these rallied cells form immune synapses.11 CD40 ligand form a crosstalk between T 
and CLL cells which stimulates leukemic B cell survival and promotes resistance to apoptosis.12,13 In addition, 
T cells in CLL are functionally11 and phenotypically14 defective, and allow malignant B cells to escape immune 
surveillance. “Pseudo-exhaustion” of effector T cells is explained by increased expression of immune 
checkpoints on CLL cells11,15 and by increased number of regulatory T cells in CLL patients.16 
 
Myeloid cells, in particular tumor associated macrophages (TAMs) and myeloid derived suppressor cells 
(MDSCs) are also important in the pathogenesis of CLL.17,18 In vitro, TAMs support the survival of CLL cells 
by cell-cell contact and the secretion of immunosuppressive cytokines.19,20 MDSCs are immunosuppressive 
cells that are found at increased frequency in CLL patients compared to healthy individuals and are associated 
with shorter lymphocyte doubling time.21-23 Both TAMs and MDSCs impair tumor immune surveillance via 
expansion of Treg cells and suppression of T-cell activation in CLL.17,21,24 
 
2.3 
Epidemiology and Clinical Course of Chronic Lymphocytic Leukemia 
 
Chronic lymphocytic leukemia is the most common leukemia of adults in Western countries with an annual 
incidence of 2 to 4.5 per 100,000 in the general population. According to the NCI Surveillance Epidemiology 
and End Results (SEER) data, it is estimated that 14,990 men and women (8,870 men and 6,120 women) will 
be diagnosed with CLL. It affects males twice as frequently as females and is a disease of older individuals 
(median age 73.0 years for Whites).25 The highest rates of incidence are seen in Caucasians followed by African 
Americans. Lower rates of incidence are seen in Asian and Hispanic populations.  
 
The complications of CLL usually arise from progressive disease. These complications are, but not limited to 
infection, hematologic abnormalities, immune phenomena, secondary cancers, and disease transformation. It 
has been estimated that up to 70% of patients with CLL will develop infections, and infections account for 
about 55% of deaths in patients with CLL. Hematologic abnormalities include autoimmune hemolytic anemia 
(AIHA) in approximately 37% of patients, pure red cell aplasia in 6% of patients, and immune mediated 
thrombocytopenia in 2 to 4% of patients.26 Secondary cancers are noted in about 11% of cases such as acute 
myeloid leukemia and other solid malignancies. Finally, disease transformation into other forms or more 
aggressive lymphomas such as diffuse large B-cell lymphoma and Hodgkin’s lymphoma occur in about 5% of 
cases.27 
 
2.4 
Treatment Options for Ibrutinib-Resistant CLL/SLL 
 
Patients who develop CLL progression on ibrutinib often have limited treatment options. Salvage therapies 
with reported outcomes are described below. 
 
2.4.1 
Salvage Chemoimmunotherapy  
 
In a retrospective cohort study of 391 CLL patients treated with frontline ibrutinib, 55 patient were treated with 
a 
subsequent 
therapy 
after 
ibrutinib 
discontinuation.28 
Anti-CD20 
monoclonal 
antibody-based 
chemoimmunotherapy produced an ORR of 50% among 9 patients. However, only 1 had discontinued ibrutinib 
for CLL progression. Further, a major limitation of conventional chemoimmunotherapy is toxicity. Rates of 
treatment-related mortality are 3.9% with fludarabine, cyclophosphamide, and rituximab (FCR) and 2.1% with 
bendamustine and rituximab (BR).29 More than 90% of patients treated with FCR and 78.5% treated with BR 
experience moderate to severe adverse events equivalent to CTCAE Grade 3 to 5.29 Hematologic toxicities such 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
9 
as severe neutropenia can occur while on treatment (81.7%) or after treatment completion.30 Infusion reactions 
related to monoclonal antibodies also limit the successful delivery of treatment. As a part of long-term toxicities, 
secondary malignancy can occur after being exposed to alkylating agents. Intergroup E2997 trial reported 8.2% 
cumulative incidence of myeloid neoplasia at 7 years after treatment with fludarabine plus cyclophosphamide 
(FC).31 
 
2.4.2 
Stem Cell Transplantation 
 
The EBMT Chronic Malignancies and Lymphoma Working Parties conducted a retrospective study to 
investigate the safety and efficacy of allogeneic hematopoietic cell transplantation in patients pre-treated with 
ibrutinib.32 Patients with CLL (n = 48) and mantle cell lymphoma (n = 22) were included in the analysis. In the 
CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and 
overall survival (OS) were 10, 30, 60, and 72%, respectively. Prior ibrutinib failure and poor performance status 
were risk factors for unfavorable RI, PFS, and OS.   
 
2.4.3 
Chimeric Antigen Receptor-Modified T cells 
 
Anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy produced an ORR of 71% among 24 
patients with CLL following prior ibrutinib therapy, including 19 who had experienced disease progression 
while receiving ibrutinib.33 Undetectable minimal residual disease in the marrow by deep IGH sequencing was 
achieved in 7 of 12 (58%) who underwent testing. However, the benefit of a deep response should be evaluated 
against  considerable toxicity – 20 patients (83%) developed cytokine release syndrome and 8 patients (33%) 
developed neurotoxicity with 1 fatal outcome. Interestingly, continuing ibrutinib therapy during CAR-T cell 
administration appears to reduce cytokine release syndrome while improving efficacy.34,35 
 
2.4.4 
Targeted Agents  
 
Idelalisib  
 
,GHODOLVLEVHOHFWLYHO\LQKLELWVSįLVRIRUPRIphosphoinositide-3-kinase (PI3K). A phase I study enrolled 54 
heavily pretreated relapsed/refractory CLL patients, and demonstrated ORR of 73% with 6 different dose levels 
of oral idelalisib (range 50-350 mg once or twice daily).36 The highest median PFS was seen in patients 
receiving 150 mg twice daily or greater (median PFS of 29 months), and no dose-limiting toxicities was 
observed. Using the 150 mg twice daily dosing, the combination of idelalisib and rituximab was compared to 
placebo and rituximab in a randomized phase 3 trial.37 The idelalisib arm had a higher ORR (81% vs 13%, p < 
0.001) and 12-month OS (92% vs 80%, p = 0.02) compared to the placebo arm. Idelalisib, combined with 
rituximab, is approved in the U.S. for the treatment of patients with relapsed CLL, for whom rituximab alone 
would be considered appropriate therapy due to other co-morbidities, and for patients with SLL who have 
received  2 prior systemic therapies. In a multicenter, retrospective cohort study, treatment with idelalisib 
resulted in an overall response rate of 46% among 37 CLL patients after ibrutinib discontinuation for any 
reason.38 A retrospective study of the French Innovative Leukemia Organization (FILO) reported an ORR of 
72% to idelalisib after ibrutinib discontinuation among 29 CLL patients.39 
 
Venetoclax  
 
CLL has dysfunctional intrinsic apoptotic pathways due to the mutation of genes encoding pro-apoptotic 
proteins, such as p53, or due to overexpression of anti-apoptotic proteins, such as Bcl-2. Venetoclax is a potent, 
orally bioavailable, small molecule inhibitor of Bcl-2 that induces apoptosis.40 A phase I study with venetoclax 
led to deep and durable remissions in 84 patients with relapsed/refractory CLL (CR or CRi in 22%).41 The most 
common adverse events were diarrhea (46%), neutropenia (43%), fatigue (34%), upper respiratory tract 
infection (29%), and cough (25%). Notably, early studies reported an 11% incidence of grade 3-4 tumor lysis 
syndrome, which decreased to <5% after dose modification with a ramp-up schedule adopted for later studies. 
In a randomized, phase 3 trial, 389 patients were randomized to venetoclax plus rituximab or BR. PFS was 
significantly longer in the venetoclax plus rituximab group than the BR group (median not reached vs 17 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
10 
months, p < 0.001).42 With extended follow-up, the venetoclax plus rituximab group also had improved OS 
(87.9% vs 79.5% at 3 years, p = 0.0093).43 Venetoclax is approved as a single agent or in combination with 
rituximab for treatment of CLL after at least one prior therapy. An interim analysis of 91 patients treated with 
venetoclax after ibrutinib discontinuation in a multicenter, phase 2 study reported an ORR of 65% (95% CI 53-
74), a median PFS of 24.7 months, and an estimated PFS rate at 12 months of 75%.44 In exploratory post-hoc 
subgroup analysis, the ORR was 54% (95% CI 39-68) among patients who discontinued ibrutinib for disease 
progression compared to 63% (95% CI 44–80) among patients who discontinued ibrutinib for toxicity. 
 
2.5 
Duvelisib 
 
2.5.1 
Mechanism of Action  
 
Duvelisib is an oral dual inhibitor of PI3K-įDQG3,.-ȖZLWKLQWKH pharmacological class of kinase inhibitors 
and is being developed as a therapeutic in hematologic malignancies. PI3Ks catalyze the production of 
phosphatidylinositol (3, 4, 5)- trisphosphate (PIP3), leading to activation of downstream effector pathways 
important for cellular survival, differentiation, and function. There are 4 mammalian isoforms of class 1 PI3Ks: 
PI3K-ĮȕįFODVVDDQG3,.-ȖFODVVE3,.-ĮDQG3,.-ȕDUHZLGHO\H[SUHVVHGDQGDUHLPSRUtant 
mediators of signaling from cell surface receptors. PI3K-ĮLVWKHLVRIRUPPRVWRIWHQIRXQGPXWDWHGLQFDQFHUV
and has a role in insulin signaling and glucose homeostasis.45,46 PI3K-ȕ LV DFWLYDWHG LQ FDQFHUV ZKHUH
phosphatase and tensin homolog (PTEN) is deleted. Both isoforms are targets of small molecule therapeutics 
in development for cancer. PI3K-įDQG3,.- ȖDUHSUHIHUHQWLDOO\H[SUHVVHGLQOHXNRF\tes and are important in 
leukocyte function. 
 
The PI3K-įDQG3,.-ȖLVRIRUPVSOD\HVVHQWLDOUROHVLQQRUPDOLPPXQHFHOOIXQFWLRQDQGDUHDOVRH[SUHVVHGLQ
malignant hematopoietic cells. Pathways mediated by PI3K-įDQG3,.-ȖDUHLQYROYHGLQGLYHUVHSURFHVVes of 
cell growth, survival, proliferation, migration, differentiation, and metabolism. Since central regulatory roles 
for either or both enzymes have been demonstrated in B cells,46-54 T cells,55-64 neutrophils,65 
macrophages/monocytes,65-68 mast cells,69-71 and natural killer (NK) cells,72-75 both PI3K-įDQG3,.-ȖDUH
believed to be important for the development and persistence of autoimmune disease and hematologic 
malignancies. 
 
2.5.2 
Absorption, Distribution, Metabolism, and Excretion 
 
Duvelisib is rapidly absorbed following oral administration, with maximal concentrations occurring 
approximately 0.5 to 2 hours after dosing. Exposure (Cmax and AUC) increased proportionally over a dose 
range of 1 to 30 mg (single dose) and 1 to 5 mg BID (multiple dose) in healthy subjects. The increase in 
exposure was slightly less than dose proportional following administration of doses up to 100 mg BID in 
subjects with hematologic malignancies. In healthy subjects, the absolute oral bioavailability of duvelisib was 
42%. In oncology subjects, the mean t1/2 of duvelisib ranged from 2.7 to 7.5 hours following multiple dose 
administration. Based on the t1/2, steady state concentrations of duvelisib are expected to be reached within 48 
to 72 hours. Accumulation was < 3-fold with twice daily dosing. 
 
DuveOLVLELVDSSUR[LPDWHO\ERXQGWRKXPDQSODVPDSURWHLQVDWDFRQFHQWUDWLRQRIȝ0 (approximate 
Cmax following 25 mg BID). The steady-state volume of distribution (Vss) for duvelisib following intravenous 
(IV) infusion was 12.3 L, suggesting duvelisib distributes into tissues. 
 
In vitro data indicate duvelisib is metabolized primarily by CYP3A4. The primary circulating entity other than 
parent drug is the inactive, mono-oxidation metabolite, IPI-656. Following single dose administration of 
duvelisib (25 mg) to healthy male subjects, overall exposure to IPI- 656 relative to duvelisib was approximately 
1.4:1. In oncology subjects, steady state exposure to IPI-656 approximated that of the parent drug. 
 
Similar to preclinical species, duvelisib and its metabolites are primarily excreted in feces, with minimal renal 
elimination of the parent drug in humans. Following oral administration of 14Clabeled duvelisib to healthy 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
11 
subjects, 92.5% of the radioactive dose was recovered, with 79.0% and 13.5% recovered in feces and urine, 
respectively. Less than 1% of the administered dose was excreted in urine as unchanged duvelisib. 
 
2.5.3 
Drug-Drug Interactions 
 
In vitro metabolism studies indicate that CYP3A4 is the predominant human CYP isozyme responsible for the 
metabolism of duvelisib; therefore, exposure to duvelisib could be impacted by other drugs that inhibit or induce 
CYP3A activity. In Study IPI-145-01, coadministration of ketoconazole (200 mg BID for 5 days) with a single 
10 mg dose of duvelisib increased duvelisib Cmax and AUC(0-inf) by 66% and 295%, respectively, compared 
to administration of duvelisib alone. PBPK simulations on coadministration of duvelisib 25 mg and 75 mg plus 
ketoconazole 200 mg BID to steady-state indicated increases in duvelisib exposure of approximately 1.59- and 
1.45-fold, respectively. In addition, PBPK simulations demonstrated that the steady-state duvelisib 25 mg BID 
and 75 mg BID concentration (without ketoconazole) is comparable to steady-state duvelisib 15 mg BID and 
40 mg BID concentration (with coadministration of ketoconazole), respectively, in subjects with advanced 
hematological malignancies. 
 
In Study IPI-145-11, exposure to duvelisib was reduced by approximately 80% when coadministered with 
rifampin (600 mg daily for 7 days), a strong CYP3A inducer. Based on these data, the concomitant use of drugs 
or foods that are strong inhibitors or inducers of CYP3A is not allowed during treatment with duvelisib. 
 
In vitro studies in human liver microsomes demonstrated that duvelisib and its primary metabolite IPI-656 are 
reversible inhibitors of CYP2C8 and CYP3A4 and mechanism-based inhibitors of CYP3A4. Model-based 
methods and PBPK modelling indicated low probability for duvelisib and IPI-656 to cause a clinically 
meaningful DDI with CYP2C8 substrates but predicted duvelisib and IPI-656 to cause clinically meaningful 
DDI with CYP3A4 substrates. In Study IPI-145-10, coadministration of duvelisib (25 mg BID for 5 days) with 
midazolam (MDZ), a sensitive CYP3A substrate, resulted in an approximate 4-fold increase in MDZ systemic 
exposure (AUC) compared to administration of MDZ alone. PBPK modeling with MDZ predicted that in 
subjects with advanced hematologic malignancies, duvelisib and IPI-656 concentrations resulting from 25 and 
75 mg BID doses would lead to approximately 5.82- and 7.37-fold MDZ exposure increases, respectively.  
 
Metabolism is the main route of elimination for ibrutinib. Ibrutinib is metabolized to several metabolites 
primarily by CYP3A and to a minor extent by CYP2D6. In vitro studies suggest that ibrutinib and PCI-45227 
are unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib and PCI-
45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses. Therefore, coadministration of 
duvelisib and ibrutinib may potentially increase systemic exposure to ibrutinib only. 
 
