Clinical trial NCT03795610
Conditions: Head and Neck Squamous Cell Carcinoma Head and Neck Cancer Head and Neck Carcinoma Head and Neck Cancer Stage IV Head and Neck Cancer Stage III HPV-Related Carcinoma HPV-Related Malignancy HPV-Related Squamous Cell Carcinoma
Keywords: HPV positive HPV negative HPV- HPV+ PI3K-γ microenvironment immunotherapy tumor resection PI3K cancer carcinoma malignancy head neck throat esophageal nasopharyngeal nasopharynx
Sponsor: Assuntina G. Sacco, MD
Start date: 2020-03-06; Completion date: 2023-08-24
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate how effective the study drug IPI-549 is against types of cancers. IPI-549 is considered experimental because it is not approved by the US Food and Drug Administration (FDA) for the treatment of cancer.

Patients will be treated with 2 weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be obtained prior to initiation of IPI-549 and at surgery.

Detailed description:
This is a phase 2 window of opportunity trial in patients with locally advanced head and neck cancer. A key objective is to provide the first proof that macrophage phenotype switching can be accomplished in humans and lay the groundwork for future trials of this novel approach to immune therapy. Patients who are candidates for surgical resection will be enrolled and treated with 2 weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be obtained prior to initiation of IPI-549 and at surgery.

The study team hypothesizes that mRNA signatures of immune response will be increased in IPI-549-treated patients. For the efficacy endpoints, RECISTv1.1 will be used.

Arms: arm 1: Patients enrolled in Arm A will receive IPI-549 40 mg by mouth daily for at least 14 days
Interventions: intervention 1: IPI-549
Intervention descriptions: intervention 1: 40mg by mouth (PO) every day (QD) for at least 14 days

Protocol documents:
ICF_001.pdf: 
Phase 2 Window of Opportunity Study of IPI-549 in Patients 
with Locally Advanced HPV+ and HPV- Head and Neck 
Squamous Cell Carcinoma 
 
NCT03795610 
 
Document Date: 05/2023 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058  
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW
1 
University of California, San Diego 
Consent to Act as a Research Subject 
Phase 2 Window of Opportunity Study of IPI-549 in Patients with Locally Advanced HPV+ 
and HPV- Head and Neck Squamous Cell Carcinoma 
(UCSD IIT 172058) 
Assuntina Sacco, M.D. and her colleagues are conducting a research study sponsored by UC San 
Diego to find out more about the experimental drug called IPI-549. You are being asked to take 
part because you have locally advanced human papillomavirus positive (HPV+) or human 
papillomavirus negative (HPV-) head and neck squamous cell carcinoma and are a candidate for 
surgical removal of your tumor. 
Your participation in this research study is voluntary.  The purpose of this Informed Consent Form 
is to inform you about the nature of this research study so that you may make an informed decision 
as to whether you would like to participate.  If you have any questions, please ask your study 
doctor or coordinator to explain any words or information that you do not understand. 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to investigate how effective the drug IPI-549 is against the type of 
cancer that you have.  
IPI-549 is considered experimental because it is not approved by the US Food and Drug 
Administration (FDA) for the treatment of cancer. 
Participation in this study is entirely voluntary.  A total of 28 participants will be enrolled at the 
University of California San Diego.   
DURATION OF THE STUDY / HOW LONG IS EACH VISIT? 
The study will involve a screening period (up to 28 days), a period where you will be required to 
take your study drug (14 days), and a safety follow up visit at approximately 30 days after your 
last dose of study drug. 
Each of your study visits can last from approximately one to 7 hours. 
WHAT ARE MY OBLIGATIONS IF I TAKE PART IN THIS STUDY? 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
2 
 
 
 
 
 
If you decide to take part in this study, you must be willing to do the following: 
 
• Take IPI-549 by mouth (for a minimum of 14 days, you will continue taking IPI-549 until 
24 hours before surgery) as long as you are on the study 
• Attend the scheduled visits 
• Tell the study staff about any other medicines that you are taking 
• Tell the study staff about any side effects of the drugs 
• You must return all unused IPI-549 supplies (the study drug) to the study doctor. 
• Undergo tumor biopsy procedure at screening.   
 
PROCEDURES 
 
Screening Procedures 
 
The Screening Visit (Visit #1) may take between 2 and 8 hours to complete and the procedures 
may be scheduled over multiple days. Some of these may be part of your regular medical care and 
may be done even if you do not join the study.  If you have had some of them recently, they may 
not need to be repeated. Your study doctor will talk to you about these tests.  
 
• You will be asked about your medical history, including previous cancer therapies.  
• You will be asked for your demographic information (initials, address, age, sex, race, and 
ethnicity).  
• You will be given a physical exam and your weight, height and vital signs will be measured 
(your heart rate, blood pressure, and temperature). Measurements of you lymph nodes, 
spleen and liver will also be made. 
• You will be asked about any medications you are taking or have taken in the past.  
• You will be asked questions about your health and how your disease affects your daily life.  
• An ECG will be taken (electrical tracing of the heartbeat or heart rhythm to see if your 
heart is functioning properly): During this procedure, you will be asked to lie down, and 
electrodes are affixed to each arm and leg and to your chest. This requires cleaning the site 
and, if necessary, shaving or clipping hair. You are usually required to remain still, and 
you may be asked to hold your breath for short periods during the procedure. 
• Samples of your blood (approximately 2-3 tablespoons) will be drawn for laboratory tests:  
o Hematology or CBC (Complete Blood Count), which includes: white blood cell 
count, red blood cell count, platelet count, hemoglobin (oxygen-carrying pigment 
in red blood cells), hematocrit (measures the amount of space red blood cells take 
up in the blood). This is to aid in diagnosing anemia (low red blood cell count which 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
3 
 
 
 
 
can result in fatigue), certain cancers of the blood, and to monitor blood loss and 
infection.  
o Blood chemistry (which measures the levels of a number of chemical substances 
that are released from various tissues in the body to evaluate the function of the 
liver and kidneys).  
o Hepatitis screening:  You will be informed of the results of the tests.  The results of 
the tests, if positive, will be reported to the county health department and entered 
in your medical record.  Your study doctor will discuss this with you. 
o Your blood may also be tested for the viruses Human Immunodeficiency Virus 
(HIV), Hepatitis B, and Hepatitis C to make sure that the study procedures are 
appropriate for you. You will be informed of the results of the tests. The results of 
the tests, if positive, will be reported to the San Diego County health department 
and entered in your medical record. Your study doctor will discuss this with you. 
If you tested positive for any of these viruses you cannot participate in this study. 
 
• An extra sample of your blood (about 3 tablespoons) will be collected to measure 
biomarkers for research purposes. Biomarkers are biological molecules found in blood, 
other body fluids, or tissues which might indicate a normal or abnormal process, or of a 
condition or disease. A biomarker may be used to see how well the body responds to a 
treatment for a disease or condition. Additional details of this extra blood collection are 
described after the study procedures below (‘Biological Samples for Research’). 
• A pregnancy test (urine) will be performed if you are a woman of child-bearing potential. 
Pregnant women cannot be on the study. 
• You will have a CT or MRI scan of your neck and chest to measure your disease.  
o CT scan: The CT (computed tomography) scanner is a free-standing machine with 
a large hole in the center. You will be asked to lie on your back with your arms 
raised above your head on a narrow table that slides into the hole. Participants who 
have difficulty with enclosed spaces such as those found with some MRI scanners 
do not usually have a problem with this type of test. A dye may be injected into a 
peripheral vein to better evaluate certain diseases and organs. The radiologist will 
decide if this is necessary. Tell the technician or radiologist if you have any allergies 
or have had difficulty with prior CT scans. It is very important that you remain still 
throughout the exam and hold your breath when asked. This will allow for better 
images. The actual scan time is usually about two minutes, although the entire 
procedure usually takes much longer.  
Risks of CT Scans:  The CT involves exposure to radiation. In addition, the imager 
makes buzzing and whirling noise while it is taking pictures.  The subject will be 
given a set of ear plugs to help with the noise. The subject may experience feelings 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
4 
 
 
 
 
of claustrophobia or anxiety.  He/she may also experience some discomfort and 
tiredness from lying still in a confined space during the imaging.  For some people, 
having to lie still on the scanning table for the length of the procedure may cause 
some discomfort or pain. 
o MRI: Magnetic Resonance Imaging (MRI) may be done instead of a CT scan. MRI 
uses magnetism instead of x-rays to build up a picture of the body. The scan is 
completely painless, but can be rather noisy and you have to lie very still inside the 
center of a large, doughnut-shaped magnet for approximately 30-60 minutes to get 
a good picture. If you have a pacemaker or other metal implants, the staff needs to 
know as the scan uses magnets.  
• Tumor Tissue Collection: During your participation in this study you will be asked to 
undergo a tumor biopsy.  A biopsy is a procedure where a sample of your tumor is removed.  
It will be a core biopsy that collects a small piece of tissue.  You may need a general 
anesthetic (be asleep for the procedure) or a local anesthetic (have only the area of the 
biopsy numbed by injection) depending on the location of your cancer.  There may be some 
temporary pain or discomfort associated with this routine procedure. The biopsy is helpful 
in describing your cancer before receiving the study drug, which allows researchers to 
determine whether a response during the study could have been predicted.   
• An extra sample of your tumor tissue will be collected to measure biomarkers for research 
purposes. Additional details of this extra tissue collection are described after the study 
procedures below (‘Biological Samples for Research’). 
 
Study Dosing Period 
Study treatment with IPI-549 (14 days prior to surgical resection) 
 
Day 1:  
This visit should include collection of side effects/serious side effects and you will be asked about 
any medications you are taking. 
 
You will be given the study drug and a drug diary and given instructions on how to fill it out and 
how to take your medication. 
 
You will be instructed to take IPI-549 orally over a 14 day cycle starting on the day of this study 
visit.  
 
You will be given IPI-549 and are expected to take it orally approximately every 24 hours. You 
should swallow IPI-549 whole with a glass of water (approximately 8 ounces or 240 mL). You 
must avoid grapefruit and grapefruit juice while on study drug. You are also advised to avoid food 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
5 
 
 
 
 
and liquids other than water from 2 hours prior to dosing until 1 hour after dosing. 
Your last dose of study drug should be taken within 24 hours of surgery 
 
Samples of your blood (approximately 2-3 tablespoons) will be drawn for laboratory tests:  
o Hematology or CBC (Complete Blood Count), which includes: white blood cell 
count, red blood cell count, platelet count, hemoglobin (oxygen-carrying pigment 
in red blood cells), hematocrit (measures the amount of space red blood cells take 
up in the blood). This is to aid in diagnosing anemia (low red blood cell count which 
can result in fatigue), certain cancers of the blood, and to monitor blood loss and 
infection.  
o Blood chemistry (which measures the levels of a number of chemical substances 
that are released from various tissues in the body to evaluate the function of the 
liver and kidneys).  
 
Pre surgery- Day 14 of study drug 
 
This study visit will take place on day 14 of taking your study drug and prior to your surgery.  
• You will be given a physical exam and your weight, height, and vital signs will be measured 
(your heart rate, blood pressure, and temperature). Measurements of you lymph nodes, 
spleen, and liver will also be made. 
• You will be asked about any medications you are taking or have taken in the past and we 
will collect your side effects/serious side effects  
• You will be asked questions about your health and how your disease affects your daily life.  
• Samples of your blood (approximately 2-3 tablespoons) will be drawn for laboratory tests:  
o Hematology or CBC (Complete Blood Count), which includes: white blood cell 
count, red blood cell count, platelet count, hemoglobin (oxygen-carrying pigment 
in red blood cells), hematocrit (measures the amount of space red blood cells take 
up in the blood). This is to aid in diagnosing anemia (low red blood cell count which 
can result in fatigue), certain cancers of the blood, and to monitor blood loss and 
infection.  
o Blood chemistry (which measures the levels of a number of chemical substances 
that are released from various tissues in the body to evaluate the function of the 
liver and kidneys).  
• An extra sample of your blood (approximately 1-2 tablespoons) will be collected to 
measure biomarkers for research purposes. Additional details of this extra blood collection 
are described after the study procedures below (‘Biological Samples for Research’). 
 
• Tumor Tissue Collection.  A tumor biopsy is a procedure where a sample of your tumor is 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
6 
 
 
 
 
removed. A sample of your tumor tissue will be collected during surgery. The biopsy is 
helpful in describing your cancer after receiving the study drug, which allows researchers 
to determine whether a response occurred during the study  
Follow up 
You will have a safety follow up visit at approximately 30 days after the last dose of study drug. 
This visit will include collection of side effects, questions about any medications that you are 
taking, and about your health and how your disease affects your daily life, a physical exam, vital 
signs and height, lab tests (CBC and the complete metabolic panel), and MRI or CT scan if your 
study doctor needs you to. 
 
Biological Samples 
 
As described in the study procedures above, blood (approximately 2-3 tablespoons) and tissue 
samples will be collected from you throughout the study.  
 
One blood and one tissue sample will be collected at the screening visit. Another blood sample 
will be collected at the pre-surgery visit (day 14 of taking the study drug), and tissue sample will 
be collected during your surgery.  
The blood and tissue tests for research will examine the effect the study drug has on your body. 
Study biospecimens (such as blood, tissue, or saliva) collected from you for this study and/or 
information obtained from your biospecimens may be used in this research or other research, and 
shared with other organizations. You will not share in any commercial value or profit derived from 
the use of your biospecimens and/or information obtained from them. Your study doctor has no 
personal or financial interest in this research.  
If you decide later that you do not want the specimens collected from you to be used for future 
research, you may tell this to Dr. Assuntina Sacco, who will use her best efforts to stop any 
additional studies.  However, in some cases, such as if your samples have already been tested, the 
data from these tests are no longer linked to your identity and cannot be removed from the research 
database  
Dr. Assuntina Sacco, her associates, or her successors in these studies will keep your DNA 
specimen and/or the information derived from it indefinitely. 
There will be no direct benefit to you from this study since you will not be provided with any 
results or information regarding your DNA test. The investigator, however, may learn more about 
head and neck squamous cell carcinoma. 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
7 
 
 
 
 
Federal and State laws generally make it illegal for health insurance companies, group health plans, 
and most employers to discriminate against you based on your genetic information. This law 
generally will protect you in the following ways:  
a) Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  
b) Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.  
c) Employers with 5 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting the 
terms of your employment. 
Be aware that these laws do not protect you against genetic discrimination by companies that sell 
life insurance, disability insurance, or long-term care insurance. 
  
RISKS OF PARTICIPATION 
Participation in this study may involve some added risks or discomforts.  While you are on this 
study, you are at risk for the side effects listed below.  You should discuss these with your study 
doctor.  There may also be other side effects that we cannot predict.  Other drugs will be given to 
make side effects less serious and uncomfortable.  Many side effects go away shortly after the 
study drug is stopped, but in some cases, side effects may be serious, long-lasting, and may even 
cause death. 
 
Risks associated with IPI-549: 
The following side effects have been observed in people who received IPI-549.  
 
Cardiac (relating to your heart) 
An increase in heart rate (An increased heart rate can result in dizziness or shortness of breath. 
During your clinic visits your heart rate will be checked.) 
 
Blood and lymphatic system disorders: 
Anemia (low red blood cell count which can result in fatigue) 
White blood cell count decreased (decreased cells that fight infection, which could result in lower 
ability to fight certain infections) 
 
Gastrointestinal Disorders: 
Diarrhea 
Nausea 
Vomiting 
Abdominal pain 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
8 
 
 
 
 
Bleeding into the stomach or intestine (gastrointestinal bleed) was observed in studies conducted 
in animals.  This could result in black tarry stools or blood in the stool. 
 
General disorders and administration site conditions: 
Feeing very tired – fatigue 
Fever 
Local swelling  
 
Metabolism and nutrition Disorders: 
Hypomagnesaemia.  Hypomagnesaemia is an electrolyte disturbance in which there is a low level 
of magnesium in the blood. Deficiency of magnesium can cause tiredness, generalized weakness, 
muscle cramps, abnormal heart rhythms, and increased irritability of the nervous system with 
tremors. 
 
Nervous system disorders: 
Headaches 
 
Vascular disorders 
Hypertension – high blood pressure 
 
Skin and subcutaneous tissue disorders: 
Rash 
Itchiness 
Maculopapular rash (which is a type of rash that is a flat, red area on the skin that is covered with 
small bumps. It may only appear red in lighter-skinned people) 
The effect of IPI-549 on the skin, specifically when in direct sunlight or with artificial ultraviolet 
(UV) light (e.g., in tanning booths) is not known. (As a general precaution, it is advised to use 
appropriate protective measures to minimize exposure to direct sunlight or artificial UV light 
during the treatment period and for at least 30 days after the last dose of IPI-549.) 
 
Liver Problems: 
Increased liver enzymes (may indicate damage to the liver) 
Blood bilirubin increased (liver problems which may cause yellowing of the skin) 
 
Respiratory, thoracic and mediastinal disorders: 
Shortness of breath 
Pleuritic pain 
 
Additional Risks and Discomforts Associated with Study Procedures 
There may be other risks associated with participation in this study that are currently 
unforeseeable. 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
9 
 
 
 
 
Risk of Testing for HIV or Hepatitis 
Participation in this study will require that you be tested for HIV and/or hepatitis. These tests are 
necessary to make sure that these study procedures would be appropriate for you. Testing for HIV 
or hepatitis may result in a diagnosis of infection with this virus. You will be informed of the 
results of these tests; if you do not wish to know the results, you should refuse to participate in this 
study. In the event that you are diagnosed with HIV or hepatitis, your regular doctor will give you 
the results in a face-to-face discussion (not by telephone or mail), counseling will be offered to 
you, and the results will be entered in your medical record and provided to the California State 
Board of Health as required by law.  In the event that you are diagnosed with HIV or hepatitis, you 
may be referred to a doctor who specializes in these illnesses. The diagnosis of HIV may result in 
earlier treatment and/or prevention of many complications from the illnesses. Efforts will be made 
to keep your personal information confidential.  Awareness of a diagnosis of these illnesses may 
have serious personal or social consequences.  Some of these consequences include possible 
difficulty obtaining health insurance or employment, and difficulty traveling to some foreign 
countries.  
 