2.5.4 
Clinical Experience in CLL 
 
Study IPI-145-07 is a 2-arm, randomized, open-label, Phase 3 study designed to evaluate the efficacy and safety 
of duvelisib compared with ofatumumab. Eligible subjects were randomized in a 1:1 ratio to 1 of 2 treatment 
arms: Arm 1 (duvelisib 25 mg BID) or Arm 2 (ofatumumab). Subjects randomized to duvelisib received 
duvelisib continuously until disease progression, subject withdrawal, or initiation of additional anticancer 
therapy. Subjects randomized to ofatumumab received ofatumumab per the approved prescribing information. 
A total of 319 subjects were randomized (duvelisib: 160 subjects; ofatumumab: 159 subjects). Duvelisib 
monotherapy resulted in statistically significant improvement in PFS and ORR compared to ofatumumab. The 
median PFS (months from randomization to either progressive disease or death) for duvelisib was 13.3 months 
(95% CI: 12.1, 16.8) and for ofatumumab was 9.9 months (95% CI: 9.2, 11.3) (p < 0.0001).6 ORR per modified 
International Workshop on CLL (IWCLL)/IWG criteria showed statistically significant superiority for 
duvelisib vs ofatumumab, with an ORR per IRC of 73.8% for duvelisib vs 45.3% for ofatumumab (p < 0.0001).6 
Reductions in target lymph nodes were observed in most subjects treated with duvelisib (85%), representing a 
statistically significant treatment effect over ofatumumab (16%) (p < 0.0001).6 Duvelisib is approved in the US 
for the treatment of relapsed or refractory CLL/SLL after  prior therapies and relapsed or refractory FL after 
 prior systemic therapies. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
12 
 
The overall hematologic malignancies safety data analyses population is comprised of pooled data as of 19 July 
2018 from studies IPI-145-02, IPI-145-06, IPI-145-07, IPI 145-12, and VS-0145-225 (n=588). Adverse events 
were analyzed for the overall heme safety population and included sub-set analyses for subjects with CLL/SLL 
or FL. In general, the safety profiles of the three populations were very similar, with the most frequent 
treatment-emergent adverse events (TEAEs) reported in the overall heme population being diarrhea/colitis 
(49.0%), neutropenia (34.7%), rash (34.7%), fatigue (33.2%), upper respiratory tract infections (22.3%) and 
pneumonia (21.6%). Grade 3 or higher 7($(VRFFXUULQJLQRIVXEMHFWVZHUHQHXWUopenia (30.1%), 
diarrhea/colitis (21.6%), pneumonia (16.5%), anemia (12.4%), transaminase elevation (11.4%), 
thrombocytopenia (11.7%) and rash (10.7%). 226 (38.4%) subjects had an TEAE leading to discontinuation of 
duvelisib. The most common TEAEs OHDGLQJ WR VWXG\ GUXJ GLVFRQWLQXDWLRQ   RI VXEMHFWV ZHUH 
diarrhea/colitis (10.0%), rash (3.4%), pneumonia (3.2%), pneumonitis (2.9%), disease progression (2.7%) and 
transaminase elevation (2.7%). Treatment-emergent serious adverse events (TESAEs) occurred in 400 (68.0%) 
VXEMHFWV 7KH PRVW IUHTXHQW 7(6$(V  2%) were: pneumonia (18.0%), diarrhea/colitis (17.7%), febrile 
neutropenia (7.0%), disease progression (6.1%), sepsis (5.4%), rash (5.1%), pyrexia (4.9%), pneumonitis 
(4.4%), renal insufficiency (3.6%), lower respiratory tract infection (3.4%), thrombosis or thromboembolism 
(2.4%) and upper respiratory tract infection (2.2%). In the All Heme group, 87 (14.8%) subjects experienced a 
TESAE leading to death. The most frequent fatal TESAEs (>1 subject) were disease progression (35 subjects, 
6.0%), pneumonia (15 subjects, 2.6%), sepsis (11 subjects, 1.9%), cardiac failure, respiratory failure (3 subjects 
each, 0.5% each), and hemorrhage intracranial, multi-organ failure, pneumonitis, rash (2 subjects each, 0.3% 
each). In CLL/SLL subjects, the most frequent fatal TESAEs were pneumonia (10 subjects, 3.0%), sepsis (9 
subjects, 2.7%), disease progression (8 subjects, 2.4%), and cardiac failure, multi-organ failure (2 subjects each, 
0.6% each).  
 
2.6 
Clinical and Scientific Justification for Protocol Design 
 
In chronic lymphocytic leukemia (CLL), ibrutinib resistance is predominantly caused by somatic mutations in 
BTK (C481) and PLCG2 (e.g. R665, S707, L846).1-3 Allele frequencies of mutations associated with ibrutinib 
resistance are often low then increase over time.2 Virtually all patients with detectable mutations eventually 
develop progressive disease.2,4 Early detection of BTK and PLCG2 mutations represents an opportunity for 
preemptive intervention to eliminate the resistant clone.2 Outcomes after ibrutinib discontinuation are poor. 
Survival after disease progression was 3.5 months for Richter transformation and 19.8 months for CLL 
progression.2  
 
Inhibition of PI3K-įwith idelalisib induces clinical response in a subset of patients previously treated with 
ibrutinib. In a multicenter, retrospective cohort study, treatment with idelalisib resulted in an overall response 
rate of 46% among 37 CLL patients after ibrutinib discontinuation for any reason.38 A retrospective study of 
the French Innovative Leukemia Organization (FILO) reported an ORR of 72% to idelalisib after ibrutinib 
discontinuation among 29 CLL patients.39 
 
In contrast to idelalisib, duvelisib is a dual inhibitor of PI3K-įDQG3,.-ȖThrough inhibition of PI3K-Ȗ
duvelisib inhibits the migration of tumor supportive T cells in response to CXCL12, a chemokine that plays an 
important role in CLL pathogenesis. Duvelisib also inhibits polarization of macrophages towards the M2 
phenotype,76 which provide survival signals to CLL cells.20,24 In a patient-derived xenograft mouse model, dual 
inhibition of PI3K-įDQG3,.-Ȗsignificantly reduced the number of splenic CLL cells compared to PI3K-į
inhibition alone.77 These data suggest that duvelisib may have improved activity in patients with CLL by 
inhibiting both PI3K-įDQG3,.-Ȗ In a BTK-null X-linked agammaglobulinemia cell line transfected with 
BTK C481S, AKT phosphorylation was abrogated by treatment with duvelisib but not ibrutinib.78 Similarly, 
duvelisib, but not ibrutinb, reduced tumor burden in immunocompromised mice xenografted with peripheral 
blood mononuclear cells from ibrutinib-resistant patients with BTK C481S mutation.79 
 
 
This study investigates duvelisib for patients with CLL who have developed progressive disease or BTK and/or 
PLCG2 mutations on ibrutinib. In general, and in reported series of patients progressing on ibrutinib, the next 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
13 
therapy has been administered sequentially. In other words, a drug that has become ineffective is discontinued 
before a second drug is started. Many clinical studies have required washout periods before the next line of 
therapy can be started. However, disease acceleration after ibrutinib discontinuation suggests that ibrutinib may 
still exert at least a partial anti-tumor effect on progressive CLL.5 To prevent disease acceleration, this study 
overlaps duvelisib and ibrutinib for the first six 28-day cycles . The duration of ibrutinib overlap is limited to 
avoid unnecessary toxicities associated with continuation of a drug (ibrutinib) that has become, at least in part, 
ineffective at controlling CLL. After the initial period of duvelisib and ibrutinib combination therapy, duvelisib 
will be continued as a single agent until disease progression or intolerance.  
 
Although the toxicity profiles of duvelisib and ibrutinib as single agents are well recognized, the safety of the 
combination of duvelisib and ibrutinib has not been evaluated. Duvelisib is associated with immune-related 
toxicities such as diarrhea/colitis, cutaneous reactions, pneumonitis, transaminase elevation. Several lines of 
evidence support the hypothesis that coadministration with ibrutinib will improve the tolerability of duvelisib. 
First, treatment with ibrutinib downregulates inflammatory cytokines in CLL patients80 and inhibits cytokine 
secretion from in vitro activated T cells.81 Second, continuing ibrutinib therapy during CAR-T cell 
administration reduced cytokine release syndrome while improving efficacy.34,35 Third, ibrutinib is approved 
for the treatment of graft-versus-host disease after allogeneic transplantation. In a phase 1-1b study combining 
3,.įLQKLELWRUXPEUDOLVLEZLWKLEUXWLQLEIRUSDWLHQWVZLWKrelapsed or refractory CLL or mantle cell lymphoma, 
no dose-limiting toxicities (DLTs) were observed and the maximum tolerated dose of umbralisib was not 
reached.82 To evaluate the safety of the combination of duvelisib and ibrutinib, this study will have a safety 
lead-in cohort starting at duvelisib of 15 mg BID and continuing the subject’s dose of ibrutinib at the time of 
study entry. 
 
2.7 
Risk/Benefit Assessment 
 
2.7.1 
 Identified and Potential Risks Related to Duvelisib 
 
The identified risks for duvelisib treatment are infections, diarrhea/colitis, cutaneous reactions, 
pneumonitis, transaminase elevation and neutropenia. Potential risks are hepatotoxicity and 
reproductive toxicity. 
 
Infections 
 
Infection, specifically upper respiratory infection and pneumonia, is one of the most common reported 
adverse events in subjects who received duvelisib. Serious, including fatal (28/588; 4.8%), infections 
occurred in 31.6% (186/588) of subjects with hematologic malignances receiving duvelisib monotherapy. The 
most common serious infections were pneumonia, sepsis, and lower respiratory infections. In a subset of 
subjects (n=442, COPIKTRA™ United States Prescribing Information [USPI]), median time to onset of any 
grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. 
Treat infections prior to initiation of duvelisib. Advise subjects to report any new or worsening signs and 
symptoms of infection such as fever or chills. For Grade 3 or higher infection, withhold duvelisib until 
infection has resolved. Resume duvelisib at the same or reduced dose. 
 
Serious, including fatal (3/588; 0.5%), Pneumocystis jirovecii pneumonia (PJP) occurred in 1.7% (10/588) of 
subjects taking duvelisib. Provide prophylaxis for PJP during treatment with duvelisib. Following completion 
of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 
FHOOVȝ/:LWKKROGGXYHOLVLELQVXEMHFWVZLWKVXVSHFWHG3-3RIDQ\JUDGHDQGSHUPDQHQWO\GLVFRQWLQXHLI3-3
is confirmed. Cytomegalovirus (CMV) reactivation/infection occurred in 1% of subjects taking duvelisib. 
Consider prophylactic antivirals during duvelisib treatment to prevent CMV infection including CMV 
reactivation. For clinical CMV infection or viremia, withhold duvelisib until infection or viremia resolves. If 
duvelisib is resumed, administer the same or reduced dose and monitor subjects for CMV reactivation by 
PCR or antigen test at least monthly 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
14 
Diarrhea/Colitis 
 
Serious, including fatal (1/588; 0.2%), diarrhea or colitis occurred in 17.7% (104/588) of subjects with 
hematologic malignancies receiving duvelisib monotherapy. In a subset of subjects (n=442, COPIKTRA™ 
USPI), the median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), 
with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 
months; 75th percentile: 1 month). Advise subjects to report any new or worsening diarrhea, stool with mucus 
or blood, or severe abdominal pain. For non-infectious diarrhea or colitis, follow the guidelines below: For 
subjects presenting with mild or moderate diarrhea (Grade 1-2) (ie, up to 6 stools per day over baseline) or 
asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents as appropriate, continue 
duvelisib at the current dose, and monitor the subject at least weekly until the event resolves. If the diarrhea is 
unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive therapy with enteric acting 
steroids (eg, budesonide). Monitor the subject at least weekly. Upon resolution of the diarrhea, consider 
restarting duvelisib at a reduced dose. 
 
For subjects presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal 
signs, or with severe diarrhea (Grade 3) (ie, more than 6 stools per day over baseline) withhold duvelisib and 
initiate supportive therapy with enteric acting steroids (eg, budesonide) or systemic steroids. A diagnostic 
work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon 
resolution of the diarrhea or colitis, restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or 
recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening diarrhea or 
colitis 
 
Cutaneous Reactions 
 
Serious, including fatal (2/588; 0.3%), cutaneous reactions occurred in 5.1% (30/588) of subjects with 
hematologic malignances receiving duvelisib monotherapy. Fatal cases included drug reaction with 
eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). In a subset of subjects 
(n=442, COPIKTRA™ USPI), the median time to onset of any grade cutaneous reaction was 3 months 
(range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day 
to 37 months, 75th percentile: 2 months). Presenting features for the serious events were primarily described 
as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, 
desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise subjects to 
report any new or worsening cutaneous reactions, including painful sores or ulcers on skin, lips, or in the 
mouth, severe rash with blisters or peeling skin, rash with itching or rash with fever. Review all concomitant 
medications and discontinue any medications potentially contributing to the event. For subjects presenting 
with mild or moderate (Grade 1-2) cutaneous reactions, continue duvelisib at the current dose, initiate 
supportive care with emollients, anti-histamines (for pruritus), or topical steroids, and monitor the subject 
closely. Withhold duvelisib for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care 
with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. 
Upon resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous 
reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue duvelisib. 
In subjects with Stevens-Johnson syndrome (SJS), TEN, or DRESS of any grade, discontinue duvelisib 
 
Pneumonitis 
 
Serious, including fatal (2/588; 0.3%), pneumonitis without an apparent infectious cause occurred in 4.4% 
(26/588) of subjects with hematologic malignances receiving duvelisib monotherapy. In a subset of subjects 
(n=442, COPIKTRA USPI), the median time to onset of any grade pneumonitis was 4 months (range: 9 days 
to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 
75% of cases resolving by 2 months. 
 
Advise subjects to report any new or worsening cough or difficulty breathing. Withhold duvelisib in subjects 
who present with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
15 
interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate 
for etiology. If the pneumonitis is infectious, subjects may be restarted on duvelisib at the previous dose once 
the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), 
treat with systemic corticosteroids, and resume duvelisib at a reduced dose upon resolution. If non-infectious 
pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe or life-
threatening non-infectious pneumonitis, discontinue duvelisib and treat with systemic steroids. 
 
Transaminase Elevation 
 
TESAEs of ALT and AST elevation occurred in 1.5% (9/588) and 1.4% (8/588) of subjects respectively. 
TESAE of transaminase increased was reported in 1 subject (0.2%). In a subset of subjects (n=442, 
COPIKTRA™ USPI), the median time to onset of any grade transaminase elevation was 2 months (range: 3 
days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months). 
 
Monitor hepatic function during treatment with duvelisib. For Grade 2 ALT/AST elevation (greater than 3 to 
5 × ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 
ALT/AST elevation (greater than 5 to 20 × ULN), withhold duvelisib and monitor at least weekly until return 
to less than 3 × ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for 
subsequent occurrence. For Grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue duvelisib. 
 
Neutropenia 
 
Grade 3 or 4 neutropenia occurred in 30.1% (177/588) of subjects with hematologic malignancies receiving 
duvelisib monotherapy. In a subset of subjects (n=442, COPIKTRA™ USPIWKHPHGLDQWLPHWRRQVHWRI
Grade 3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 
months. 
 
Monitor neutrophil counts at least every 2 weeks for the first 2 months of duvelisib therapy, and at least 
weekly in subjects with neutrophil counts less than 1.0 Gi/L (Grade 3-4). Withhold duvelisib in subjects 
presenting with neutrophil counts less than 0.5 Gi/L (Grade 4). Monitor until ANC is greater than 0.5 Gi/L, 
resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence. The use 
of granulocyte-colony stimulating factor (GCSF) when appropriate per ASCO guidelines87 is recommended. 
 