Allergic Reactions:  As with any drug, there is the chance of an allergic reaction, which may 
include difficulty breathing, rash, flushing, weakness, dizziness, lightheadedness, and swelling. 
 
Risks of blood draws:  There is a risk of discomfort or pain, bleeding, swelling and a small arm 
bruise and swelling when blood is drawn.  Rarely, a clot or infection may occur at the site of the 
blood draw.  Some people also become faint, dizzy, or light-headed during or immediately after 
the blood draw. 
 
Risks of ECG: Up to 12 self-adhesive electrodes (small blunt pieces of metal) will be attached to 
your skin on your arms, legs and chest. The areas where the electrodes will be placed will be 
cleaned; some areas may need to be shaved. Some skin irritation can occur where the electrodes 
are placed. Once the electrodes are placed, the test will begin.  The test is completely painless and 
takes less than a minute to perform. After the test, the electrodes are removed. 
 
Risks of tumor biopsy:  Pain, bleeding and infection at the biopsy site may occur.  In rare cases, 
more severe bleeding may occur inside your body that may require hospitalization, surgery and 
blood transfusions or may result in death.  It is very rare, but you may have an allergic reaction to 
the numbing medication, which may include difficulty breathing, rash, flushing, low blood 
pressure and swelling.  Additionally, there is a moderate risk of nerve injury and local paralysis 
(complete loss of muscle function, which may or may not be permanent) or numbness if the biopsy 
is done on a lymph node close to nerves.  Your study doctor will further explain the risks involved 
with a biopsy.   
 
Reproductive Risks:  You should not become pregnant or father a baby while on this study because 
the drugs in this study can affect a fetus and cause serious birth defects.  Women should not 
breastfeed a baby while on this study.  Some of the drugs used in this study may make you unable 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
10 
 
 
 
 
to have children in the future.  It is important you understand that you need to use birth control 
while on this study.  If you are female and capable of child-bearing, a pregnancy test will be done 
before the study begins in order to be as sure as possible that you are not pregnant.  Your 
participation requires that you use contraception methods (such as (e.g., condoms, implants, 
injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized 
partner) to prevent pregnancy for the duration of the study and through 120 days after the last dose 
of study medication.  Ask about counseling and more information about preventing pregnancy. 
 
Risks from X-rays and/or Scans:  During your participation in this research study, you will be 
exposed to radiation from scheduled x-rays and/or imaging scans. The total exposure resulting 
from these imaging studies is calculated to be approximately 7.9 mSv. This amount is more than 
you would receive from one year of natural exposure in the San Diego area, which is approximately 
1.6 mSv. Cumulative exposure from radiation may increase your risk of developing certain types 
of cancer in the future. 
 
The principal investigator for this research study has determined and verified that all of the imaging 
scans prescribed for this study would typically be performed as part of the standard medical care 
required to adequately monitor your current illness. Scans are typically done as part of your 
standard care to assess your disease.  Radiation exposure may be decreased if non-radiation 
imaging alternatives are utilized, such an MRI instead of a CT. If you are especially concerned 
with radiation exposure, or you have had a lot of x-rays or imaging scans already, you should 
discuss this with study doctor for this study, Dr. Assuntina Sacco, or your regular doctor.  
 
Risks of MRI Scans:  As part of this study, Magnetic Resonance Imaging (MRI) may be done.  
The imager makes a loud, banging noise while it is taking pictures.  You will be given a set of ear 
plugs to help with the noise. You may experience feelings of claustrophobia or anxiety.  You may 
also experience some discomfort and tiredness from lying still in a confined space during the 
imaging.  There are no known effects from exposure to magnetic fields (MRI). However, some 
people undergoing this procedure become anxious.  If this happens to you, you can stop the 
procedure at any time. If you have metal clips or plates in your body or a pacemaker, you should 
tell your study doctor about it. MRI may not be appropriate under some of the following 
conditions:  a cardiac pacemaker; metal fragments in eyes, skin, or body;  heart valve replacement;  
brain clips;  venous umbrella;  being a sheet-metal worker or welder;  aneurysm surgery; 
intracranial bypass; renal or aortic clips;  prosthetic devices such as middle ear, eye, joint, or penile 
implants;  joint replacements;  hearing aid;  neurostimulator;  insulin pump;  I.U.D.;  being 
pregnant or trying to become pregnant;  shunts/stents;  metal mesh/coil implants;  metal 
plate/pin/screws/wires, or any other metal implants;  and permanent eyeliner and/or eyebrows.  
 
Risks of IV Contrast: As part of this study a CT scan may be done. There may be some reactions 
related to the contrast dye used in CT scans. Contrast dye is usually administered when you get a 
CT scan. Contrast dye may also be used in MRI scans. Some people may develop hives and itching 
or other allergic symptoms from this dye, swelling of the heart, cramps of the voicebox, breathing 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
11 
 
 
 
 
distress caused by narrowing of the airways in lungs, low blood pressure, with loss of 
consciousness, and in rare cases, severe loss of blood and fluids leading to shock and death, 
fainting, seizures, and irregular heartbeats.  In addition, if you have low kidney function, this dye 
can temporarily or permanently decrease your kidney function.  
Risks of Genetic Testing:  Some people involved in genetic studies have felt anxious about the 
possibility of carrying an altered gene that they could possibly pass on to their children.  Even 
though we will do our best to keep your information confidential, there is the possibility that your 
genetic risk for certain diseases is accidently divulged to the wrong source, if that happens you 
might be discriminated against obtaining life or health insurance, employment or ability to adopt 
children. 
Risks of Loss of Confidential Information: There is also a small risk that information from your 
health records will be released to an unauthorized party. We will do our best to make sure that 
your personal information will be kept private.  The chance that this information will be given to 
someone else is very small. An identification code assigned by the study team to each participant 
will be used in place of your name to protect your identity when reporting trial-related data.  
 
BENEFITS OF PARTICIPATION 
 
If you agree to take part in this study, there may not be direct medical benefit to you.  Other 
participants in the future, however, may benefit from the information learned from this research 
study, and the investigators may learn more about IPI-549. 
 
ALTERNATIVES TO PARTICIPATION 
 
If you choose not to take part in or stop participating in this research study, there may be other 
treatments.  Refusal to take part in this study will not cause penalty or loss of benefits to which 
you are otherwise entitled. 
 
You do not have to participate in this study to receive treatment for your cancer.  Other possible 
treatments include treatment with other drugs or drug combinations, participation in other research 
studies, or supportive care only (no cancer treatment).   
 
Please talk to your study doctor about these and other options 
 
WHAT ARE THE COSTS/COMPENSATION FOR PARICIPATION? 
 
The study drug, IPI-549, will be supplied at no cost while you take part in this study. The cost of 
getting the study drug, IPI-549, ready for you is also provided at no cost.   
 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
12 
 
 
 
 
It is possible the study drug, IPI-549, may not continue to be supplied while you are on the study. 
Although not likely, if this occurs, your study doctor will talk to you about your options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of caring 
for your cancer while in this study, including the costs of your surgery, tests, procedures, or 
medicines to manage any side effects, unless you are told that certain tests are supplied at no cost.  
Before you decide to be in the study, you should check with your health plan/insurance company 
to find out exactly what they will pay for.  
 
Examples of procedures and drugs that may be billed include the following: blood tests for routine 
analysis (blood cell count, blood chemistry, and pregnancy tests), physical exams, imaging scans, 
and other standard tests and procedures used to evaluate your disease. 
 
There will be no payment to you for participating in this study.   
 
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I PARTICIPATED? 
 
If you are injured as a direct result of participation in this research, the University of California 
will provide any medical care you need to treat those injuries. The University will not provide any 
other form of compensation to you if you are injured. You may call the UC San Diego Office of 
IRB Administration at (858) 246-4777 for more information about this, to inquire about your rights 
as a research subject or to report research-related problems. 
 
VOLUNTARY PARTICIPATION 
 
Participation in this study is entirely voluntary.  If you choose not to participate or wish to withdraw 
your consent to participate in these study procedures at any time, it will in no way affect your 
regular treatments or medical care at this institution or loss of benefits to which you are entitled.  
Please contact Dr. Assuntina Sacco or a member of her study team, if you wish to withdraw from 
participation.   
 
You will be informed of any new findings that might affect your willingness to continue 
participating in the study. 
 
If health conditions occur which would make your participation in this study possibly dangerous, 
or if other conditions occur that would make participation in this study detrimental to you or your 
health, then your study doctor may discontinue your participation in this study.  
 
Your study doctor or sponsor may stop your participation in this study at any time without your 
consent if: 
• You become pregnant; 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
13 
 
 
 
 
• You cannot follow the instructions given to you; 
• You experience an unacceptable side effect; 
• Dr. Assuntina Sacco or UCSD decides to end the study. 
 
DO YOU HAVE ANY QUESTIONS? 
 
Dr. Assuntina Sacco and/or _______________________________has explained this study to you, 
and answered your questions.  You may contact Dr. Assuntina Sacco at (858) 822-5800.  You may 
also call the hospital 24-hour paging system at (858) 657-7000 and ask for the oncologist on-call.  
If you have other questions or research-related problems, you may call the Moores UCSD Cancer 
Center Clinical Trials Office at (858) 822-5354. 
If you have questions about your rights as a research participant, your participation in this study, 
and/or concerns about this study, you may call the UC San Diego Office of IRB Administration (a 
group of people who review the research study to protect your rights and welfare) at (858) 246-
4777. 
A description of this clinical trial will be available on 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 
 
The confidentiality of your research records will be maintained to the extent allowed by law.  This 
includes using locked filing cabinets and the use of passwords will be required to access your 
personal data on computers.  Access to your information will be limited to study personnel who 
need to use it for the purpose of the research in this study. Only the minimum necessary 
information required will be collected, stored, used and reported.  Your medical information will 
not be made publicly available unless disclosure is required by law or regulation. 
 
Data obtained from this study will be given to the sponsor of this study, UCSD, V Foundation, and 
Infinity Pharmaceuticals, and/or its representatives, and may be published or given to regulatory 
authorities, including the Food and Drug Administration (FDA), Department of Health and Human 
Services (DHHS) agencies, the UCSD Institutional Review Board, the Moores UCSD Cancer 
Center Data and Safety Monitoring Board (DSMB) and other governmental agencies in the United 
States or other countries in which regulatory approval of IPI-549 may be sought.  Your identity 
will remain confidential. Study data is labeled with a code instead of your name or other 
information that can easily identify you. 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
14 
 
 
 
 
You will be asked to sign a separate HIPAA authorization form to allow the study team to access 
and share information from your medical record.  Your permission as described in this informed 
consent and HIPAA document does not have an automatic expiration date. 
 
 
 
 
 
SIGNATURE AND CONSENT 
 
Your participation in this study is voluntary, and you may refuse to participate or withdraw from 
the study at any time without prejudice or loss of benefits to which you are otherwise entitled.  You 
will receive a signed copy of this consent document and a copy of “The Experimental Subject’s 
Bill of Rights” to keep. 
 
You agree to participate. 
 
 
________________________________ 
Printed Name of Participant 
 
 
 
 
                                                                  
 
_________________ 
Signature of Participant 
 
 
 
 
Date 
 
 
 
 
___________________________________ 
Printed Name of Person Obtaining Consent 
 
 
 
                                                                   
 
__________________ 
Signature of Person Obtaining Consent 
Date 


Principal Investigator:  Assuntina Sacco, MD 
OIA Project 172058   
 
UCSD IIT A. Sacco, MD IPI-549 
Main Consent ver 3  
Protocol ver 6 dated 12/03/2021 
11/17 ab/ ee; 02/18 ab; 04/18 ab; 08/18 ee; 10/18 ee; 01/19 ee, 7/2020 kdz, 1/21kr; 01/2022 TH, 6/6ss, 05/23 DW 
15 
 
 
 
 
UC San Diego Office of IRB Administration 
 
University of California, San Diego 
(858) 246-4777 
 
9500 Gilman Drive, Mail Code 0052 
(858) 246-3329 (FAX)  
 
La Jolla, CA 92093-0052 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
The faculty and staff of the University of California, San Diego wish you to know: 
Any person who is requested to consent to participate as a subject in a research study 
involving a medical experiment, or who is requested to consent on behalf of another, has the 
right to: 
1. 
Be informed of the nature and purpose of the experiment. 
2. 
Be given an explanation of the procedures to be followed in the medical experiment, 
and any drug or device to be used. 
3. 
Be given a description of any attendant discomforts and risks reasonably to be 
expected from the experiment. 
4. 
Be given an explanation of any benefits to the subject reasonably to be 
expected from the experiment, if applicable. 
5. 
Be given a disclosure of any appropriate alternative procedures, drugs, or devices 
that might be advantageous to the subject, and their relative risks and benefits. 
6. 
Be informed of the avenues of medical treatment, if any, available to the 
subject after the experiment if complications should arise. 
7. 
Be given an opportunity to ask any questions concerning the experiment or 
the procedures involved. 
8. 
Be instructed that consent to participate in the medical experiment may be withdrawn 
at any time, and the subject may discontinue participation in the medical experiment 
without prejudice. 
9. 
Be given a copy of a signed and dated written consent form when one is required. 
10. 
Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or 
undue influence on the subject’s decision. 
 
If you have questions regarding a research study, the researcher or his/her assistant will be glad 
to answer them. You may seek information from the UC San Diego Office of IRB 
Administration - established for the protection of volunteers in research projects - by calling 
(858) 246-4777 from 7:30 AM to 4:00 PM, Monday through Friday, or by writing to the above 
address. 

Prot_SAP_002.pdf: 
Phase 2 Window of Opportunity Study of IPI-549 in Patients 
with Locally Advanced HPV+ and HPV- Head and Neck 
Squamous Cell Carcinoma 
 
NCT03795610 
 
Document Date: 12/3/2021 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 6.0 
Protocol Date: December 03, 2021 
Page 1 of 45 
Phase 2 Window of Opportunity Study of IPI-549 in Patients with Locally Advanced HPV+ 
and HPV- Head and Neck Squamous Cell Carcinoma 
PROTOCOL 
Study Chair (Principal Investigator) 
Ezra Cohen, M.D. 
Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Phone: 858-534-6161 
Fax: 858-822-5754 
Email: ecohen@ucsd.edu 
Study Site 
UCSD Moores Cancer Center 
3855 Health Sciences Drive #0698 
La Jolla, CA 92093-0698 
Protocol Number 
172058 
IND Number: 
141417 
IND Holder Name: 
Ezra Cohen, MD 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 6.0 
Protocol Date: December 03, 2021 
Page 2 of 45 
 
 
 
LIST OF INVESTIGATORS 
 
 
PRINCIPAL INVESTIGATOR 
Ezra Cohen, M.D. 
Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0658 
Phone: 858-534-6161 
Fax: 858-822-5754 
Email: ecohen@ucsd.edu 
 
CO-INVESTIGATORS 
Judith Varner, Ph.D. 
Professor of Medicine 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093-0820 
Phone: 858-822-0086 
Fax: 858-822-1325 
Email: jvarner@ucsd.edu 
 
BIOSTATISTICIAN 
Karen Messer, Ph.D. 
Professor of Family Medicine & Public Health 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive #0901 
La Jolla CA, 92093-0901 
Phone: 858-822-6823 
E-mail: kmesser@ucsd.edu 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 6.0 
Protocol Date: December 03, 2021 
Page 3 of 45 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
UCSD Principal Investigator / Study Chair 
 
 
 
Printed Name 
 
 
 
Signature 
Date 
 
 
 
 
Participating Site Principal Investigator 
 
 
 
Printed Name 
Institution 
 
 
 
Signature 
Date 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 6.0 
Protocol Date: December 03, 2021 
Page 4 of 45 
 
 
TABLE OF CONTENTS 
STUDY SCHEMA ........................................................................................................................ 6 
......................................................................................................................................................... 6 
STUDY SUMMARY ..................................................................................................................... 7 
1.0 
INTRODUCTION ........................................................................................................ 11 
2.0 
BACKGROUND AND RATIONALE ....................................................................... 11 
2.1 
Immunotherapy in HNSCC ........................................................................................................................ 11 
2.2 
Study Agent ............................................................................................................................................... 12 
2.2.1 
IPI-549 
12 
2.2.2 
Summary of Pharmacology of IPI-549 
12 
2.2.3 
Rationale for IPI-549 as a Potential Therapy for Patients with Cancer 
12 
2.3 
Rationale .................................................................................................................................................... 13 
3.0 
STUDY OBJECTIVES ................................................................................................ 13 
3.1 
Primary Objectives..................................................................................................................................... 13 
3.2 
Secondary Objectives ................................................................................................................................. 14 
3.3 
Endpoints ................................................................................................................................................... 14 
3.4 
Primary Endpoints ..................................................................................................................................... 14 
3.5 
Secondary Endpoints ................................................................................................................................. 14 
3.6 
Exploratory endpoints ................................................................................................................................ 15 
4.0 
PATIENT ELIGIBILITY ........................................................................................... 15 
4.1 
Inclusion Criteria ....................................................................................................................................... 15 
4.2 
Exclusion Criteria ...................................................................................................................................... 16 
5.0 
TREATMENT PLAN .................................................................................................. 17 
5.1 
Study Design .............................................................................................................................................. 17 
5.2 
Treatment Dosage and Administration ...................................................................................................... 17 
5.3 
Duration of Study Treatment ..................................................................................................................... 17 
5.4 
Duration of Follow Up ............................................................................................................................... 17 
5.5 
Discontinuation from Study Participation .................................................................................................. 17 
6.0 
STUDY PROCEDURES.............................................................................................. 18 
6.1 
Definitions of Study Assessments .............................................................................................................. 18 
6.1.1 
Medical history 
18 
6.1.2 
Review subject eligibility criteria 
18 
6.1.3 
Concomitant medications 
18 
6.1.4 
Physical exam 
18 
6.1.5 
Adverse event assessment 
18 
6.1.6 
Clinical Laboratory Tests 
18 
6.1.7 
ECG 18 
6.1.8 
Tumor Biopsy and Research Blood Collection 
19 
6.2 
Screening/Baseline Procedures .................................................................................................................. 22 
7.0 
ADVERSE EVENTS.................................................................................................... 22 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 6.0 
Protocol Date: December 03, 2021 
Page 5 of 45 
 