Hepatotoxicity 
 
No findings of acute liver failure, or death associated with liver failure, have been observed in any clinical 
study with duvelisib. However, elevations in ALT and/or AST have been seen in subjects receiving duvelisib. 
Transaminase elevations were generally asymptomatic and reversible upon stopping drug. Subjects dosed 
with duvelisib in clinical trials have experienced elevated ALT in combination with elevated bilirubin, 
typically in the context of a complicated medical history. Elevations generally occurred early in duvelisib 
dosing, after which duvelisib was held and the events resolved. 
 
Monitor hepatic function during treatment with duvelisib. For Grade 2 ALT/AST elevation (greater than 3 to 
5 × ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 
ALT/AST elevation (greater than 5 to 20 × ULN), withhold duvelisib and monitor at least weekly until return 
to less than 3 × ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for 
subsequent occurrence. For Grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue duvelisib. 
 
Reproductive Toxicity 
 
There are no available human data informing the associated risk of reproductive toxicity with duvelisib. 
Pregnant and lactating women are excluded from clinical trials with duvelisib. Based on findings in animals 
and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman. In 
animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
16 
caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation 
loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities 
(malformations) at maternal doses approximately 10 times and 39 times the maximum recommended human 
dose (MRHD) of 25 mg BID in rats and rabbits, respectively. Advise pregnant women of the potential risk to 
a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to 
use effective contraception during treatment and for at least 30 days after the last dose. 
 
 2.7.2 
Identified and Potential Risks Related to Ibrutinib 
 
Bleeding-related events 
 
There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and without 
thrombocytopenia.  These include primarily minor hemorrhagic events such as contusion, epistaxis, and 
petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial 
hemorrhage and hematuria. Use of ibrutinib in subjects requiring other anticoagulants or medications that 
inhibit platelet function may increase the risk of bleeding. Subjects with congenital bleeding diathesis have not 
been studied. See Section 5.7.3  for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or 
supplements. See Section 5.5.1 for guidance on ibrutinib management with surgeries or procedures. 
 
Cardiac Arrhythmias  
 
Atrial fibrillation and atrial flutter, and cases of ventricular tachyarrhythmia including some fatal events,  have 
been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, acute 
infections, and a previous history of cardiac arrhythmia. Subjects who develop arrhythmic symptoms (eg, 
palpitations, lightheadedness) or new onset of dyspnea should be evaluated clinically, and if indicated, have an 
ECG performed. For cardiac arrhythmia that persists, consider the risks and benefits of ibrutinib treatment and 
follow the protocol dose modification guidelines (see Section 5.4.2). 
 
Cytopenias 
 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported in 
subjects treated with ibrutinib. 
 
Diarrhea 
 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and combination 
therapy. Other frequently reported gastrointestinal events include nausea, vomiting, and constipation. These 
events are rarely severe. Should symptoms be severe or prolonged follow the protocol dose modification 
guidelines (see Section 5.4). 
 
Infections 
 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects treated with 
ibrutinib therapy. Some of these reported infections have been associated with hospitalization and death. 
Consider prophylaxis according to standard of care in subjects who are at increased risk for opportunistic 
infections. Although causality has not been established, cases of progressive multifocal leukoencephalopathy 
(PML) and hepatitis B reactivation and pneumocystis pneumonia have occurred in patients treated with 
ibrutinib. Subjects should be monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting 
and jaundice) and appropriate therapy should be instituted as indicated 
 
Tumor Lysis Syndrome (TLS) 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
17 
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-agent ibrutinib 
or in combination with chemotherapy. Subjects at risk of TLS are those with comorbidities and/or risk factors 
such as high tumor burden prior to treatment, increased uric acid (hyperuricemia), elevated lactate 
GHK\GURJHQDVH/'+EXON\GLVHDVHDWEDVHOLQHDQGSUHဨH[LVWLQJNLGQH\DEQRUPDOLWLHV 
 
Non-Melanoma Skin Cancer 
 
Non-melanoma skin cancers have occurred in patients treated with ibrutinib. Monitor patients for the 
appearance of non-melanoma skin cancer. 
 
Rash 
 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in combination with 
chemotherapy. Most rashes were mild to moderate in severity. Isolated cases of severe cutaneous adverse 
reactions (SCARs) including Stevens-Johnson syndrome (SJS) have been reported in subjects treated with 
ibrutinib. Subjects should be closely monitored for signs and symptoms suggestive of SCAR including SJS. 
Subjects receiving ibrutinib should be observed closely for rashes and treated symptomatically, including 
interruption of the suspected agent as appropriate. In addition, hypersensitivity-related events including 
erythema, urticaria, and angioedema have been reported. 
 
Interstitial lung disease 
 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. Subjects should be 
monitored and evaluated for symptoms (eg, dyspnea, cough or pyrexia) and treated symptomatically, including 
interruption of the suspected agent as appropriate. Should symptoms develop follow the protocol dose 
modification guidelines. 
 
Leukostasis 
 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number of 
circulating lymphocytes (>400,000/μL) may confer increased risk.  
 
Lymphocytosis 
 
Upon initiation of treatment, a reversible increase in lymphocyte countVLHLQFUHDVHIURPEDVHOLQH
and an absolute count >5000/μL), often associated with reduction of lymphadenopathy, has been observed in 
most subjects with CLL/SLL) treated with ibrutinib as a single agent. This effect has also been observed in 
some subjects with mantle cell lymphoma (MCL) treated with ibrutinib. This observed lymphocytosis is a 
pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical 
findings. In both disease types, lymphocytosis typically occurs during the first few weeks of ibrutinib therapy 
(median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in subjects with MCL and 14 
weeks in subjects with CLL/SLL. This pharmacodynamic effect was less prominent or not observed in other 
indications. 
 
Hypertension 
 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects for new onset 
of hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust existing anti-
hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
 
2.7.3 
Risks Related to Blood Draws 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
18 
No major risks are involved with blood draws. Minor complications including bleeding, pain, and hematoma 
formation at the site of blood draws, vasovagal reactions or infections may rarely occur. 
  
2.7.4 
Risks Related to CT Scans 
 
CT (computed tomography) uses special x-ray equipment to obtain image data from different angles around 
the body and then uses computer processing of the information to show a cross-section of body tissues and 
organs. Oral and/or intravenous contrast agents will be used and are usually well tolerated. However, some 
subjects will experience allergic reactions to intravenous contrast. To lower the risk of allergic reactions, low 
allergenic contrast agents are administered at NIH clinical center.  In addition, subjects will be advised that 
approximately 2-7% of patients who receive contrast agents will experience a temporary reduction in kidney 
function lasting up to 2 weeks following infusion and that in rare instances, permanent renal damage can 
result from the use of the IV contrasting agent. Therefore, in subjects with impaired kidney function, we will 
not use intravenous contrast. 
 
The amount of radiation subjects will receive from the research scans in this study is 1.3 rem of radiation 
annually, which is below the guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects 
by the NIH Radiation Safety Committee.  All female subjects will receive pregnancy testing prior to radiation 
exposure. 
 
2.7.5 
Risks Related to Bone Marrow Biopsy 
 
The anesthetic can cause some temporary stinging and burning. A pulling sensation and discomfort may be 
felt as the marrow is withdrawn. Although rare, there is a potential for bleeding at the site, local infection, and 
nerve injury causing pain. Bleeding can be stopped by applying local pressure, and infection can be treated 
with antibiotics. 
 
 
2.7.6 
Risks Related to Lymph Node Biopsy 
 
The anesthetic can cause some temporary stinging and burning. After a core needle biopsy, the site may be 
tender for 2 to 3 days.  
An excisional biopsy may require general anesthesia. For 1 to 2 days after general anesthesia, subjects may 
feel tired and have a mild sore throat from intubation.  After an excisional biopsy, the site may feel tender, 
firm, swollen, and/or bruised. 
2.7.7 
Risks Related to Lymphapheresis 
The possible risks from lymphapheresis include bleeding from the site where the blood is extracted and 
returned, lightheadedness, infection, low blood pressure, and muscle cramping. 
Known Potential Benefits 
 
Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic 
leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. This indication is 
approved under accelerated approval based on efficacy and safety analysis of patients with at least 2 prior 
lines of therapy. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
19 
Assessment of Potential Risks and Benefits 
The median survival after CLL progression on ibrutinib is only 19.8 months.2 Treatment options after 
ibrutinib discontinuation are limited. The potential to achieve remission and prolong survival with duvelisib 
therapy for these patients outweighs the known potential risks of treatment. 
 
3.0 
STUDY DESIGN  
 
This is a single-center, open-label phase 2 study for CLL patients who have developed progressive disease or 
BTK and/or PLCG2 mutations on ibrutinib. The study has a single treatment arm using duvelisib with ibrutinib 
for the first six 28-day cycles followed by duvelisib alone. Treatment plan is discussed in detail in Section 6.0. 
 
Notwithstanding the expectation that tolerability of the combination will be favorable, there will be a safety 
lead-in based on a 3+3 dose-escalation design (Table 1). The starting dose will be duvelisib 15 mg BID and 
continuing the subject’s dose of ibrutinib at the time of study entry. The maximum tolerated dose (MTD) is 
defined as the highest dose at which 0 or 1 subject out of 6 subjects has experienced a DLT. The decision to 
escalate, de-escalate or suspend dose escalation is outlined in Table 1. If the MTD is determined to be duvelisib 
25 mg BID, subjects enrolled at DL1 will increase the dose of duvelisib to 25 mg BID after the first cycle or at 
the time MTD is determined, whichever occurs later. During the safety lead-LQVXEMHFWVZLOOEHHQUROOHG
week apart between each subject. Subjects enrolled in the safety lead-in will be included in the analysis of study 
endpoints. 
 
Table 1. Dose De-escalation Rules Based on Number of Subjects with DLTs 
Number of Patients with DLTs 
Decision 
DL1: duvelisib 15 mg BID 
0 DLT out of 3 subjects 
Enroll up to 3 subjects at DL2 
1 DLT out of 3 subjects 
Enroll up to 3 more subjects at DL1 
1 DLT out of 6 subjects 
Enroll up to 3 subjects at DL2 
 2 DLT out of 4 to 6 subjects 
Terminate study 
DL2: duvelisib 25 mg BID 
0 DLT out of 3 subjects 
Proceed to phase 2 study at DL2 
1 DLT out of 3 subjects 
Enroll up to 3 additional subjects at DL2 
1 DLT out of 6 subjects 
Proceed to phase 2 study at DL2 
'/7RXWRI4 to 6 subjects 
Enroll up to 3 additional subjects at DL1 if only 3 
subjects have been treated at DL1. Enroll up to 33 
subjects at DL1 if 0-1 DLT found in the first 6 
subjects treated. 
 
The study will use a Simon two-stage minimax design and enroll 18 subjects in the first stage. If ˺ 4 subjects 
achieve a response, the study will stop for futility; otherwise, the study will proceed to the second stage and 
enroll an additional 15 subjects for a total of 33 evaluable subjects.  
 
4.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
 
4.1 
Inclusion Criteria 
 
x 
$JH 18 years 
x 
Diagnosis of CLL or SLL as defined by the following: 
x 
CLL: clonal B cells 5,000 cells/PL in the peripheral blood. 
x 
SLL: lymphadenopathy with histopathological evaluation consistent with SLL, absence of cytopenia 
caused by clonal marrow infiltrate, and <5,000 B cells/PL in the peripheral blood 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
20 
x 
Immunophenotype: co-expression of CD5, CD19, CD20, and CD23. CD23 negative cases may be 
included if there is an absence of t(11;14). 
x 
Current treatment with ibrutinib for CLL. 
x 
Mutations in BTK and/or PLCG2 (from a Clinical Laboratory Improvement Amendments (CLIA)-certified 
laboratory) with measurable disease characterized by at least 1 of the following: 
x 
/\PSKDGHQRSDWK\O\PSKQRGHPHDVXULQJFPLQWKHJUHDWHVWGLDPHWHU 
x 
Splenomegaly: spleen measuring > 13 cm in craniocaudal length 
x 
/\PSKRF\WRVLV%FHOOVȝ/ 
x 
%RQHPDUURZLQILOWUDWLRQ&//FRPSULVLQJRIDOOFHOOV 
or  
Progressive disease characterized by at least 1 of the following when compared with nadir values: 
x 
Lymphadenopathy: appearance of any new enlarged lymph nodes (1.5 cm) or an increase by 50% in 
greatest determined diameter of any previous site (1.5 cm). 
x 
Splenomegaly: an increase in the cranio-caudal dimension of the spleen by 2 cm from nadir, on 
imaging or physical exam. 
x 
Lymphocytosis: an increase in the number of blood lymphocytes by 50% over nadir with 5,000 
cells/PL B cells not attributable to redistribution of leukemia cells from lymphoid tissues to the blood 
related to treatment with kinase inhibitor. 
x 
Cytopenia: occurrence of cytopenia directly attributable to CLL and unrelated to autoimmune 
cytopenia or treatment, DVGRFXPHQWHGE\DGHFUHDVHRI+EOHYHOVJG/RUJG/RUE\DGHFUHDVH
RISODWHOHWFRXQWVRU,000/PL, if the marrow biopsy is consistent with the cytopenia resulting 
from increased marrow infiltration of clonal CLL cells. 
x 
Eastern Cooperative Oncology Group (ECOG) performance status of 2. 
x 
Adequate organ function as defined in Table 2. 
 
Table 2. Summary of adequate organ function for eligibility 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 1000/PL 
Platelets 
75,000/PL 
Renal 
 
Serum creatinine 
< 2.0 mg/dL 
Hepatic 
 
Serum total bilirubin 
;8/1except subjects with Gilbert’s Syndrome 
AST (SGOT) and ALT (SGPT) 
3.0 X ULN  
x 
)RUZRPHQRIFKLOGEHDULQJSRWHQWLDO:&%3QHJDWLYHVHUXPȕKXPDQFKRULRQLFJRQDGRWURSLQȕK&*
pregnancy test within 7 days before first treatment (WCBP defined as a sexually mature woman who has 
not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 
consecutive months for women >55 years of age) 
x 
Willingness of male and female subjects who are not surgically sterile or postmenopausal to use medically 
acceptable methods of birth control for the duration of the study treatment and 3 months after the last dose 
of duvelisib  
x 
Willingness and ability to participate in all required evaluations and procedures in this study protocol 
including swallowing capsules without difficulty 
x 
Ability to understand the purpose and risks of the study and provide signed and dated informed consent 
and authorization to use protected health information (in accordance with national and local subject privacy 
regulations) 
 
4.2 
Exclusion Criteria 
 
x 
Richter transformation of CLL into an aggressive lymphoma 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
21 
x 
History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung 
function 
x 
Prior history of drug-induced colitis or pneumonitis 
x 
Known hypersensitivity to any of the study drugs 
x 
Major surgery within 4 weeks prior to screening 
x 
Central nervous system (CNS) non-Hodgkin lymphoma (NHL); lumbar puncture not required unless CNS 
involvement is clinically suspected 
x 
Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects with detectable viral 
load) 
x 
Infection with hepatitis B or hepatitis C : 
 
Subjects with a positive hepatitis B surface antigen (HBsAg)) will be excluded 
 
Subjects with or hepatitis C antibody (HCV Ab) will be excluded, unless they have received 
curative treatment for hepatitis C virus (HCV) and have undetectable viral RNA by PCR. 
 