 
7.1 
Adverse Event Monitoring ......................................................................................................................... 23 
7.2 
Severity ...................................................................................................................................................... 23 
7.3 
Seriousness ................................................................................................................................................ 24 
7.4 
Relationship ............................................................................................................................................... 25 
7.5 
Prior experience ......................................................................................................................................... 25 
7.6 
Reporting Requirements for Adverse Events ............................................................................................. 25 
7.6.1 
Expedited Reporting 
25 
7.6.2 
Routine Reporting Requirements 
26 
8.0 
AGENT INFORMATION ........................................................................................... 26 
8.1 
Agent IPI-549 ............................................................................................................................................ 26 
9.0 
STATISTICAL CONSIDERATIONS ....................................................................... 28 
9.1 
Study Design/Study Endpoints .................................................................................................................. 28 
9.2 
Sample Size and Accrual ........................................................................................................................... 28 
10.0 
STUDY MANAGEMENT ........................................................................................... 29 
10.1 
Conflict of Interest ..................................................................................................................................... 29 
10.2 
Institutional Review Board (IRB) Approval and Consent ......................................................................... 30 
10.3 
Subject Data Protection .............................................................................................................................. 30 
10.4 
Data and Safety Monitoring/Auditing ........................................................................................................ 30 
10.5 
Adherence to the Protocol .......................................................................................................................... 31 
10.6 
Amendments to the Protocol ...................................................................................................................... 31 
10.7 
Record Retention ....................................................................................................................................... 31 
11.0 
ETHICAL CONSIDERATIONS ................................................................................ 32 
11.1 
Ethical Conduct of Study ........................................................................................................................... 32 
11.2 
Subject Data Protection .............................................................................................................................. 32 
12.0 
REFERENCES ............................................................................................................. 33 
13.0 
APPENDICES .............................................................................................................. 34 
Appendix A. Performance Status ............................................................................................................................ 34 
Appendix B: Patient Pill Diary [be sure to bring this diary and pill bottles with you to your next study visit. ....... 36 
Appendix C: Medications or foods known to inhibit or induce CYP3A ................................................................. 37 
Appendix D: Medications associated with prolongation of the QTC and/or with torsades de pointes .................... 39 
Appendix E: CYP2C8 OR CY2C9 SUBSTRATES ................................................................................................ 41 
Appendix F: P-GP Substrates and medications that are inhibitors of P-GP ............................................................ 42 
Appendix G: Pharmacodynamic changes observed in peripheral blood of MARIO3 TNBC patients after 15 
day treatment with eganelisib in combination with atezolizumab + nab-paclitaxel 


UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 6 of 45 
 
 
UCSD Moores Cancer Center 
CONFIDENTIAL 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
 
 
 
STUDY SCHEMA 
 
 
 
 
• Baseline tumor 
measurement 
• Tumor biopsy (non- 
 
Patients with Locally 
Advanced, Previously 
Untreated HNSCC Amenable 
to Surgical Resection 
 
Therapy: 
 
IPI-549 40 mg QD* PO 
days 1-14 
 
 
2 weeks 
 
 
Surgical Tissue Specimen 
 
 
 
 
 
Standard Therapy 
Survival, Toxicity Follow-Up 
*Final dose based on ongoing Phase 1 study 


UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 7 of 45 
 
 
[NCT02637531] 


UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 8 of 45 
 
 
UCSD Moores Cancer Center 
CONFIDENTIAL 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
 
 
 
STUDY SUMMARY 
 
Title 
Phase 2 Window Study of IPI-549 in Patients with Locally Advanced HPV+ or 
HPV- Head and Neck Squamous Cell Carcinoma 
Short Title 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
Phase 
2 
Methodology 
Single arm, unblinded 
Study Duration 
2 years 
Study Center(s) 
University of California, San Diego 
Objectives 
1. To detect a change in the PI3Kgamma regulated gene expression signature 
of immune suppression. 
2. To detect change in myeloid, T cell composition and immune activation 
markers by IHC as well as TCR sequencing 
3. To determine safety and tolerability of IPI-549 and change in tumor size in 
patients with locally advanced HNSCC. 
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria 
Eligible patients (n=15) with pathologically confirmed locally advanced, 
previously untreated HNSCC that is amenable to surgical resection. 
Study Product(s), Dose, 
Route, Regimen 
IPI-549, 40 mg QD PO* 
*Final dose based on ongoing Phase 1 study 
[NCT02637531] 
Duration of administration 
At least 14 days 
Reference therapy 
N/A 
Statistical Methodology 
We anticipate enrolling 15 subjects. Within subject change from the post-treatment 
to the pre-treatment sample in the immune activation signature will be the primary 
endpoint. We will test the hypothesis of an increase in this signature using a one 
sided paired t-test at 5% significance level. With 15 subjects we have 80% power 
to detect a difference in the mean signature equal to 0.68 standard deviations. 
A safety stopping rule will halt the study if at any time 3 or more subjects have 
observed progression prior to surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 9 of 45 
 
 
 
SCHEDULE OF EVENTS 
 
Procedure 
Screen/ Baseline 
(≤ 28 days) 
Window of 
Opportunity 
Week 1 Day 1 
(±3 days) 
Pre-Surgery10 
Week 2 Day 14 
(±3 days) 
Follow-up 
Approximately 30 days ( ±7 
days)after last dose of study 
drug 
Informed Consent 
Within 28 days 
Eligibility 
X 
Medical History 
X 
Demographics 
X 
Concomitant Medications 
Assessment 
X 
X 
X 
X9 
Adverse Event Assessment 
X 
X 
X9 
Physical Exam1 
X 
X 
X 
X 
Vital Signs and Height 
X 
X 
X 
ECOG PS 
X 
X 
X 
CBC with Diff2 
Within 7 days 
X 
X 
X 
CMP3 
Within 7 days 
X 
X 
X 
Pregnancy test4 
Within 72 hours 
HIV (as clinically indicated) 
X (Within 7 days) 
HEP B & C (as clinically indicated) 
X (Within 7 days) 
ECG (12-lead) 
X 
Tumor tissue collection5 
X 
X11 
Blood Collection for Correlative 
studies6 
X(Within 7 days) 
X 
MRI or CT (neck & chest) 
X7 
IPI-549 administration8 
X 
Safety follow up 
X 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 10 of 45 
 
 
 
 
IPI-549 is 14 days in length with the last administration within 24 hours of surgery. 
 
1. Full physical exam at baseline; targeted physical exam at other time points. 
2. CBC with Diff: Complete blood count with differential. 
3. CMP: Comprehensive metabolic panel (bicarbonate, calcium, chloride, creatinine, glucose, potassium, sodium BUN, albumin, 
bilirubin total, alkaline phosphatase, total protein, ALT, AST). 
4. Pregnancy test for females of child-bearing potential only. 
5. Tumor tissue collection: See Section 6.1.8 for specifications. 
6. Blood for correlative studies should be collected at the same time blood is drawn for CBC and CMP if possible. 40 mL blood to be 
collected at baseline; 30 mL blood to be collected at pre-surgery visits. See Section 6.1.8. 
7. Scans will be performed when clinically indicated. 
8. IPI-549 administration (Section 5.2): administered PO 40 mg QD until 24 hours prior to date when surgery is performed. Not 
allowed less than 24 hours of surgery. 
9. In Follow-Up period, concomitant medications will be collected at Safety Follow-Up visit (approximately 30 (+7) days after the 
last dose of study drug) and for SADs. During this period, adverse events will be collected at Safety Follow-Up and SAEs until 90 
days after last does of study drug. 
10. Surgery is to be performed no later than 48 hours after last dose of therapy. Therapy should continue until the day before surgery. 
11. Tumor tissue collection to occur during surgery. 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 11 of 45 
 
 
 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 12 of 45 
 
 
 