Subjects with a positive hepatitis B core antibody (HBcAb) must have negative hepatitis B virus 
(HBV) deoxyribonucleic acid (DNA) to be eligible, must receive prophylaxis with entecavir (or 
equivalent) concomitant with duvelisib treatment, and must be periodically monitored for HBV 
reactivation by institutional guidelines 
 
Investigators who strongly believe that a positive HBcAb is false due to passive immunization from 
previous immunoglobulin infusion therapy should consider the risk-benefit for the patient given 
the potential for reactivation 
x 
Infection with human immunodeficiency virus (HIV): 
 
Subjects must be receiving antiretroviral therapy, have undetectable HIV RNA viral load and CD4 
cell count  200/ȝL to be eligible, must continue antiretroviral therapy concomitant with duvelisib 
treatment, and must be periodically monitored for suppression of viral load and potential drug-drug 
interactions between antiretrovial therapy and duvelisib 
x 
Infection with human T-lymphotropic virus type 1 
x 
History of tuberculosis treatment within the 2 years prior to randomization 
x 
History of chronic liver disease, veno-occlusive disease, alcohol abuse, or illicit drug use 
x 
Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids >20 mg of 
prednisone (or equivalent) once daily (QD) 
x 
Ongoing treatment for systemic bacterial, fungal, or viral infection at screening 
 
NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded 
if all other inclusion/exclusion criteria are met 
x 
Administration of a live or live attenuated vaccine within 6 weeks of randomization 
x 
Concurrent administration of medications or foods that are strong inhibitors or inducers of cytochrome 
P450 3A (CYP3A). No prior use within 2 weeks before the start of study intervention. 
x 
Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or herpes zoster 
(VZV) at screening 
x 
Baseline left ventricular ejection fraction (LVEF) < 45% 
x 
Baseline QT interval corrected with Fridericia’s method (QTcF) > 500 ms 
 
NOTE: criterion does not apply to subjects with a right or left bundle branch block (BBB) 
x 
Subjects with clinically significant medical condition of malabsorption, inflammatory bowel disease, 
chronic conditions which manifest with diarrhea, refractory nausea, vomiting, or any other condition that 
will interfere significantly with drug absorption  
x 
Female subjects who are pregnant or breastfeeding 
x 
Concurrent active malignancy that requires treatment except malignancies treated with antihormonal 
therapy alone, nonmelanoma skin cancer, or carcinoma in situ of the cervix. 
x 
History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication 
or a pacemaker within the last 6 months prior to screening 
x 
Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary 
condition, uncontrolled diabetes and inflammatory GI diseases such as Crohn’s Disease) or any important 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
22 
medical illness or abnormal laboratory finding that would, in the investigator’s judgment, increase the risk 
to the subject associated with his or her participation in the study 
 
5.0 
TREATMENT PLAN   
 
5.1 
Drug Administration 
 
Duvelisib is an orally administered product. Duvelisib will be administered with or without food. The drug dose 
is 25 mg BID or 15 mg BID. The capsules should be swallowed whole. Each dose of duvelisib is taken around 
the same time each day. If a dose is missed by fewer than 6 hours, subjects will take the missed dose 
immediately and take the next dose as usual. If a dose is missed by more than 6 hours, subjects will wait and 
take the next dose at the usual time. 
 
Ibrutinib is an orally administered product. Ibrutinib will be administered with a glass of water and with or 
without food. Subjects will continue the same dose of ibrutinib prior to study enrollment for the first six 28-day 
cycles. Each dose of ibrutinib is taken around the same time each day. The capsules should not be opened, 
broken, or chewed. The tablets should not be cut, crushed, or chewed. 
 
5.2 
Treatment Schedule 
 
All cycles will be 28 (± 7) days long. In cycles 1-6, duvelisib and ibrutinib will be administered. From cycle 7 
onwards, duvelisib will be administered alone until disease progression or intolerance. 
 
5.3 
Dose Limiting Toxicities 
 
The DLT evaluation period is defined as the first cycle after starting duvelisib. The following will qualify for a 
DLT: 
x 
Death related to duvelisib or ibrutinib 
x 
Any AE which leads to discontinuation or decrease in duvelisib dose per Sections 5.4.1 and 5.5.1 during 
the DLT window 
 
5.4 
Dose Modification Guidelines 
 
5.4.1 
Dose Modification of Duvelisib 
 
Toxicities attributed to duvelisib will be managed per Table 3, Table 4 and Section 11.2.1 with dose reduction, 
treatment hold, or discontinuation of duvelisib. 
 
Table 3. Duvelisib Dose Modification and Toxicity Management 
Toxicity 
Grade 
Management 
Non-hematologic  
Infections 
*UDGH 3 
x 
Withhold duvelisib until resolved 
x 
Duvelisib can be resumed at the same or reduced dose 
after resolution of a grade ˻ 3 infection based on the 
discretion of the Investigator (Table 4) 
Clinical CMV infection 
or 
viremia 
(positive 
PCR or antigen test) 
x 
Withhold duvelisib until resolved 
x 
Resume at the same or reduced dose (Table 4) 
x 
If duvelisib is resumed, monitor patients for CMV 
reactivation (by PCR or antigen test) at least monthly 
PJP 
x 
For suspected PJP, withhold duvelisib until evaluated  
x 
For confirmed PJP, discontinue duvelisib 
Non-infectious 
diarrhea or colitis 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 
x 
No change in dose 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
23 
stools per day over 
baseline)  responsive to 
antidiarrheal agents 
OR 
Asymptomatic (Grade 
1) colitis 
x 
Initiate supportive therapy with antidiarrheal agents as 
appropriate 
x 
Monitor at least weekly until resolved 
Mild/moderate  
diarrhea (Grade 1-2, up 
to 6 stools per day over 
baseline) unresponsive 
to antidiarrheal agents 
x 
Withhold duvelisib until resolved  
x 
Initiate supportive therapy with enteric acting steroids 
(e.g., budesonide)  
x 
Monitor at least weekly until resolved 
x 
Resume at a reduced dose (see Table 4) 
Severe diarrhea (Grade 
3, > 6 stools per day 
over baseline) 
OR 
Abdominal pain, stool 
with mucus or blood, 
change in bowel habits, 
peritoneal signs 
x 
Withhold duvelisib until resolved 
x 
Initiate supportive therapy with enteric acting steroids 
(e.g., budesonide) or systemic steroids 
x 
Monitor at least weekly until resolved 
x 
Resume at a reduced dose (see Table 4) 
x 
For recurrent Grade 3 diarrhea or recurrent colitis of any 
grade, discontinue duvelisib 
Life-threatening 
x 
Discontinue duvelisib 
Cutaneous 
reactions 
Grade 1-2 
x 
No change in dose 
x 
Initiate supportive care with emollients, antihistamines 
(for pruritus), or topical steroids 
x 
Monitor closely 
Grade 3 
x 
Withhold duvelisib until resolved 
x 
Initiate supportive care with emollients, antihistamines 
(for pruritus), or topical steroids 
x 
Monitor at least weekly until resolved 
x 
Resume at reduced dose (see Table 4) 
x 
If severe cutaneous reaction does not improve, worsens, 
or recurs, discontinue duvelisib 
Life-threatening 
x 
Discontinue duvelisib 
SJS, TEN, DRESS (any 
grade) 
x 
Discontinue duvelisib 
Pneumonitis 
without suspected 
infectious cause 
Moderate symptomatic 
(Grade 2) 
x 
Withhold duvelisib 
x 
Treat with systemic steroid therapy 
x 
If pneumonitis recovers to Grade 0 or 1, duvelisib may 
be resumed at reduced dose (see Table 4) 
x 
If non-infectious pneumonitis recurs or patient does not 
respond to steroid therapy, discontinue duvelisib 
Severe (Grade 3) or 
life-threatening 
x 
Discontinue duvelisib 
x 
Treat with systemic steroid therapy 
ALT/AST 
elevation 
3 to5 × upper limit of 
normal (ULN) (Grade 
2) 
x 
Maintain duvelisib dose 
x 
Monitor at least weekly until return to < 3 × ULN 
> 5 to 20 × ULN (Grade 
3) 
x 
Withhold duvelisib and monitor at least weekly until 
return to < 3 × ULN 
x 
Resume duvelisib at same dose (first occurrence) or at a 
reduced dose for subsequent occurrence (see Table 4) 
> 20 × ULN (Grade 4) 
x 
Discontinue duvelisib 
Hematologic 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
24 
Neutropenia 
Absolute 
neutrophil 
count (ANC) 0.5 to 1.0 
Gi/L  
x 
Maintain duvelisib dose 
x 
Monitor ANC at least weekly 
x 
G-CSF may be administered per Section 5.5.1 
ANC < 0.5 Gi/L 
x 
Withhold duvelisib 
x 
Monitor ANC until > 0.5 Gi/L 
x 
Resume duvelisib at same dose (first occurrence) or at a 
reduced dose for subsequent occurrence (see Table 4) 
x 
G-CSF may be administered per Section 5.5.1 
Thrombocytopenia Platelet count 25 to < 
50 Gi/L (Grade 3) with 
grade 1 bleeding 
x 
No change in dose 
x 
Monitor platelet counts at least weekly 
Platelet count 25 to < 
50 Gi/L (Grade 3)  with 
grade 2 bleeding 
OR 
Platelet count < 25 
Gi/L (Grade 4) 
x 
Withhold duvelisib 
x 
Monitor platelet counts until  25 Gi/L and resolution of 
bleeding (if applicable) 
x 
Resume duvelisib at same dose (first occurrence) or 
resume at a reduced dose for subsequent occurrence (see 
Table 4) 
 
Table 4. Dose Modification Levels 
Dose Level 
Dose 
Initial dose 
25 mg BID 
Dose reduction 
15 mg BID 
Subsequent dose reduction 
Discontinue duvelisib if subject is unable to tolerate 15 mg BID 
 
5.4.2 
Dose Modification of Ibrutinib 
 
Since subjects are on ibrutinib therapy prior to the initiation of duvelisib, treatment-emergent hematologic 
toxicities will be attributed to duvelisib and managed per Section 5.4.1. ,QWHUUXSWLEUXWLQLEIRUDQ\JUDGH 3 
non-hematologic toxicities attributed to ibrutinib. Once the symptoms of the toxicity have resolved to Grade 1 
or baseline (recovery), ibrutinib may be reinitiated at the original dose. If the toxicity reoccurs, reduce dose by 
140 mg per day. A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist 
or recur following two dose reductions, discontinue ibrutinib. 
 
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre- and post-surgery depending upon 
the type of surgery and the risk of bleeding. 
 
5.5 
Permanent Discontinuation of Study Drug Administration 
 
Duvelisib and/or ibrutinib may be continued in subjects who develop progressive disease until the start of next 
treatment for CLL to prevent acceleration of disease related to treatment withholding. Subjects who 
permanently discontinue study drug administration for treatment-related adverse events will be followed for 
resolution of the event. Subjects will remain on study until they meet off study criteria in Section 9.7. 
 
5.5.1 
Permanent Discontinuation of Duveslisib 
 
x 
Confirmed PJP 
x 
Life-threatening non-infectious diarrhea or recurrent grade 3 diarrhea 
x 
Life-threatening colitis or recurrent colitis of any grade 
x 
Life-threatening cutaneous reaction or SJS, TENS, or DRESS (any grade) or grade 3 cutaneous reaction 
that does not improve, worsens, or recurs 
x 
Grade 3 pneumonitis without suspected infectious cause or grade 2 non-infectious pneumonitis that recurs 
or does not respond to steroid therapy 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
25 
x 
Grade 4 ALT/AST elevation 
x 
Pregnancy or unwillingness to use acceptable method of contraception 
x 
Progressive disease (duvelisib may be continued until the start of next treatment as described above) 
 
5.5.2 
Permanent Discontinuation of Ibrutinib 
 
x 
Life-threatening cardiac arrhythmia  
x 
Pregnancy or unwillingness to use acceptable method of contraception 
x 
Progressive disease (ibrutinib may be continued until the start of next treatment as described above) 
 
5.6 
Concomitant Medications and Therapies 
 
Subjects may continue most medications they were prescribed prior to study enrollment for comorbid 
conditions. All concomitant medications, including over the counter drugs, will be recorded. 
 
5.6.1 
Supportive Medications and Care 
 
Subjects should receive appropriate supportive care as deemed clinically indicated by the investigator including, 
but not limited to: 
x 
Pneumocystis jirovecii pneumonia (PJP) prophylaxis: sulfamethoxazole/trimethoprim (or alternative agent 
in case of sulfa allergy) will be administered during treatment with duvelisib and continued until the 
absolute CD4+ T-FHOOFRXQW!ȝ/ 
x 
Antiviral prophylaxis: acyclovir or valacyclovir will be administered during treatment with duvelisib 
x 
Transfusions: packed red blood cells and/or platelets will be transfused as clinically indicated.   
x 
Granulocyte-colony stimulating factor (G-CSF): filgrastim or peg-filgrastim may be administered per 
American Society of Oncology guidelines.83 
x 
Steroids (e.g. systemic, enteric, or topical) may be administered to manage toxicities. 
 
Refer to Table 3 for duvelisib dose modification and toxicity management. 
 
5.6.2 
Medications that Inhibit or Induce CYP3A 
 
CYP3A4 has been identified as the primary contributor to the metabolism of duvelisib and ibrutinib. The 
concomitant use of drugs or foods that are strong inhibitors or inducers of CYP3A (Appendix B) should be 
avoided during treatment with duvelisib monotherapy or in combination with ibrutinib. Co-administration with 
a strong CYP3A inhibitor may increase the risk of duveslisib and ibrutinib toxicities. Reduce or withhold the 
dose of duvelisib and ibrutinib when co-administered with a strong CYP3A4 inhibitor. 
 
5.6.3 
QT Prolonging Agents 
 
Any medications known to cause QT prolongation should be used with caution during treatment with ibrutinib; 
periodic ECG and electrolyte monitoring should be considered.  
 
5.6.4 
Antiplatelet Agents and Anticoagulants 
 
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet function. In 
an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were 
observed. Bleeding events of any grade, including bruising and petechiae, occurred in subjects treated with 
ibrutinib. Subjects with congenital bleeding diathesis have not been studied. Subjects requiring the initiation of 
therapeutic anticoagulation therapy (e.g. atrial fibrillation) should be observed closely for signs and symptoms 
of bleeding and the risks and benefits of continuing ibrutinib treatment should be considered.   
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
26 
5.6.5 
Lifestyle Considerations 
 
Birth control 
Female subjects of reproductive potential and male subjects with female partners of reproductive potential must 
use effective contraception during treatment and for at least 30 days after the last dose of duvelisib. Male 
subjects must also refrain from donating sperm during their participation in the study and for 30 days after the 
last dose of duvelisib.  
 
Effective methods of contraception include:  
x 
True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), and withdrawal are not effective 
methods of contraception. 
x 
Sterilization 
x 
Female subject or female partner of male subject: When a woman of childbearing potential has had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior 
to study entry. In case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment. 
x 
Male subject or male partner of female subject: (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate). 
x 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
x 
Hormonal methods of contraception associated with inhibition of ovulation: oral, implantable, injectable, 
intravaginal, or transdermal contraception. 
 
Acceptable methods of contraception include: 
x 
Barrier methods of contraception: condom, diaphragm, or cervical/vault cap with spermicidal 
foam/gel/film/cream/vaginal suppository. 
 
Supplements 
Supplements such as fish oil and vitamin E preparations should be avoided during treatment with ibrutinib.  
 
5.6.6 
Prohibited Concomitant Medications and Therapy 
 
 
Table 5. Duvelisib Prohibited Concomitant Therapies 
Prohibited Concomitant 
Therapy 
Guidance 
Use of Vaccines 
For all subjects, the use of live or live attenuated vaccines is prohibited during 
the treatment with study intervention. 
 
The use of inactivated (or killed) vaccines (such as pneumococcal pneumonia 
vaccine) is allowed during the study, however subjects and their physicians 
should be aware that the effectiveness of any vaccine administered 
concomitantly with duvelisib may be diminished. The ability to generate an 
immune response to any vaccine following the administration of duvelisib has 
not been studied. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
27 
Prohibited Concomitant 
Therapy 
Guidance 
Immunosuppressants 
Subjects 
are 
not 
to 
receive 
ongoing 
treatment 
with 
chronic 
immunosuppressants (e.g., cyclosporine) or systemic steroids for > 1 week at 
doses > the equivalent of 20 mg prednisone QD. 
 