1.0 
INTRODUCTION 
This protocol proposes to examine the anti-tumor efficacy of IPI-549 in patients with 
locally advanced HPV+ or HPV- HNSCC. Subjects who are candidates for surgical resection will 
be enrolled and treated with IPI-549 for 2 weeks prior to surgery. Tumor tissue for research 
purposes will be obtained by core biopsy prior to treatment and at surgery after 2 weeks of 
treatment. Tissue will be evaluated by RNA profiling for two PI3Kγ-regulated immune 
suppression signatures that we previously identified; changes in immune responses will be 
validated by performing immunohistochemistry to detect myeloid and T cell composition and 
activation status and by genomic sequencing to detect changes in intra-tumor T cell receptor (TCR) 
clonality. 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Immunotherapy in HNSCC 
Immune therapy holds great promise for the treatment of cancer patients, as novel 
immunotherapeutic agents such as the checkpoint inhibitors pembrolizumab and nivolumab (anti- 
PD-1) have recently demonstrated potent anti-tumor activity in a subset of cancer patients. 
Disappointingly, clinical responses to these checkpoint inhibitors occurred in only 20% of patients 
with head and neck squamous cell carcinoma (HNSCC), a devastating disease that is associated 
with considerable morbidity and mortality. Improved therapeutic approaches that target the 
mechanisms of immune escape from checkpoint inhibitors could hold great promise for patients 
with HNSCC and other cancers. Recent studies from our lab and others show that immune 
suppressive Tumor Associated Macrophages (TAMs) and Myeloid Derived Suppressor Cells 
(MDSCs) promote escape from checkpoint inhibitors. Signals from the tumor microenvironment 
polarize these myeloid cells towards an immunosuppressive phenotype that is characterized by 
high levels of Arginase, TGFß, IL10 and low levels of MHCII, IL12, iNOS and T cell 
chemoattractants such as CXCL9 and CXCL10. TAMs and MDSCs then suppress CD8+ T-cell 
recruitment, survival, and cytotoxic function, thereby inhibiting effective anti-tumor immune 
responses. Novel immune therapeutics that circumvent resistance to checkpoint inhibitors could 
provide benefit to numerous cancer patients, including patients with HNSCC. 
We recently identified a novel pathway by which TAMs and MDSCs inhibit 
responsiveness to checkpoint inhibitors [1, 2]. We found that phosphatidylinositol-4,5- 
bisphosphate 3-kinase gamma (PI3Kγ), a myeloid cell selective isoform of PI3-Kinase, mediates 
immune suppression in TAMs and MDSCs by inhibiting NFkB activation and promoting mTor, 
S6K and c/EBPß activation, thereby leading to transcription of immune suppressive factors that 
inhibit T cell responses to tumors. Our results demonstrated that PI3Kγ, the major PI3K isoform 
in myeloid cells, promotes resistance to checkpoint inhibitors and stimulates tumor progression as 
selective inactivation of PI3Kγ suppressed myeloid cell expression of immune suppressive factors 
and inhibited tumor progression in mouse models of HNSCC, lung, breast, and pancreatic 
carcinoma, as well as melanoma and glioblastoma. Importantly, PI3Kγ inhibition stimulated 
responses to checkpoint inhibitors, leading to eradication of tumors and long-term anti-tumor 
immunological memory in mouse models of HNSCC. 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 13 of 45 
 
 
Importantly, we also identified a PI3Kγ-regulated gene expression signature that is 
associated with outcome in HNSCC and lung cancer patients. Notably, high expression of a PI3Kγ- 
regulated immune suppression signature was associated with decreased patient survival in these 
patients. Conversely, low expression of this signature was associated with extended survival in 
these patients. These results suggested that a PI3Kγ-regulated immune suppression signature could 
be used to identify cancer patients who are candidates for PI3Kγ inhibitor therapy and to monitor 
clinical responses to PI3Kγ-inhibitors. 
 
2.2 
Study Agent 
2.2.1 IPI-549 
The PI3K-γ isoform plays important roles in immune cell function and migration, including the 
immune suppressive tumor microenvironment. IPI-549 is a potent and selective PI3K- γ inhibitor 
that is being developed by Infinity Pharmaceuticals, Inc. (Infinity) as an orally administered 
potential therapeutic in multiple cancer indications. 
2.2.2 
Summary of Pharmacology of IPI-549 
Biochemical, cellular, and receptor binding assays showed that IPI-549 is a potent inhibitor of 
PI3K-γ that is highly selective over other protein and lipid kinases, GPCRs, ion channels, and 
transporters. Cellular proliferation assays demonstrated that IPI-549 does not have a direct growth 
inhibitory effect on human solid tumor cells lines. In vitro functional assays demonstrated that IPI- 
549 blocks bone marrow derived murine myeloid cell polarization to the M2 macrophage 
phenotype in response to IL-4 and macrophage colony-stimulating factor, and macrophage 
migration towards CXCL12, but does not inhibit Concanavalin A-induced T cell activation as 
measured by IFN-γ production. These data indicate the potential for IPI-549 to block immune 
suppressive macrophage development but not certain T cell activities that are important for the 
anti-tumor effect mediated by cytotoxic T cells. 
The effect of IPI-549 on tumor growth was evaluated in vivo using immune competent, 
murine syngeneic solid tumor models. Mice treated with IPI-549 demonstrated significant tumor 
growth inhibition in multiple syngeneic models. Tumor growth inhibition was dose-dependent 
with dose-proportional plasma and tumor exposure for IPI-549. Studies to elucidate the mechanism 
of tumor growth inhibition indicated that IPI-549 affects immune-suppressive myeloid cell 
numbers and/or function, leading to an increase in cytotoxic T cell activity. Studies in both nude 
and CD8 T cell-depleted mice demonstrated the T-cell-dependence of IPI-549 mediated tumor 
growth inhibition. 
2.2.3 Rationale for IPI-549 as a Potential Therapy for Patients with Cancer 
PI3K-γ is expressed in immune cells and has limited, if any, expression in epithelial cancer 
cells. Furthermore, PI3K-γ is the predominant catalytic isoform found in myeloid cells [2]. In 
myeloid cells PI3K-γ is activated by GPCRs, the Toll Like Receptors/Interleukin 1 Receptors and 
RTKs [2]. The role of myeloid cells in promoting tumor growth has been demonstrated in multiple 
preclinical mouse models [3]. Tumors and their associated stroma secrete chemokines that attract 
precursor monocytes that differentiate into macrophages. The tumor associated macrophages as 
well as dendritic cells and granulocytes (collectively known as myeloid derived suppressor cells 
[MDSC]), actively support the proliferation of the tumor cells while at the same time acting to 
suppress host antitumor activity [4]. 


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Pre-clinical data from a tumor bearing mouse knockout model of PI3K-γ results in a 
reduced influx of myeloid cells, and reduced vascularization of the tumor, resulting in reduced 
tumor growth, suggesting that PI3K-γ inhibition can play a critical role in disrupting the MDSCs 
[2]. 
The established role of PI3K-γ in the biology of the tumor microenvironment supports 
testing IPI-549 in patients with cancer, both as a single agent, and in combination with other drugs. 
The PI3K-γ isoform plays important roles in immune cell function and migration, including the 
immune suppressive tumor microenvironment. IPI-549 is a potent and selective PI3K- γ inhibitor 
that is being developed by Infinity Pharmaceuticals, Inc. (Infinity) as an orally administered 
potential therapeutic in multiple cancer indications. 
 
2.3 
Rationale 
HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) are deadly and 
disfiguring cancers with limited therapeutic options; while checkpoint inhibitors have promise as 
new cancer therapeutics, they have demonstrated limited activity in HNSCC. However, we found 
that inhibitors of PI3Kγ, such as Infinity Pharmaceutical’s highly selective inhibitor, IPI-549, 
repolarized tumor associated macrophages to reverse immune suppression and stimulate anti- 
tumor immunity in animal models of HNSCC. We identified a signature of immune suppression 
in mouse models of HPV+ and HPV- HNSCC that was reversed by PI3Kγ inhibition [5]. Using 
TCGA data, we found that this same signature was associated with poor outcome in HPV+ and 
HPV- HNSCC patients [5]. Our results suggest that selective PI3Kγ inhibitors might promote anti- 
tumor immune responses in HNSCC patients. We hypothesize that treatment with the selective 
PI3Kγ inhibitor IPI-549 will switch mRNA expression signatures of immune suppression in 
patient tumors to signatures of immune activation. These signatures could then serve as 
surrogate biomarkers of IPI-549 efficacy. Therefore, we propose to establish a Phase II window 
of opportunity clinical trial to evaluate the effect of IPI-549 on biomarkers of immune suppression. 
Patients with resectable HNSCC will be treated with the investigational, highly selective PI3Kγ 
inhibitor IPI-549 for two weeks prior to surgical resection; pre- and post-treatment biopsies will 
be evaluated for changes in the PI3Kγ-responsive gene expression signature of immune 
suppression we previously identified. Additionally, we will monitor for changes intratumoral and 
circulating immune cell populations in collaboration with Dr. Lisa Coussens, OHSU, using 
multiplex immunohistochemistry. These studies will be useful in identifying biomarkers of 
response that will allow optimization of future therapeutic strategies for HNSCC. 
 