Note: Acute treatment for underlying autoimmune disorders (e.g., reactive 
airway disease, rheumatoid arthritis, etc.) with corticosteroid doses > 20 mg 
SUHGQLVRQH RU HTXLYDOHQW 4' IRU   ZHHN LV SHUPLWWHG GXULQJ WKH VWXG\
&RUWLFRVWHURLGGRVHVRIPJprednisone or equivalent QD are permitted 
during the study for physiological replacement or chronic treatment for 
underlying autoimmune disorders (e.g., reactive airway disease, rheumatoid 
arthritis, etc.).  
Other Anticancer Therapy 
or Investigational Agents 
During study intervention period, subjects are not to receive any additional 
anticancer therapy or other investigational agents not outlined in the protocol. 
Medications or Foods that 
Strongly Inhibit or Induce 
CYP3A4 
Use of a strong CYP3A inhibitor or inducer is prohibited. Co-administration 
with a strong CYP3A inhibitor increases duvelisib exposure which may 
increase the risk of duvelisib toxicities. Co-administration with a strong 
CYP3A inducer decreases duvelisib exposure which may reduce duvelisib 
efficacy. 
  
Appendix B provides a list of medications and foods known to inhibit (Table 
7) or induce (Table 8) CYP3A. Please note that these tables do not provide a 
comprehensive list of all medications which may modulate CYP3A activity. 
Abbreviations: CYP3A: cytochrome P450 3A; QD: once daily 
   
Table 6. Duvelisib Concomitant Therapies: Use with Caution 
Concomitant Therapy: 
Use with Caution 
Guidance 
Medications or Foods that 
Weakly or Moderately 
Inhibit or Induce 
CYP3A4 
Please discuss use of weak or moderate CYP3A inhibitors and inducers with 
the Medical Monitor. 
Section XX provides a list of medications and foods known to inhibit (Table 
XX) or induce (Table XX) CYP3A. Please note that these tables do not 
provide a comprehensive list of all medications which may modulate CYP3A 
activity. 
Medications that are 
Substrates of CYP3A 
x Co-administration with duvelisib decreases AUC of a 
sensitive CYP3A4 substrate which may decrease the 
efficacy of these drugs. Consider finding an alternative 
drug that is not a substrate of CYP3A4. Table 9 in 
Appendix B provides a list of medications known to be 
substrates of CYP3A. Please note that Table XX 
 
Table is not a comprehensive list of all medications which may be substrates 
of CYP3A. The Sponsor should be contacted with any questions regarding 
concomitant use of medications that are CYP3A substrates. 
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A; QD: once daily. 
 
6.0 
CLINICAL EVALUATIONS 
 
Procedures or tests conducted at outside institutions or as part of other NIH protocols may be used for screening 
or baseline purposes provided they were performed within the defined time frame. 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
28 
6.1 
Screening and Baseline Assessments 
 
Screening assessment for subject eligibility will be performed as part of 97-H-0041 or other NIH 
protocols. Subject eligibility is based on meeting all of the study inclusion criteria and none of the 
exclusion criteria as detailed in Section 4.0. Baseline tests will be performed within 4 weeks before 
starting duvelisib, unless otherwise specified.  
x 
AE/SAE assessment: the AE reporting period begins from the time that the patient provides informed 
consent through and including 30 calendar days after the last study drug dose. 
x Medical history: clinically relevant past medical history includes medical diagnoses and/or 
conditions that are 1) currently ongoing, or 2) occurred within 1 year of study enrollment, or 3) 
occurred before 1 year of study enrollment and potentially associated with major organ 
dysfunction or long-term sequelae (e.g. hypertension, hyperlipidemia, diabetes, surgery of major 
organ system, any malignancy except non-melanoma skin cancer) 
x Concomitant medication review 
x ECOG performance status (PS) 
x 
Physical exam 
x 
HLA typing (at any time before starting duvelisib) 
x 
Complete blood count (CBC) with differential  
x 
Acute care and mineral panels (includes Na, K, Cl, CO2, creatinine, glucose, BUN, phosphorus, 
magnesium, albumin, and calcium) 
x 
Total protein, uric acid, and LDH  
x 
Hepatic panel (includes alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin) 
x 
Reticulocyte count 
x 
PT, PTT 
x 
Serum protein electrophoresis with immunofixation (SPEP) 
x 
Serum free light chains and quantitative immunoglobulins  
x 
C-reactive protein (CRP) 
x 
Beta-2 microglobulin (B2M) 
x 
Haptoglobin and direct antiglobulin test (DAT) 
x 
Iron panel (includes ferritin, transferrin, iron), folate, and vitamin B12 
x 
Thyroid function panel (thyroid stimulating hormone, free T4, T3) 
x 
Hepatitis B and C virus Ab (within 12 weeks before starting duvelisib). For subjects with a positive HBcAb, 
hepatitis B DNA PCR will be performed. 
x 
HIV and HTLV-I/II Ab (within 12 weeks before starting duvelisib) 
x 
CMV and EBV PCR (blood) (within 12 weeks before starting duvelisib) 
x 
Lymphocyte phenotyping (T, B, NK)  
x 
For WCBP, one negative pregnancy tests (within 1 week before starting duvelisib) 
x 
Peripheral blood flow cytometry for CLL  
x 
CLL FISH (includes probes for 11q-, +12, 13q-, 17p-, t(11:14)) 
x 
Unstimulated and CpG-stimulated karyotype 
x 
IGHV mutation analysis (at any time before starting duvelisib) 
x 
CT of the neck, chest, abdomen and pelvis 
x 
BM aspirate and biopsy  
x 
EKG 
x 
Research blood (up to 80 mL) 
x 
Lymphapheresis for research (optional) 
x 
Lymph node biopsy for research (optional) 
 
6.2 
On Therapy Assessments 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
29 
6.2.1 
Cycles 1-6  
 
Tests will be performed at the end of Cycles 1-6, unless otherwise specified. Each cycle is 28 (± 7) days.  
 
x 
AE/SAE assessment 
x 
Interval history 
x 
Concomitant medication review  
x 
ECOG PS 
x 
Physical exam 
x 
CBC with differential (every 2 weeks for Cycles 1-2, tests conducted at outside institutions are accepted) 
x 
Acute care and mineral panels 
x 
Total protein, uric acid, and LDH  
x 
Hepatic panel 
x 
Reticulocyte count 
x 
CRP 
x 
B2M 
x 
Haptoglobin, DAT 
x 
HBV DNA Quantitative PCR (subjects with positive HBcAb only) 
 
Additional tests will be performed at the end of Cycles 3 and 6. 
 
x 
Serum free light chains and quantitative immunoglobulins 
x 
Lymphocyte phenotyping (T, B, NK) 
x 
Peripheral blood flow cytometry for CLL (at the end of Cycle 6 only) 
x 
CT of the neck, chest, abdomen and pelvis 
x 
Bone marrow biopsy and aspirate 
x 
Research blood (up to 80 mL) 
 
6.2.2 
Cycle 7 Onwards  
 
After Cycle 6, tests will be performed every 3 months (± 15 days), unless otherwise specified. 
 
x 
AE/SAE assessment 
x 
Interval history 
x 
Concomitant medication review  
x 
ECOG PS 
x 
Physical exam 
x 
CBC with differential 
x 
Acute care and mineral panels 
x 
Total protein, uric acid, and LDH  
x 
Hepatic panel 
x 
Reticulocyte count 
x 
B2M 
x 
Haptoglobin, DAT 
x 
HBV DNA Quantitative PCR (subjects with positive HBcAb only) 
x 
Lymphocyte phenotyping (T, B, NK) (every 6 months) 
x 
Peripheral blood flow cytometry for CLL (when subject meets all other criteria for complete remission as 
detailed in Section 7.0) 
x 
CT of the neck, chest, abdomen and pelvis (after 12 months on duvelisib, then annually) 
x 
Bone marrow biopsy and aspirate (when subject meets all other criteria for complete remission as detailed 
in Section 7.0) 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
30 
x 
Bone marrow flow cytometry for CLL (when subject meets all other criteria for complete remission as 
detailed in Section 7.0) 
x 
Research blood (up to 80 mL, optional) 
 
6.2.3 
Time of Progressive Disease or Suspicion of Progressive Disease 
 
x 
AE/SAE assessment 
x 
Interval history 
x 
Concomitant medication review  
x 
ECOG PS 
x 
Physical exam 
x 
CBC with differential 
x 
Acute care and mineral panels 
x 
Total protein, uric acid, and LDH  
x 
Hepatic panel 
x 
Reticulocyte count 
x 
B2M 
x 
Haptoglobin, DAT 
x 
Serum free light chains and quantitative immunoglobulins 
x 
CRP 
x 
CMV and EBV PCR (blood)  
x 
Lymphocyte phenotyping (T, B, NK) 
x 
Peripheral blood flow cytometry for CLL 
x 
CT of the neck, chest, abdomen and pelvis 
x 
Research blood (up to 80 mL) 
x 
CLL FISH (includes probes for 11q-, +12, 13q-, 17p-, t(11:14)) (optional) 
x 
Unstimulated and CpG-stimulated karyotype (optional) 
x 
PET scan (optional) 
x 
Bone marrow biopsy and aspirate (optional) 
x 
Bone marrow flow cytometry for CLL (optional) 
x 
Lymph node biopsy (optional) 
6.3 
Safety Assessment after Permanent Discontinuation of Duvelisib 
 
Safety assessments will be performed in subjects who are able to return for follow-up after permanent 
discontinuation of duvelisib. Tests will be performed 30 days (+ 7 days) after last dose of duvelisib is 
administered or before the next treatment starts, whichever occurs first. 
 
x 
AE/SAE assessment 
x 
Interval history 
x 
Concomitant medication review  
x 
ECOG PS 
x 
Physical exam 
x 
CBC with differential 
x 
Acute care and mineral panels 
x 
Total protein, uric acid, and LDH  
x 
Hepatic panel 
x 
Reticulocyte count 
x 
B2M 
x 
Haptoglobin, DAT 
x 
HBV DNA Quantitative PCR (subjects with positive HBcAb only) 
x 
Lymphocyte phenotyping (T, B, NK) 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
31 
 
6.4 
Follow-Up Assessments 
 
After the Safety Assessment in Section 6.3, subjects who discontinue treatment for an AE in the absence of 
disease progression or new anti-CLL therapy will be followed for progression and survival every 6 months (± 
30 days). After subjects progress or start new anti-CLL therapy, they will be followed yearly (±30 days) for 
survival. Survival follow-up may be conducted by phone. 
 
Subjects who discontinue treatment for disease progression or start new anti-CLL therapy will be followed 
yearly (± 30 days) for survival. Survival follow-up may be conducted by phone. 
 
7.0 
CRITERIA FOR RESPONSE 
 
Response assessments will follow iwCLL 2008 guidelines9 and incorporate clarifications for lymphocytosis 
associated with kinase inhibitors.84 Response includes complete response, partial response, and partial response 
with lymphocytosis (Table 4). 
 
Table 4. Response Definition 
Response 
CRD 
PRE 
PRL 
PDF 
SDG 
Group A 
Lymph 
nodesA 
None 1.5 cm 
Decrease 
50% 
Decrease 
50% 
Increase  
or any new 
lesion > 1.5 cm 
Change of -
49% to +49% 
Spleen and/or 
liver sizeB 
Spleen <13 cm; 
liver size 
normal 
Decrease 
50% 
Decrease 
50% 
Increase 
or new 
splenomegaly 
Change of -
49% to +49% 
Blood 
lymphocytes 
ȝ/ 
 
Decrease 
50% 
Increase or 
decrease < 50% 
Increase 
and > 5000ȝ/ 
B cells 
Change of -
49% to +49% 
Group B 
Platelet count 
 ȝ/ 
ȝ/
or increase 
50% over 
baseline 
ȝ/
or increase 
50% over 
baseline 
Decrease 
50% secondary 
to CLL 
Change of -
49% to +49% 
Hemoglobin 
 g/dL 
JG/RU
increase 
over baseline 
JG/RU
increase 
over baseline 
Decrease 
50% secondary 
to CLL 
Increase < 11.0 
g/dL or < 50% 
over baseline, 
or decrease < 2 
g/dL 
Neutrophils 
ȝ/ 
N/A 
N/A 
< ȝ/
secondary to 
CLL 
N/A 
Bone 
marrowC 
Normocellular, 
< 30% 
lymphocytes, 
no B-lymphoid 
nodules 
N/A 
N/A 
N/A 
N/A 
A Sum of the products (SPDs) of up to 6 lymph nodes as evaluated by CT scans or if CT scan is unavailable, 
by physical exam. For PD, at least one of the target lesions should be pathologically enlarged (long axis > 1.5 
cm). 
B Spleen and liver size will be assessed by CT scans. Given the impact of numerous medical conditions, liver 
size should only be counted if hepatomegaly is clearly attributable to lymphoid involvement. 
C Complete response requires confirmation with bone marrow biopsy. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
32 
D For CR, all group A and B parameters must be met. For CR with incomplete marrow recovery (CRi), all 
criteria must be met, except for persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to 
CLL, but related to drug toxicity. 
E For PR, at least 2 group A parameters and 1 group B parameter must be met, if previously abnormal. If only 
1 parameter of both groups A and B was abnormal before therapy, only 1 needs to improve. 
F For progressive disease (PD), at least 1 parameter must be met on two consecutive assessments within 3 
months or transformation to a more aggressive histology. Change in each parameter is relative to baseline or 
nadir values. 
G For SD, criteria for CR, PR, PRL, or PD have not been met. 
 
Abbreviations 
CR: complete remission; CRi: complete response with incomplete marrow recovery; PR: partial remission; 
PRL: partial remission with lymphocytosis; PD: progressive disease; SD: stable disease 
 
8.0 
ANCILLARY LABORATORY RESEARCH STUDIES 
 
8.1 
Collection of Samples  
 
Blood samples: A volume not to exceed 550 mL of peripheral blood will be requested during the initial 8-week 
period.  Subsequent research blood draws will typically consist of <100 mL of peripheral blood at follow up 
visits (not to exceed 550 mL in any 8-week period). 
 
Lymphapheresis: Lymphapheresis procedure for research may be obtained before starting duvelisib, and/or in 
subjects with persistent lymphocytosis, and/or at progression of disease or suspicion of progressive disease.  
 
Bone marrow biopsies and aspirate: Bone marrow biopsy cylinder and up to 10 mL of bone marrow aspirate 
may be obtained for research as indicated in Section 6.0.  
 
Lymph node biopsies: An excisional or core needle lymph node biopsies may be obtained before starting 
duvelisib, and/or during treatment, and/or at progression of disease or suspicion of progressive disease.  
 
During the course of participating on this study, an additional 10 mL of blood (NIH visits only) and 5 mL of 
bone marrow aspirate each time a patient has a bone marrow examination may be requested. These samples 
will be stored with the subject’s permission for other exploratory laboratory research studies reviewed and 
approved by the IRB.  Research samples will be coded and stored in the secure laboratory of Dr. Wiestner.  
 
8.2 
Intended Use 
 
These specimens will not be used for diagnostic purposes.  
 
The translational and correlative endpoints of the study require analysis of samples from blood, bone marrow, 
and lymph node for immune cell phenotyping and targeted or whole exome sequencing. 
 
Leftover and additional samples may be used for the descriptive or exploratory ancillary research studies, 
including, but not limited to, studies approved by the NIH Intramural IRB. 
 
8.3 
Storage, Tracking and Disposition of Samples and Data 
 
Storage: All samples will be stored in the laboratory of Dr. Wiestner. Collected samples will be de-identified 
prior to storage following current NHLBI DIR BSI Policy. Efforts to ensure protection of patient information 
include: 
x 
Each sample is assigned a unique number.  