3.0 
STUDY OBJECTIVES 
This is a phase 2 window of opportunity trial in patients with locally advanced HNSCC. A 
key objective is to provide the first proof that macrophage phenotype switching can be 
accomplished in humans and lay the groundwork for future trials of this novel approach to immune 
therapy. Subjects who are candidates for surgical resection will be enrolled and treated with 2 
weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core 
biopsies will be obtained prior to initiation of IPI-549 and at surgery. 
 
3.1 
Primary Objectives 
1. To detect IPI-549-induced changes in PI3Kγ-regulated signatures of immune suppression. 


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3.2 
Secondary Objectives 
1. To measure changes in myeloid and T cell composition and activation status by 
immunohistochemistry and TCR sequencing. 
2. To determine safety and tolerability of IPI-549 and change in tumor size in patients 
with locally advanced HNSCC. 
3. To measure changes in peripheral cytokines and immune cells 
 
3.3 
Endpoints 
 
We hypothesize that mRNA signatures of immune response will be increased in IPI-549-treated 
HNSCC patients.  For the efficacy endpoints, RECISTv1.1 will be used. 
 
Primary Endpoints 
 
We hypothesize that the 5-gene mRNA immune response signature from Kaneda et al. [2] will 
increase with treatment. 
 
Specifically, the signature is: s= IL12A + IL12B + IFNG + CD8A – IL6, measured by RNA 
expression levels from a custom Nanostring Immune Profiling panel. 
 
Secondary Endpoints 
 
1. Adverse events related to IPI-549 (description, grade [CTCAE v5.0], and seriousness). 
2. T cell receptor (TCR) sequencing from blood obtained at baseline, surgery, end of treatment 
or at time of disease progression. 
3. Comparison of pre- vs. post-treatment tumor tissue for CD8 expression by 
immunohistochemistry 
4. Comparison of pre- vs. post-treatment peripheral cytokines and immune cells. 
 
We hypothesize that the 42-mRNA signature of PI3Kγ [2] will increase with treatment. Gene 
expression will be assessed by Nanostring custom panel. 
Specifically, the signature is comprised of the sum of 21 immune response and T-cell 
activation genes, plus the sum of 10 antigen presentation genes, minus the sum of 11 immune 
suppression genes [2] listed below. 
Gene lists for the PI3Kgamma activation signature are: 
• Immune suppression genes: PDGFA PDGFB HBEGF PLAU F3 IFIT1 
CD276 IL6 CCL7 CCL4 ID2 
• Immune response, T cell activation genes: IER3 ADORA2A CCR7 RASGRP1 CXCR3 
CX3CR1 IL12B IL12A CD4 CD8A CD8B GZMA GZMK GZMH GZMM IFNG CD28, 
LAT LAG3 ZBP1 BTLA MALT1 


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• Antigen presentation genes: 
HLA_DMA HLA_DMB HLA_DRB5 HLA_DOB CIITA 0 HLA_DQA2 HLA_DRA 
HLA_DOA HLA_DQB2 CD74. 
Exploratory endpoints 
 
 
Three IHC panels to assess myeloid and T cell content and activation states, each panel is 
expected to increase with treatment 
• Lymphoid panel: PD-1, CD3, RORgt, CD56, CD8, Tbet, GATA3, FoxP3 PD-L1, CD20, 
CD45, p16 
• Myeloid panel: Tryptase, CD68, CSF1R, DC-SIGN, CD66b, CD83, CD163, MHCII, PD- 
L1, CD3/20/56, CD45, p16 
• T cell activation panel: CD3, CD4, CD8, IDO, Tbet, CD68, PD-1, Eomes, Ki67, Granzyme 
B, CD45 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
1. Patients must have locally advanced, previously untreated HNSCC (unknown primary or 
any primary site except cutaneous or EBV-related nasopharynx cancer) that is amenable 
to surgical resection 
2. Age 18 years or older 
3. Patients must be able to administer IPI-549 by mouth and have no evidence of 
malabsorption 
4. Patients must be able to undergo a core tumor biopsy with tissue available for analytics 
 
5. There must be at least 2 weeks between initiation of IPI-549 and surgical resection 
6. ECOG performance status 0-2 
7. Patient has adequate organ function as defined below: 
 
Test Name 
Laboratory Value 
Absolute Neutrophil 
Count 
≥ 1.0 x 109/L 
Platelet count 
≥ 75 x 109/L (transfusion independent for > 7 days) 
Hemoglobin 
≥ 8.0 g/dL (may receive transfusions) 
Total bilirubin 
≤ 1.5 x institution’s upper limit of normal (ULN) 
AST and ALT 
≤ 2.5 X institutional upper limit of normal 
Serum creatinine 
≤ 1.5 x institution’s ULN, or creatinine clearance ≥ 60 ml/min 


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8. Female patient of childbearing potential has a negative serum or urine pregnancy within 7 
days prior to receiving the first dose of study medication. 
9. Female patient of childbearing potential agrees to use 2 methods of birth control or be 
surgically sterile, or abstain from heterosexual activity for the course of the study through 
120 days after the last dose of study medication. 
Note: Females of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year. 
 
10. Male patient with a partner of childbearing potential agrees to use an adequate method of 
contraception starting with the first dose of study therapy through 120 days after the last dose 
of study therapy. 
 
4.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation. 
Subjects are to be excluded from the study if they meet any of the following criteria: 
 
1. Cutaneous squamous cell carcinoma (SCC) or Epstein-Barr virus (EBV) related nasopharynx cancer 
2. Severe allergic or anaphylactic reaction to IPI-549. 
NOTE: Subjects with a history of anaphylaxis to other agents are eligible for study participation. Subjects 
who have received alternative therapies, including prior IPI-549, are eligible for study participation 
3. Major surgery within 4 weeks prior to initiation of study drug 
4. Subjects who have been treated with chemotherapy, biologic therapy, or other investigational agent 
within < 5 times the half-life of the agent or < 28 days (whichever is shorter) of starting study drug 
5. Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus (HCV) 
6. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids 
7. Ongoing systemic bacterial, fungal, or viral infections at Screening 
NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all 
other inclusion/exclusion criteria are met 
8. Administration of a live vaccine within 6 weeks of first dose of study drug 
9. Administration of any of the following within 2 weeks prior to the administration of study drug: 
a. Strong inhibitors or inducers of CYP3A4, including grapefruit, grapefruit juice and herbal 
supplements 
b. P-glycoprotien (P-gp) inhibitors 
c. Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow therapeutic range 
d. Medications associated with QTc interval prolongation or Torsades de Pointes 
10. Baseline QT interval corrected with Fridericia’s method (QTcF) > 480 ms (average of triplicate 
readings) 
11. Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g. gastric bypass surgery, 
gastrectomy) 
12. Female subjects who are pregnant or breastfeeding 
13. Concurrent active malignancy other than nonmelanoma skin cancer, carcinoma in situ of the cervix, or 
prostate intraepithelial neoplasia 
14. History of peptic ulcer and/or gastrointestinal bleed that have not resolved 
15. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary 
condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important 


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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 
Study Design 
This is a phase 2 window of opportunity trial in patients with locally advanced HNSCC. Subjects 
who are candidates for surgical resection will be enrolled and treated with 2 weeks of IPI-549, a 
specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be 
obtained prior to initiation of IPI-549 and at surgery. 
 
5.2 
Treatment Dosage and Administration 
 
IPI-549 will be administered 40 mg orally over a 14 day cycle. Dose of IPI-549 will be determined 
based on observed toxicity in ongoing Infinity clinical trial (NCT02637531). IPI-549 should be self- 
administered orally (approximately every 24 hours). IPI-549 should be swallowed whole with a glass 
of water (approximately 8 ounces or 240 mL). Subjects must avoid grapefruit and grapefruit juice while 
on study drug. Subjects should be advised to avoid food and liquids other than water from 2 hours prior 
to dosing until 1 hour after dosing. 
 
5.3 
Duration of Study Treatment 
IPI-549 for 2 weeks prior to surgical resection. Subjects will be monitored continuously for toxicity 
while on study therapy. Toxicity will be assessed using the NCI-CTCAE, v. 5.0 or higher. There will 
be no dose modification allowed on study. Missed doses should be recorded on the pill diary. Any 
grade 3 toxicity will result in discontinuation of IPI-549. If at any time 3 or more subjects have 
observed progression prior to the start of definitive treatment the study will be halted. 
 
5.4 
Duration of Follow Up 
All subjects will have a Safety Follow-up visit approximately 30 (+ 7) days after the last dose of 
study drug. At minimum this visit should include collection of AEs/SAEs and concomitant 
medications/procedures. This will be a clinic visit. The following activities will be performed 
during the visit, assessment of concomitant medications, adverse events, physical exam, vital signs 
and height, ECOG PS, CBC with differential, CMP . MRI or CT scan will be performed if 
clinically indicated. 
 