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
33 
x 
Vials holding patient samples are labeled with the sequential laboratory accession ID number that does 
not contain any personal identifier information. 
x 
An electronic database is used to store patient information related to the coded samples  
x 
The laboratory is located in a controlled access building and laboratory doors are kept locked. Visitors 
to the laboratory are required to be accompanied by laboratory staff at all times.   
x 
Hard copy records or electronic copies of documents containing patient information are kept in the 
locked laboratory or other controlled access locations.   
 
Tracking: Samples will be ordered and tracked through the CRIS Sunrise. If CRIS Sunrise is unavailable, NIH 
Form 2803-1 will be completed and will accompany the specimen and be filed in the medical record.  Samples 
will not be sent outside the NIH without an executed MTA or CTA. 
 
End of study procedures: Samples from consenting subjects will be stored until they are no longer of scientific 
value or if a subject withdraws consent for their continued use, at which time they will be destroyed.  
 
Loss or destruction of samples: If a major breech occurs in  the tracking and storage of samples, the IRB will 
be notified. 
 
9.0 
BIOSTATISTICAL CONSIDERATIONS 
 
9.1 
Primary Endpoint 
 
x 
The best overall response rate includes CR, PR, and PRL and will be assessed per Section 7.0. Safety of 
duvelisib plus ibrutinib combination 
 
9.2 
Secondary Endpoints 
 
x 
Progression-free survival (time from treatment initiation to progression of disease or death from any cause) 
x 
Overall survival (time from treatment initiation to death from any cause) 
x 
Duration of response (time from initial response to progression of disease) 
x 
Best response 
x 
Safety of duvelisib as monotherapy 
 
9.3 
Exploratory Endpoints 
 
x 
Immune cell profiling at baseline, during combination treatment with ibrutinib plus duvelisib, and during 
duvelisib monotherapy 
x 
Minimal residual disease by flow cytometry in peripheral blood and/or bone marrow 
x 
Quantification of allele frequency of BTK and PLCG2 mutations (if present at baseline) during treatment 
x 
Targeted or whole exome sequencing of sequential tumor samples to assess clonal evolution. 
x 
Measurement of gene expression in cells or tissues. Techniques frequently used include RNA sequencing, 
gene expression profiling on microarrays, quantitative RT-PCR, Western blotting, flow cytometry and 
ELISA assays. 
x 
Measurements of drug concentrations, biologic molecules and disease markers in blood, serum, and 
plasma. 
x 
Culture of cells from research subjects to investigate molecular disease mechanisms, model host tumor 
interactions, and to test effect of drugs on cell survival and cellular functions. 
x 
Transplantation of human cells into mice (xenograft model) to study disease biology and to investigate 
the effect of experimental therapy. 
x 
Modifications of cells using standard expression systems or biologic molecules, e.g. interfering RNA, to 
investigate the effects of candidate genes on cellular functions. 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
34 
 
9.4 
Sample Size  
 
There are limited data to estimate the true ORR for patients who have developed BTK and/or PLCG2 mutations 
and/or disease progression following treatment with ibrutinib. In a retrospective cohort study, patients treated 
ZLWK WKH 3,.į LQKLELWRU LGHODOLVLE after discontinuing ibrutinib for any reason had an ORR of 46%.38 A 
retrospective study of the French Innovative Leukemia Organization (FILO) reported an ORR of 72% to 
idelalisib after ibrutinib discontinuation among 29 CLL patients.39 Neither reported the efficacy of idelalisib 
for ibrutinib-resistant CLL separately. This study will use a Simon two-stage minimax design to test the null 
hypothesis (H0) that the ORR after 6 cycles is ˺ 20%. If the true ORR is 40%, the following two-stage design 
would have a power of 80% with a type 1 error of 0.05. 
 
In the first stage, the study will enroll 18 subjects and assess ORR after 6 cycles. If ˺ 4 subjects achieve a 
response, the study will stop for futility and H0 is not rejected. If ˻ 5 subjects achieve a response, the study 
will proceed to the second stage and enroll an additional 15 subjects for a total of 33 evaluable subjects. The 
null hypothesis will be rejected if  responses are observed in 33 subjects. 
 
Efficacy and safety will be assessed in the intent-to-treat population defined as eligible subjects who provide 
written informed consent. Up to 3 additional subjects may be enrolled to account for inadvertent enrollment of 
ineligible subjects. 
 
9.5 
Statistical Methods 
 
The planned analyses will include descriptive statistics on the proportions of overall response. The response 
probabilities will be estimated using the sample proportions and their inferences including confidence intervals 
and hypotheses testing will be evaluated using binomial distributions. PFS, OS, and DOR will be analyzed 
using appropriate nonparametric tools in survival analysis such as Kaplan-Meier estimates taking consideration 
of random censoring.   
 
In addition, methods based on survival analysis, cumulative incidence rates and other competing risk models 
will be used to evaluate the effect of treatment.  Graphical tools will be used to display the appropriate estimates 
(i.e. estimated proportions and Kaplan-Meier curves) and their corresponding 95% confidence intervals.  
 
9.6 
Study Stopping Rules   
 
The study will be halted pending discussions with Verastem, Inc., the FDA and NIH Intramural IRB regarding 
safety and the need for protocol revisions if any of the following conditions are met: 
x 
If  2 DLTs at DL-1 per Section 3.0. 
x 
If treatment related serious adverse events (TRSAEs) that occur during the treatment period substantially 
exceed an anticipated rate. 
 
The following specified TRSAEs determined to be related to treatment will be considered for early stopping of 
the study: 
x 
Death   
x 
Grade 4 non-hematologic toxicity, except abnormal laboratory values which are not clinically significant 
or isolated in nature and which resolve within 7 days, including electrolyte abnormalities that respond to 
medical intervention 
 
The anticipated rate of these specified TRSAEs within the first 6 cycles (completion of primary endpoint) is 
anticipated to be 20%. Following Geller, et al.,85 the study’s stopping rule is determined by a Bayesian 
approach. The stopping boundary for an experiment is reached if the Bayesian posterior probability that the true 
probability of developing one or more of the specified TRSAEs exceeds this benchmark rate of 20% is at least 
90%. We take our prior distribution to be a beta distribution so that our prior clinical opinion is worth 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
35 
approximately 20% of the weight we will place on the new data. This gives prior parameters Įȕ .4, 5.6). 
Hence, in deciding to stop the study, data from the study will dominate over prior opinion. Monitoring TRSAEs 
will start when the first 3 subjects are evaluable for TRSAEs within the first 6 cycles. 
 
Number of  subjects 
in the experiment 
Stop if the number of subjects who have developed 
any of the specified TRSAEs reaches: 
3 - 4 
3 
5 - 8 
4 
9 - 12 
5 
13 - 16 
6 
17 - 20 
7 
21 - 24 
8 
25 - 28 
9 
29 - 32 
10 
33 
11 
 
 
The performance of the above stopping rule was investigated by a simulation study. In each simulation run, a 
study with 33 independent Bernoulli trials was generated, each had a probability p for having TRSAE and q=1-
p for not having TRSAE and compared the TRSAE outcomes with the above stopping boundary to determine 
whether the study was stopped. The simulation was repeated 100,000 times and the proportion of stopped studies 
computed (i.e. “number of stopped studies”/100,000) which were stopped using the above stopping rule.  The 
following table summarizes the proportions of stopped studies under a number of scenarios for p: 
 
Probability of TRSAE = p 
0.1 
0.15 
0.20 
0.25 
0.30 
0.40 
Proportion of Stopped Studies 
1% 
6% 
19% 
40% 
63% 
93% 
Average number of subjects 
32.7 
31.7 
29.4 
25.8 
21.4 
13.4 
Average number TRSAEs 
3.3 
4.8 
5.9 
6.5 
6.4 
5.4 
 
These results suggest that the study’s stopping rule has a low probability of stopping a study when the 
proportion of TRSAE is  20%, and the probability of stopping a study is high when the true proportion of 
TRSAE > 20%. Based on these results, the Bayesian stopping rule has satisfactory statistical properties.  
 
9.7 
Off Study Criteria 
 
Subjects will be taken off study for: 
x Subject choice to withdraw from the study 
x Lost to follow-up 
x Death 
x Study termination 
 
When a subject withdraws from the study, the reason for withdrawal must be documented in source documents. 
Efforts will be made to obtain partial withdrawal of consent in order to continue to collect survival data on all 
subjects who were enrolled in the study. 
 
When a subject is lost to follow-up, efforts will be made by the study site personnel to contact the subject and 
determine the reason for study discontinuation. 
 
Completion of the study:  Subjects will be followed indefinitely until an off study criterion is met or the study 
is closed to further follow up care. Once study participation is complete, the subject will be referred back to his 
or her referring physician for consideration of standard therapy or evaluated for eligibility for other NIH 
protocols. 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
36 
10.0 
SAFETY ASSESSMENT AND MONITORING 
 
Principal Investigator (PI):  Accrual, efficacy and safety data will be monitored by the PI Clare Sun, M.D., 
and by the accountable and medically responsible investigator, Adrian Wiestner, M.D., Ph.D. 
 
NIH Intramural IRB:  Prior to implementation of this study, the protocol and the proposed patient consent 
and assent forms will be reviewed and approved by the properly constituted Institutional Review Board (IRB) 
operating according to 45 CFR 46. Quality assurance and control monitoring will be consistent with the NHLBI 
Division of Intramural Research Clinical Research Quality Assurance and Quality Control Policy. Accrual and 
safety data will also be monitored and reviewed annually by the IRB. 
 
NHLBI DSMB:  The NHLBI Data And Safety Monitoring Board (DSMB) will review the protocol, progress 
report, accrual, efficacy and safety data at six- or twelve-month intervals as scheduled.  All AEs observed during 
the clinical trial as detailed in Section 10.3.4 will be reported to the DSMB at the regularly scheduled DSMB 
meeting. The DSMB may recommend early termination of the study for considerations of safety and efficacy.  
 
Verastem, Inc.: Verastem will approve all amendments to the protocol or informed consent prior to submission 
to the IRB so long as the protocol is open to accrual or sample and/or data analysis continues. An annual 
progress report, any amendments to the protocol, and any change in the status of the protocol will be forwarded 
to Verastem, Inc. 
 
10.1 
Assessment of Safety 
 
 
10.1.1 Severity 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized to describe 
the severity of AEs (Table 5). 
 
Table 5. Adverse Event Grade (Severity) Scale 
Grade 
Severity 
Description 
1 
Mild 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
2 
Moderate 
Minimal, local or noninvasive 
intervention indicated; limiting age-appropriate 
instrumental ADLA 
3 
Severe or medically significant 
Hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-
care ADLB 
4 
Life-threatening 
Urgent intervention indicated 
5 
Death related to AE 
Death related to AE 
A Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
B Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
10.1.2 Causality Assessments 
 
The following general guideline will be followed: 
Unrelated 
Another cause of the AE is more plausible; a temporal sequence cannot be established with 
the onset of the AE and administration of the investigational product; or, a causal 
relationship is considered biologically implausible. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
37 
 
10.1.3 Pregnancy 
 
A subject must immediately inform the Investigator if the subject or subject’s partner becomes pregnant from 
the time of consent to 30 days after the last dose of study drug(s). Any female subjects receiving study drug(s) 
who become pregnant must immediately and permanently discontinue study drug(s). The Investigator should 
counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus. The 
pregnant woman should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. Although pregnancy itself is not regarded as an AE unless there is cause to 
believe that the study intervention may have interfered with the effectiveness of contraceptive medication or if 
the outcome of pregnancy meets SAE criteria (miscarriage or congenital anomaly/birth defect, etc.), in which 
case it should be reported in the same manner and timelines as an SAE, the outcome will need to be documented. 
Any SAEs associated with pregnancy (e.g. congenital abnormalities/birth defects/spontaneous miscarriage or 
any other serious events) must additionally be reported. In addition, any infant death or congenital anomaly 
occurring after 30 days that the Investigator suspects is related to the in-utero exposure to the study intervention 
should also be reported as an SAE. Hospitalization for normal delivery of a healthy newborn is not an SAE. 
Consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant 
until 30 days old will be requested. Subjects will be followed for disease progression and survival until they 
meet off study criteria in Section 9.7. 
 
 
Any pregnancy must be reported to Verastem, Inc. within 24 hours of the Investigator’s knowledge of the 
pregnancy using a Pregnancy Report Form. The Investigator will observe the pregnant woman until 
completion of the pregnancy and must notify Verastem, Inc. of the outcome within 24 hours of the 
Investigator’s knowledge of the pregnancy outcome using a Pregnancy Outcome Form. This notification 
includes pregnancies resulting in live, normal births. 
 
10.2 
Documentation, Data Collection, and Reporting  
 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points during the study.  
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during questioning, or 
detected through physical examination, clinically significant laboratory test, or other means will be recorded in 
the patient’s medical record. Each AE/SAE is to be evaluated for duration, severity, seriousness, and causal 
relationship to the study drugs.  The action taken with study drug and the outcome must also be recorded.   
 
Hospitalizations for elective surgery or other medical procedures that are not related to a TEAE are not 
considered SAEs. Hospitalization, which in the opinion of the Investigator, is unrelated to the study 
intervention, and due to purely non-medical circumstances (e.g., respite care, lack of a caretaker at home, lack 
Unlikely to 
be Related: 
A temporal sequence with the onset of the adverse event and administration of the 
investigational product is improbable, but not impossible. Concurrent or underlying disease, 
or the use of other drugs or procedures provide plausible explanations for the adverse event. 
Possibly 
Related 
There is a clinically plausible time sequence between onset of the AE and administration of 
the investigational product, but the adverse event could also be attributed to concurrent or 
underlying disease, or the use of other drugs or procedures. Possibly related should be used 
when the investigational product is one of several biologically plausible adverse event 
causes. 
Probably 
Related: 
There is a clinically plausible time sequence between onset of the adverse event and 
administration of the investigational product, and the adverse event is unlikely to be 
attributed to concurrent or underlying disease, or the use of other drugs or procedures. 
Clinical response to withdrawal of the investigational product may indicate the adverse 
event is probably related. Rechallenge with the investigational drug is not required. 
Definitely 
Related 
The AE is clearly related to use of the investigational product. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
38 
of transportation home) are also not considered to be SAEs. Progressive Disease (PD) under study (including 
signs and symptoms of progression) if documented by use of appropriate methods, should not be reported as 
an SAE unless the outcome of the PD is fatal during the study or within the safety reporting period. If the 
malignancy has a fatal outcome during the study or within the safety reporting period, then the event should be 
reported using the term "disease progression" with a Common Terminology Criteria for Adverse Events 
(CTCAE) severity of Grade 5. Death should not be reported as an SAE. The primary reason for a subject’s 
death should be reported as an SAE, with death reported as the outcome. 
 
The following AEs will be recorded in the patient’s medical record but not captured in the database: 
x 
Laboratory values that do not result in discontinuation from the study, are not deemed to be 
clinically significant, or do not require treatment or therapeutic intervention. 
x 
Grade 1 AEs 
 
All other AEs/SAEs will be captured on the appropriate case report form (CRF). Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. AEs will be followed to adequate resolution or stability. 
 
10.3 
Reporting Period for AEs 
 
The AE reporting period for this study begins when the patient provides written informed consent and ends 
with the safety follow-up visit. If an SAE is present at the safety follow-up visit or within 30 days of the last 
dose of study drug (whichever is later), it should be followed to resolution or until the Investigator assesses the 
subject as stable, a new anticancer therapy is initiated, or the subject is lost to follow-up or withdraws consent. 
Resolution/stable means the subject has returned to baseline state of health or the Investigator does not expect 
any further improvement or worsening of the event. 
 
10.4 
FDA, NIH IRB, and CD Reporting 
 
10.4.1 NIH Intramural IRB reporting 
  
x Expedited Reporting 
x Events requiring expedited reporting will be submitted to the IRB per Policy 801 “Reporting Research 
Events”. 
x  
x Reports to the IRB at the time of Continuing Review: 
x The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” to determine IRB reporting 
requirements. 
x  
x Reports to the CD: 
x The PI or designee will refer to NHLBI DIR Policy to determine CD reporting requirements and timelines.  
 
10.5 
Safety Reporting to the Pharmaceutical Collaborator 
 
All events listed below concerning the Verastem, Inc. product must be reported within 24 hours of knowledge of 
the event or within the defined timeframe to Verastem, Inc. Safety and Pharmacovigilance (email: 
rtpsafety@ppdi.com, facsimile: 888-529-3580). 
x 
All SAEs regardless of attribution 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
39 
x 
Any Safety Information including, but not limited to: 
o Pregnancies including partner pregnancies  
o Breastfeeding 
o Overdose 
o Transmission of an infectious agent through contamination of a Verastem product 
x 
Copies of any correspondence or telephone conversation logs with the applicable Regulatory Authorities 
regarding all SAEs, regardless of attribution, within a reasonable time frame 
 
The Investigator will provide additional information to Verastem, Inc. about SAEs or Safety Information upon 
request. 
 
10.6 
FDA Regulatory Requirements (Waived) 
An IND application with the FDA is not required for this study.  The proposed research with duvelisib 
and ibrutinib meets the exemption requirements noted in 21 CRF 312.2, specifically: 
1. The drug products are lawfully marketed in the United States. 
2. The investigation is not intended to be reported to FDA as a well-controlled study in support 
of a new indication and there is no intent to use it to support any other significant change in 
the labeling of the drug. 
3. In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug.  
4. The investigation does not involve a route of administration, dose, patient population, or other 
factor that significantly increases the risk (or decreases the acceptability of the risk) associated 
with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
5. The investigation is conducted in compliance with the requirements for review by an IRB (21 
CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
6. The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). 
10.7 
Considerations for Other Reportable Events 
 
Unanticipated Problems 
Definition: 
Any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; and 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others (which many include research staff, family 
members or other individuals not directly participating in the research) at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
expected. 
Reporting: 


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40 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board (IRB) as per 
Policy 801 and to the NHLBI Clinical Director per NHLBI guidelines. 
Protocol Deviations 
NIH Definition: 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research protocol.  
x 
Major deviations: Deviations from the IRB approved protocol that have, or may have the potential to, 
negatively impact the rights, welfare or safety of the subject, or to substantially negatively impact the 
scientific integrity or validity of the study. 
x 
Minor deviations: Deviations that do not have the potential to negatively impact the rights, safety or 
welfare of subjects or others, or the scientific integrity or validity of the study. 
 
Reporting: 
It is the responsibility of the investigator to use continuous vigilance to identify and report deviations to the 
NIH Institutional Review Board as per Policy 801 and to the NHLBI Clinical Director per NHLBI guidelines. 
 
11.0 
BIOSPECIMEN AND DATA MANAGEMENT PLAN 
 
11.1 
Data Management 
 
The PI will be responsible for overseeing entry of data into an in-house password protected electronic system 
and ensuring data accuracy, consistency and timeliness. The PI, associate investigators/research nurses and/or 
a contracted data manager will assist with the data management efforts to ensure that data is verifiable and 
evaluable. Data will be abstracted from Clinical Center progress notes and investigations as well as from outside 
medical records. Laboratory data from NIH will be imported electronically from CRIS into an in-house clinical 
trial database. Laboratory values from outside physicians will be entered into the system.  
 
Research data will be prospectively collected by authorized personnel and entered into an NHLBI, 21 CFR 11 
compliant, database which will consist of the study specific set of electronic CRFs (e-CRFs) used for 
capturing, managing and reporting clinical research data. 
 
We will maintain the confidentiality of identifiable private information collected in this Clinical Trial and 
protect the privacy of the individual human subjects. Primary data containing individually identifiable 
information obtained during the conduct of the protocol will be kept in secure network drives or in approved 
alternative sites that comply with NIH information security standards. Neither individual personal identifiers 
nor the key linking coded data to individuals will be released to third parties including Verastem, Inc. without 
prior IRB approval.  
 
11.2 
Data Sharing and Future Use of Data 
 
De-identified human data generated for use in future and ongoing research will be shared through a NIH-
funded or approved repository (ClinicalTrials.gov) and BTRIS. At the completion of data analysis, data will 
be submitted to ClinicalTrials.gov either before publication or at the time of publication or shortly thereafter.  
 
Research data may be shared with qualified non-collaborator recipients following publication of the primary 
research results after removal of PII.  Refusal of a research subject participant to permit future use of data--
other than required in the protocol --will be honored.  Limitations in data sharing and future use of data due to 


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Clare Sun, M.D. 
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41 
contractual obligations (e.g., CRADAs) or intellectual property proceedings (such as patent filings) will be 
honored. 
 
11.3 
Future Use of Biospecimens 
 
Following analyses of biospecimens for primary research purposes, remaining samples suitable for future 
research will be stored in manner that conforms with DIR policy (such as BSI) or in a publicly accessible 
research biospecimen repository following IRB approval. Biospecimens may be destroyed only when permitted 
by the clinical director and the IRB. 
 
Any future research use of biospecimens not defined in the protocol in which NHLBI investigators are engaged 
in research (e.g., they are undertaking research activities and hold the key that identifies research subjects) 
requires IRB review and approval.  Coded biospecimens (NHLBI investigators hold the key that identifies 
research subjects) to be shared outside of NIH for future research use requires an executed transfer agreement 
and may require IRB approval if results will be returned and re-identified.  Unlinked biospecimens (no key to 
identify research subjects exists) to be shared outside of NIH for future research use requires an executed 
transfer agreement.  Refusal of a research subject participant to allow for future use of identifiable 
biospecimens--other than required in the protocol or for appropriate regulatory purposes --will be honored. 
 
 
11.4  
Clinical Monitoring  
 
As per ICH-GCP 5.18 and FDA 21 CFR 312.5 clinical protocols are required to be adequately monitored by 
the study sponsor. The monitoring  of this study will be conducted by Clinical  Research Associates 
(CRAs)/Monitors employed by an independent contract organization working under an agreement with NHLBI 
to monitor aspects of the study in accordance with the appropriate regulations and the approved protocol. The 
objectives of a monitoring visit will be: 1) to verify the existence of signed informed consent form (ICF) and 
documentation of the ICF process for each monitored subject; 2) to verify the prompt and accurate recording 
of all monitored data points, and prompt reporting of all SAEs; 3) to compare abstracted information with 
individual subjects’ records and source documents (subject’s charts, laboratory analyses and test results, 
physicians’ progress notes, nurses’ notes, and any other relevant original subject information); and 4) to help 
ensure investigators are in compliance with the protocol. The monitors also will inspect the clinical site 
regulatory files to ensure that regulatory requirements (Office for Human Research Protections-OHRP) and 
applicable guidelines (ICH-GCP) are being followed.  During the monitoring visits, the investigator (and/or 
designee) and other study personnel will be available to discuss the study progress and monitoring visit. 
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent hospital or 
clinical records readily available for inspection by the local IRB, the site monitors, and the NHLBI staff for 
confirmation of the study data. 
 
12.0 
HUMAN SUBJECT PROTECTION 
 
The investigator(s) accept their responsibilities for protecting the rights and welfare of human research subjects 
and will permit, with reasonable advance notice and at reasonable times, the designated research monitors to 
monitor the conduct of the research, as well as to audit source documents to the extent necessary to verify 
compliance with FDA Good Clinical Practice and the approved protocol. 
 
12.1 
Rationale for Subject Selection 
 
12.1.1  Predicted Distribution by Gender, Age and Race 
 
CLL is a rare neoplasm that comprises a substantial proportion of all leukemia in middle-aged persons and is 
the most common type among elderly persons in western populations.  Epidemiologic studies suggest that 
distribution by gender will be 66% males and 33% females.13 CLL is more common in Caucasian and African-
American but rare in Hispanics and very rare in the Asian population. This study will be open to all patients 


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42 
who fit the inclusion criteria and provide informed consent to protocol participation. We would predict that 
distribution should be comparable to that seen on the NHLBI Hematology Branch screening protocol as 
follows:  
x 
by gender: 33% females; 66% males 
x 
by age: ages 23-79, median 60   
x 
by race: 2% Asian, 11% Black, 8% Hispanic, 79% White 
 
12.1.2  Special Populations:  
 
Justification for exclusion of children: CLL is uncommon in patients less than 45 years of age and is virtually 
unknown in patients less than 20 years of age. At the time of diagnosis, more than 95% of patients are 45 years 
old and above.86 CLL may also be, biologically, a different disease in children.  Ibrutinib has not been studied 
in human subjects under 18 years of age. For these reasons, individuals < 18 years old have been excluded from 
protocol participation.   
 
Justification for exclusion of pregnant women: There are no clinical studies that were done on pregnant 
women, and it is unknown whether duvelisib, ibrutinib, or their metabolites are excreted in human milk. In 
addition, it is highly unlikely that a woman of pre-menopausal age will present with CLL because it is a 
malignancy of B cells that predominantly affects the elderly population. Diagnosis is typically made in adults 
over the age of 50 and more than half of the people with CLL are over the age of 70.  
 
Justification for exclusion of patients with impaired hepatic or renal function: No specific clinical studies 
have been conducted to date in patients with impaired hepatic or renal function. To minimize risks, patients 
enrolled must have adequate hepatic and renal function as defined in eligibility and exclusion criteria. 
 
Justification for exclusion of cognitively impaired subjects 
Cognitively impaired and institutionalized persons will not participate in this study.  Subjects must be able to 
provide informed consent, and understand and comply with the treatment plan and follow-up. 
 
Recruitment: The study will be listed on the ClinicalTrials.gov, Clinical Center Research Studies, and the 
NHLBI patient recruitment websites. The NHLBI DIR Patient Recruitment Office (PRO) will work with the 
Investigator to ensure accrual goals are being met. All recruitment materials and tools will use IRB-approved 
language and information to include standard recruitment contacts. 
 
• 
Anticipated accrual rate: approximately 12 subjects per year 
• 
Anticipated number of sites and participants to be enrolled from the U.S. and outside the U.S.: 1 
• 
Source of participants (e.g., inpatient hospital setting, outpatient clinics, student health service, or general 
public): outpatient clinic, general public, physician referrals 
• 
Medical records provided from outside referral sources will be reviewed to determine possible eligibility 
• 
A Strategic Recruitment Plan (SRP) has been developed in conjunction with the NHLBI Patient 
Recruitment Office. Recruitment strategies that will be ongoing throughout recruitment period of trial may 
include 1) distribution of a recruitment flyer in the NIH campus, patient advocacy organizations and the 
community; 2) updating study information on clinicaltrials.gov, NIH Search the Studies, and a dedicated 
recruitment page on the Clinical Center Office of Patient Recruitment website; 3) the use of 
ResearchMatch for identification of study candidates; 4) promoting the study on the official NIH social 
media account with IRB approved language and images; 5) distribution of a recruitment information on 
NIH listservs; and 7) distribution of a physician-to-physician letter to local hematologists/oncologists.
  
 
Payment for participation:  $0 – Subjects will not be compensated for their participation in this study. There is 
no payment for the blood samples obtained for research. 
 


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43 
Reimbursement for protocol participation travel, food, and lodging will be consistent with NHLBI DIR 
Travel and Lodging Compensation of Clinical Research Subjects policy or institutional guidelines.   
 
For travel from home:  Travel from home for the first NIH visit will not be reimbursable. If the patient 
consents to protocol participation travel home following the first visit will be reimbursable. Subjects will be 
reimbursed 100% of government rate for travel once the subject has been determined eligible to participate and 
signs consent. 
 
Competition with other Branch protocols: The study is the only active treatment protocol for subjects who 
develop BTK and/or PLCG2 mutations or progressive disease on ibrutinib. There will be little competition 
with existing NHLBI protocols. 
 
12.2 
Risks in Relation to Benefit 
 
The benefits to the subject could be a reduction or a disappearance of CLL, resulting in improved quality of 
life, decreased susceptibility to infections, and foremost, significant improvement in survival time. 
Potentially, treatment with other therapies could also be avoided or postponed.  
 
12.3 
Informed Consent Process and Procedures 
 
The investigational nature and research objectives of this trial, the procedure and its attendant risks and 
discomforts will be carefully explained to the subject and a signed informed consent document will be 
obtained prior to entry onto this study.   
 
At any time during participation in the protocol, should new information become available relating to risks, 
adverse events, or toxicities, this information will be provided orally or in writing to all enrolled or 
prospective patient participants.  Documentation will be provided to the IRB and if necessary the informed 
consent amended to reflect relevant information. 
 
 
12.4 
Conflict of Interest 
 
Verastem, Inc. is providing duvelisib for this study to NIH without charge. No NIH investigator involved in 
this study receives any payment or other benefits from Verastem, Inc.. The principal investigator assures that 
each associate investigator received a copy of the NIH’s Guide to preventing conflict of interest. No members 
of the research team reported a potential conflict of interest.   
 
12.5 
Technical Transfer Agreements 
 
The protocol has an associated CRADA: between NHLBI and Verastem, Inc. 
 
12.6 
 
Protocol Amendments 
 
Per the IST Agreement, any amendments to the protocol or informed consent form must be sent to Verastem, 
Inc. for review and approval prior to submission to the IRB. Written verification of IRB approval will be 
obtained before any amendment is implemented. 
 
12.7 
 
Publication Policy 
 
Per the IST Agreement, the Investigator is required to submit to Verastem, Inc. a copy of a planned publication 
(abstract, poster, oral presentation or manuscript) prior to the submission thereof for publication or disclosure.  
If safety information is contained within the document, the Investigator shall provide details regarding the 
safety events (patient identifier, reported term and causality) to Verastem, Inc. Verastem, Inc. may provide 


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Clare Sun, M.D. 
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44 
scientific comments and suggestions understanding that the Investigator has sole editorial responsibility, and 
retains the authority to make the final determination on whether or not to incorporate Verastem, Inc. comments 
or requests for additional information. 
 
13.0 
PHARMACEUTICALS  
 
13.1 
Duvelisib 
 
Product Description: Duvelisib is a synthetic small molecule compound manufactured in high enantiomeric 
and chemical purity. The duvelisib drug substance is a freebase, hydrate (hydration can vary with humidity), 
white-to-off-white solid, and is chemically stable under the recommended storage condition of 2 to 30°C. 
 
Formulation, Packaging, and Storage: The duvelisib drug product is supplied as capsules in 3 strengths for 
oral administration: 5 mg, 15 mg and 25 mg. The drug product consists of a blend of duvelisib drug substance 
formulated with compendial (USP, Ph. Eur., JP) excipients. The gelatin capsule is not compendial, however 
the capsule components comply with compendial requirements. The drug product is provided as a white 
powder encapsulated in corresponding capsule sizes and colors. Capsules are packaged in opaque high-
density polyethylene (HDPE) bottles with induction sealed child resistant caps or thermoform blister strips 
with push-through lidding packaged into wallets. 
 
The drug product bottles or blister strips should be stored at room temperature (15 to 30°C). The capsules are 
intended for oral administration. Caution is required when handling duvelisib. Personnel dispensing duvelisib 
should follow standard procedures for the handling of investigational drugs, including avoidance of eye or 
skin contact with the drug product. If there is exposure to the drug product, the individual should be treated 
for physical exposure (skin washing) or inhalation (move to fresh air, as necessary), and, if needed, seek 
medical advice. When duvelisib capsules are dispensed for self-administration, they should only be handled 
by the study subject. After handling capsules, the subject should wash his or her hands thoroughly. If 
someone who is not enrolled in a duvelisib clinical trial swallows a capsule or inhales drug powder from a 
broken capsule, he or she should contact the relevant Investigator to determine whether safety monitoring is 
necessary. The Investigator should report the incident to Versatem, Inc. Capsules should always be stored in 
the container provided to the study subject. 
 
Dosage and Administration: Refer to Section 5.1. 
 
Overdose: In the case of overdose, supportive care should be administered as indicated. 
 
Supply: The drug product duvelisib is manufactured and supplied by Verastem, Inc. 
 
Shipping:  
National Institutes of Health 
Investigational Drug Management and Research Section 
Clinical Center Pharmacy Department, Room 1C230  
10 Center Drive, MSC 1196, Building 10 
Bethesda, Maryland 20892-1196 
 
13.2 
Ibrutinib 
 
Product Description: Ibrutinib is commercially available. Note for more detailed and comprehensive 
background information please refer to the ibrutinib Package Insert. Chemical name of ibrutinib is PCI-
32765-00, which is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 d]pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one. PCI-32765-00 is a white to off-white crystalline solid, and given as an oral 
formulation containing micronized PCI-32765-00. 
 


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Clare Sun, M.D. 
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45 
Formulation, Packaging, and Storage: Ibrutinib is provided as 140 mg white opaque capsules or tablets in 4 
strengths: 140 mg, 280 mg, 420 mg, and 560 mg. The capsules are packaged in white HDPE bottles with a 
chil-resistant closure. The tablets are packaged in a carton of one folded blister card containing two 14-count 
blister strips. Store bottles or tablets at room temperature 20°C to 25°C (68°F to 77°F). Excursions are 
permitted between 15°C and 30°C (59°F to 86°F). 
 
Dosage and Administration: Refer to Section 5.1. 
 
Overdose: There is no specific experience in the management of ibrutinib overdose in patients. One healthy 
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. 
Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive 
treatment. 
 
Supply: Commercially available from the NIH Clinical Center Pharmacy Department. 
 
13.3 
Accountability Procedures 
 
Drug accountability records will be maintained for all clinical supplies. All empty and partially used vials and 
clinical trial supplies will be destroyed locally according to the institution’s standard operating procedures for 
drug destruction.  The pharmacy will maintain detailed documentation of the number and identification of 
vials which are destroyed, and copies of these documents will be provided to the sponsor.  Disposition of all 
unused boxes of study drug will be carried out according to instructions provided by the sponsor at the end of 
the study after drug accountability is performed by the study monitor. 
 
14.0 
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Bilancio A, Okkenhaug K, Camps M, et al. Key role of the p110delta isoform of PI3K in B-cell antigen 
and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta 
function in B cells. Blood 2006;107:642-50. 
51. 
Dil N, Marshall AJ. Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell 
cytokine production and differentiation. Mol Immunol 2009;46:1970-8. 
52. 
Durand CA, Hartvigsen K, Fogelstrand L, et al. Phosphoinositide 3-kinase p110 delta regulates natural 
antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J Immunol 
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53. 
Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. 
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Zhang TT, Okkenhaug K, Nashed BF, et al. Genetic or pharmaceutical blockade of p110delta 
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Okkenhaug K, Bilancio A, Farjot G, et al. Impaired B and T cell antigen receptor signaling in p110delta 
PI 3-kinase mutant mice. Science 2002;297:1031-4. 
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57. 
Garcon F, Patton DT, Emery JL, et al. CD28 provides T-cell costimulation and enhances PI3K activity 
at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 
2008;111:1464-71. 
58. 
Haylock-Jacobs S, Comerford I, Bunting M, et al. PI3Kdelta drives the pathogenesis of experimental 
autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation. J 
Autoimmun 2011;36:278-87. 
59. 
Jarmin SJ, David R, Ma L, et al. T cell receptor-induced phosphoinositide-3-kinase p110delta activity 
is required for T cell localization to antigenic tissue in mice. J Clin Invest 2008;118:1154-64. 
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Liu D, Uzonna JE. The p110 delta isoform of phosphatidylinositol 3-kinase controls the quality of 
secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets. 
J Immunol 2010;184:3098-105. 
61. 
Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B. The p110delta 
isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 
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62. 
Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG. Cutting edge: 
Differential roles for phosphoinositide 3-kinases, p110 gamma and p110 delta, in lymphocyte chemotaxis and 
homing. Journal of Immunology 2004;173:2236-40. 
63. 
Soond DR, Bjorgo E, Moltu K, et al. PI3K p110delta regulates T-cell cytokine production during 
primary and secondary immune responses in mice and humans. Blood 2010;115:2203-13. 
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Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T cell development requires 
the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J 
Immunol 2005;175:2783-7. 
65. 
Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs 
unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and 
progression. Cancer Cell 2011;19:715-27. 
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Konrad S, Ali SR, Wiege K, et al. Phosphoinositide 3-kinases gamma and delta, linkers of coordinate 
C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation. The Journal of 
biological chemistry 2008;283:33296-303. 
67. 
Marwick JA, Caramori G, Stevenson CS, et al. Inhibition of PI3Kdelta restores glucocorticoid function 
in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 2009;179:542-8. 
68. 
Randis TM, Puri KD, Zhou H, Diacovo TG. Role of PI3Kdelta and PI3Kgamma in inflammatory 
arthritis and tissue localization of neutrophils. Eur J Immunol 2008;38:1215-24. 
69. 
Ali K, Bilancio A, Thomas M, et al. Essential role for the p110delta phosphoinositide 3-kinase in the 
allergic response. Nature 2004;431:1007-11. 
70. 
Kim MS, Radinger M, Gilfillan AM. The multiple roles of phosphoinositide 3-kinase in mast cell 
biology. Trends Immunol 2008;29:493-501. 
71. 
Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD. Inhibition of phosphoinositide 3-kinase delta 
attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. Faseb J 
2006;20:455-65. 
72. 
Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical 
role in NK cell terminal maturation and cytokine/chemokine generation. The Journal of experimental medicine 
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73. 
Kim N, Saudemont A, Webb L, et al. The p110delta catalytic isoform of PI3K is a key player in NK-
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Saudemont A, Garcon F, Yadi H, et al. p110gamma and p110delta isoforms of phosphoinositide 3-
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75. 
Tassi I, Cella M, Gilfillan S, et al. p110gamma and p110delta phosphoinositide 3-kinase signaling 
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Kutok J, Ali J, Brophy E, et al. The potent and selective phosphoinositide-3-kinase-gamma inhibitor, 
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Chen SS, Ham S, Rai KR, McGovern K, Kutok JL, Chiorazzi N. Dual Inhibition of PI3K-Delta and 
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Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in 
chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2. 
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Rev Immunol 1998;17:1-52. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
50 
APPENDIX A:  SCHEDULE OF EVENTS 
EVALUATION AND ASSESSMENTS  
  
Screen and 
Baseline Visit  
  
  
  
After C6D28 
Progression 
of Disease  
Permanent 
D/C of 
Duvelisib 
PROTOCOL TIMEPOINT 
  
  
  
C1D28 
C2D28 
C3D28 
C4D28 
C5D28 
C6D28 
  
After C6D28 
Unscheduled 
Visit 
*30 days 
after last 
dose 
Window +/- days  
  
+/- 4 wks 
  
+/- 7D  
+/- 7D  
+/- 7D  
+/- 7D  
+/- 7D  
+/- 7D  
  
+/- 15D 
  
+ 7D 
day /month 
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical  
  
  
  
  
  
  
  
  
  
  
  
  
  
Consent 
  
X 
  
  
  
  
  
  
  
  
  
  
  
History  
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
Physical Exam  
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
ECOG PS 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
Concomitatnt Medication Review  
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
Labs 
  
  
  
  
  
  
  
  
  
  
  
  
  
HLA Typing 
  
X1 
  
  
  
  
  
  
  
  
  
  
  
CBC with Differential 
  
X 
  
X4 
X4 
X 
X 
X 
X 
  
X 
X 
X 
Acute Care & Mineral Panel 
  
X 
  
X  
X 
X 
X 
X 
X 
  
X 
X 
X 
Tot. protein, Uric Acid, LDH 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
Hepatic Panel 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
Reticulocyte Count 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
PT, PTT 
  
X 
  
  
  
  
  
  
  
  
  
  
  
SPEP with IFE 
  
X 
  
  
  
  
  
  
  
  
  
  
  
SFL with qIG 
  
X 
  
  
  
X 
  
  
X 
  
  
X 
  
CRP 
  
X 
  
X 
X 
X 
X 
X 
X 
  
  
X 
  
ȕ0LFURJOREXOLQ 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
+DSWRJORELQ 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
DAT 
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
X  
X 
Iron studies (ferritin, transferrin, iron) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
)RODWH9LW% 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Thyroid function panel  (thyroid stimulating hormone, free T4, T3) 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test 
  
X3 
  
  
  
  
  
  
  
  
  
  
  
Lymphocyte phenotyping (T, B, NK)  
  
X 
  
  
  
X 
  
  
X 
  
X5 
X 
X 
,*+9PXWDWLRQDQDO\VLVEORRGRU%0" 
  
X1 
  
  
  
  
  
  
  
  
  
  
  
3HULSKHUDOEORRGIORZF\WRPHWU\IRU&// 
  
X 
  
  
  
  
  
  
X 
  
X7 
X 
  


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
51 
&//),6+LQFOXGHVSUREHVIRUT-T-, 17p-, t(11:14)) 
  
X 
  
  
  
  
  
  
  
  
  
O 
  
Unstimulated and CpG-stimulated karyotype  
  
X 
  
  
  
  
  
  
  
  
  
O 
  
Viral Studies  
  
  
  
  
  
  
  
  
  
  
  
  
  
Viral Studies (HIV, Hepatitis B & C, HTLV-I/II)  
  
X 
  
  
  
  
  
  
  
  
  
  
  
HBV DNA Quantitative PCR 
  
X2 
  
X2 
X2 
X2 
X2 
X2 
X2 
  
X2 
X2 
X2 
CMV and EBV  
  
X 
  
  
  
  
  
  
  
  
  
X  
  
STUDY MEDICATION  
  
  
  
  
  
  
  
  
  
  
  
  
  
Duvelisib 
  
  
  
X 
X 
X 
X 
X 
X 
  
X 
  
  
Ibrutinib  
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
EVALUATIONS 
  
  
  
  
  
  
  
  
  
  
  
  
  
CT Neck, CAP  
  
X 
  
  
  
X 
  
  
X 
  
X6 
X 
  
PET Scan  
  
  
  
  
  
  
  
  
  
  
  
O 
  
Bone Marrow Asiprate and Biopsy  
  
X 
  
  
  
X 
  
  
X 
  
X7 
X 
  
Bone marrow flow cytometry for CLL  
  
O 
  
  
  
O 
  
  
O 
  
X7 
O 
  
EKG  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Research Samples  
  
  
  
  
  
  
  
  
  
  
  
  
  
Lymphapheresis 
  
O 
  
  
  
  
  
  
  
  
  
O1 
  
/\PSKQRGHELRSV\ 
  
O 
  
  
  
  
  
  
  
  
  
O1 
  
5HVHDUFKEORRGXSWRP/ 
  
X 
  
  
  
X 
X 
X 
X 
  
O 
X 
  
 
O = Optional  
2 PD\EHREWDLQHGEHIRUHVWDUWLQJGXYHOLVLEDQGRULQVXEMHFWVZLWKSHUVLVWHQWO\PSKRF\WRVLVDQGRUDWSURJUHVVLRQRIGLVHDVHRUVXVSLFLRQRISURJUHVVLYHGLVease 
; DWDQ\WLPHEHIRUHVWDUWLQJGXYHOLVLE 
; )RUVXEMHFWVZLWKDSRVLWLYH+%F$EKHSDWLWLV%'1$3&5ZLOOEHSHUIRUPHG 
X3  :&%3RQHQHJDWLYHSUHJQDQF\WHVWVZLWKLQZHHNEHIRUHVWDUWLQJGXYHOLVLE 
; HYHU\ZHHNVIRU&\FOHV-WHVWVFRQGXFWHGDWRXWVLGHLQVWLWXWLRQVDUHDFFHSWHG 
; WREHSHUIRUPHGHYHU\PRQWKV 
; WREHSHUIRUPHGHYHU\PRQWKVIRUVW\HDURQGXEHOLVLEWKHQDQQXDOO\ 
; ZKHQVXEMHFWPHHWVDOORWKHUFULWHULDIRUFRPSOHWHUHPLVVLRQDVGHWDLOHGLQ6HFWLRQ 
*  7HVWVZLOOEHSHUIRUPHGGD\VGD\VDIWHUODVWGRVHRIGXYHOLVLELVDGPLQLVWHUHGRUEHIRUHWKHQH[WWUHDWPHQWVWDUWV, whichever occurs first. 
 
  
 
 
 
 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
52 
 
APPENDIX B: CYP3A INHIBITORS, INDUCERS, AND SUBSTRATES 
 
Medications or Foods Known to Inhibit CYP3A 
 
The following list provides medications or foods known to induce or inhibit CYP3A activity. Note that this 
is not a comprehensive list of all medications or foods which may modulate CYP3A activity. Additional 
information can be found at: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/uc
m093664.htm 
 
Note: Subjects receiving duvelisib are prohibited from concomitant use of medications or foods that are 
known to be strong inhibitors or inducers of CYP3A. 
 
Table 7. Classification of In Vivo Inhibitors of CYP3A 
Strong Inhibitors1 
Moderate inhibitors2 
Weak inhibitors3 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice4, indinavir, 
itraconazole, ketoconazole,  
lopinavir/ritonavir, 
mibefradil5 
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice4, 
imatinib, verapamil 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo6, 
goldenseal6, 
isoniazid, nilotinib, 
oral contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for 
WKDW&<3E\-fold or > 80% decrease in CL. 
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold or 50-80% decrease in CL. 
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 2-fold but equal to or more than 5-fold or 20-50% decrease in CL. 
4. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when 
another preparation was used (e.g., low dose, single strength).  
5. Withdrawn from the United States market because of safety reasons. 
6. Herbal product.  
 
Medications Known to Induce CYP3A 
 
Table 8. Classification of In Vivo Inducers of CYP3A 
6WURQJ,QGXFHUV
decrease in AUC 
Moderate Inducers 
50-GHFUHDVHLQ$8& 
Weak Inducers 
20-GHFUHDVHLQ$8& 
Avasimibe1, arbamazepine, 
phenytoin, rifampin, St. John’s 
Wort2,3 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Amprenavir, aprepitant, 
armodafinil, Echinacea3 
pioglitazone, prednisone, 
rufinamide 
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A. 
1. Not a marketed drug. 
2. The effect of St. John’s Wort varies widely and is preparation-dependent. 
3. Herbal product. 


19-H- 
Clare Sun, M.D. 
DATE: August 02, 2019-revised on December 05, 2019 
53 
Medications Known to Be CYP3A Substrates 
 
Known sensitive CYP3A substrates and CYP3A substrates with a narrow therapeutic range are listed in  
 
Table . Drugs or foods that are substrates of CYP3A should only be used if medically necessary and 
therapeutic alternatives do not exist.  
Additional information can be found at  
x 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteraction
slabeling/ucm093664.htm 
x 
http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687 
 
Table 9. Cytochrome P450 3A (CYP3A) Substrates 
Sensitive CYP3A Substrates 
budesonide 
buspirone 
eplerenone 
eletriptan 
felodipine 
fluticasone 
lovastatin 
midazolam 
saquinavir 
sildenafil 
simvastatin 
triazolam 
vardenafil 
CYP3A Substrates with a Narrow Therapeutic Range 
alfentanil 
astemizole  
cisapride  
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine  
sirolimus 
tacrolimus 
terfenadine