 
5.5 
Discontinuation from Study Participation 
Patients may be removed from study participation for the following reasons (in addition to those 
listed for discontinuation of study treatment): 
• The patient or legal representative withdraws consent for follow-up; 
• The patient is lost to follow-up; 
• The patient dies; 
• It is the decision of the investigator. 


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• Severe allergic or anaphylactic reaction to IPI-549 
• Disease progression prior to surgery 
• Pregnancy 
• Severe or life-threatening toxicity 
6.0 
STUDY PROCEDURES 
Refer to the study Schedule of Events for procedures. 
 
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at 
study treatment completion/early study treatment discontinuation, and during the follow-up 
period. 
 
6.1 
Definitions of Study Assessments 
6.1.1 Medical history 
A complete medical, surgical and oncology history as well as history of infections are 
obtained at screening. Any changes from Screening (e.g. worsening severity or abnormal 
findings) are considered to be adverse events (AEs). 
6.1.2 Review subject eligibility criteria 
Review of eligibility criteria as described in Section 3 to ensure subject qualification for 
study entry. 
6.1.3 Concomitant medications 
At Screening, concomitant/previous medications and procedures will be assessed including 
all medications/procedures that have occurred since the last visit. 
6.1.4 Physical exam 
A full physical exam (PE) will be performed at Screening and will include vital signs 
(temperature, blood pressure [sitting for 5 minutes], pulse rate, and respiratory rate), height, 
and weight. If vital signs need to be repeated during a single visit, assessments should be 
conducted approximately 5 minutes apart. Subsequent exams may be directed as appropriate. 
6.1.5 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See Section 7 for 
Adverse Event monitoring and reporting. 
6.1.6 
Clinical Laboratory Tests 
Blood chemistry, hematology, and βhCG pregnancy tests will be administered throughout the 
study to monitor safety. 
6.1.7 ECG 
At the treatment termination visit, a standard 12-lead ECG will be conducted following an 
approximate 10-minute rest period and obtained in triplicate within approximately a 5- 
minute time period. QTc measurements will use the Fridericia’s correction method (QTcF). 
ECGs will be read locally by the Investigator. Tumor assessment 


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6.1.8 Tumor Biopsy and Research Blood Collection 
Tumor tissue will be obtained by core biopsy prior to treatment and at surgery after 2 weeks 
of treatment. The goal of the planned laboratory correlative studies is to further characterize the 
biology of PI3Kγ inhibition, to gain a better understanding of the impact of IPI-549 on the tumor 
microenvironment, and explore potential biomarkers. See Section 3 for further details. 
 
6.1.9 Research Sample Collection Guidelines 
Specimens should be collected as outlined below and ALL samples should be labeled with the 
following: 
• Protocol number 
• Institution 
• Patient’s de-identified study number 
• Date of biopsy or surgery 
 
6.1.9.1 
Tumor tissue from initial biopsy 
Tumor tissue will be collected from a diagnostic core biopsy preferably performed within 28 days 
of initiating study treatment. 
 
When possible, 4 core biopsies should be taken for lesions > 1.5 cm, otherwise 2 cores should be 
taken. 
• If 4 cores are obtained, 1 core should be fresh frozen and the rest should be formalin-fixed 
paraffin embedded (FFPE). 
 
• If < 4 cores are obtained, tissue for research should be FFPE after being divided into the 
research and diagnostic documentation blocks according to the Pathology staff’s 
specifications. 
 
Ten (10) unstained sections (4-5 micron slices) or one (1) 20 micron roll-ups from FFPE tissue are 
desired. 
 
Fresh frozen samples should be stored in liquid nitrogen and FFPE samples at room temperature 
until shipment. 
 
6.1.9.2 
Tumor tissue from surgical resection 
Tumor tissue for research will be collected from only material in excess of that needed for routine 
clinical care as determined by a staff pathologist. 
 
Depending on the amount of tissue available, tissue should be collected for research in the 
following order of preference: 
1. Ten (10) unstained sections (4-5 micron slices) and one (1) 20 micron roll-ups from FFPE 
tissue. 
2. 10 unstained sections from fresh frozen tissue. 


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Fresh frozen samples should be stored in liquid nitrogen and FFPE samples at room temperature 
until shipment. 
 
6.1.9.3 
Peripheral Blood Mononuclear Cells (PBMCs) 
Blood for PBMCs will be collected prior to study treatment at screening (may be collected at the 
same time as blood drawn for routine laboratory tests) and at the time of surgery. 
 
Blood samples will be collected in two heparin green top tubes (approximately 20 ml). Samples 
should be processed the day of collection according to the PBMC isolation protocol in the 
Laboratory Manual. 
 
PBMCs should be stored at -80°C. 
 
6.1.9.4 
Buffy Coat 
Blood samples will be collected in one EDTA purple top tube (approximately 10 ml) prior to study 
treatment at screening (may be collected at the same time as blood drawn for routine laboratory 
tests). 
 
Samples should be processed the day of collection according to the buffy coat isolation protocol 
in the Laboratory Manual. 
 
Samples should be stored at -80°C. 
 
6.1.9.5 
Serum Cytokines 
Blood samples will be collected in one yellow-gold top serum separation tube (approximately 5 
mL) prior to study treatment at screening (may be collected at the same time as blood drawn for 
routine laboratory tests) and at the time of surgery. 
 
Samples should be processed the day of collection according to the instructions provided below: 
1. Fill tube completely. Invert 5-6 times and stand upright for a minimum of 30 minutes to 
clot. 
2. Centrifuge within 2 hours at 1000-1300g for 10 minutes at room temperature. 
3. Aliquot into two 2 mL labeled cryovials. 
4. Store samples at -65°C to -85°C. 
5. Ship samples monthly to The Forsyth Institute: 
 
The Forsyth Institute 
c/o Danielle Stephens, MS 
The Forsyth Institute 
245 First St. 
Cambridge, MA 02142 
 
6.1.9.6 
Flow Cytometry Analysis 


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Blood samples will be collected in one purple and black speckled Cyto-Chex tube 
(approximately 5 mL) prior to study treatment at screening (may be collected at the same time as 
blood drawn for routine laboratory tests) and at the time of surgery. 
Samples should be processed the day of collection according to the instructions provided below: 
1. Fill Cyto-Chex tube completely. 
2. Immediately after collection, invert gently 10 times to ensure proper mixing. 
3. Do NOT centrifuge. Do NOT open tube. 
4. Ship ambient with Gel packs on the day of collection to Primity Bio: 
 
Primity Bio 
C/O Erika O’donnell 
48383 Fremont Blvd, Suite 118 
Fremont, CA 94538 
USA 
 
5. Email package tracking information to: 0109@primitybio.com 
 
6.1.10 Specimen Handling 
Sample handling and storage will be coordinated by 
Sharmeela Kaushal 
Moores Cancer Center, 3345/3G, GG 
3855 Health Sciences Drive 
La Jolla, CA 92093-0819 
Phone: 858-822-7661 
 
6.1.11 Specimen Banking 
Patient samples collected for this study will be retained in the UCSD Moores Cancer Center 
Biorepository for analysis and future cancer research. Specimens will be stored indefinitely or until 
they are used up. Samples will be labeled with the protocol number, subject’s de-identified study 
number and collection date. The link between study number and medical record number will be 
viewed over a password secured encrypted server-client. 
 
The study research coordinator at each local site will review their subject's medical record for 
demographic and clinical information pertaining to the subject's general medical history, 
diagnosis, and outcomes of any treatments received. This information will be transmitted to and 
retained by the Coordinating Site UCSD. Samples and data extracted from the subject's medical 
record will be coded with a de-identified study number so that the subject's name and identifying 
information will be removed. A log that links the subject's name and identifiers to the study number 
will be maintained in a secure database distinct from the secure database into which the subject's 
clinical information will be entered by study personnel. 
 
Dissemination of specimens for research is at the discretion of the Study Chair, Dr. Cohen. 
Potential research collaborators outside of UCSD who approach the Moores Cancer Center for 
clinical specimens will be required to complete an agreement (Material Transfer Agreement or 
recharge agreement) stating that the specimens will only be released for use in disclosed research, 


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and any specimen left over from research will either be returned to the Cancer Center or destroyed. 
Any data obtained from the use of clinical specimen will be the property of UCSD for publication 
and any licensing agreement will be strictly adhered to. These outside collaborators may include 
for-profit biotechnology corporations interested in collaborating with UCSD investigators in 
research diagnostic, prognostic assays and drug development. 


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The specimens, DNA, and their derivatives may have significant therapeutic or commercial value. 
The Informed Consent form contains this information and informs the subject that there is the 
potential for financial gain by UCSD, the investigator or a collaborating researcher or entity. 
 
If patients later decide they do not want their specimens collected to be used for future research, 
they may tell this to the local site principal investigator, who will inform the Study Chair Dr. 
Cohen. Dr. Cohen will use his best efforts to stop any additional studies and to destroy the 
specimens. Samples stored in the Biorepository will be destroyed; for samples that have been 
disseminated outside of the Biorepository, Dr. Cohen will contact the recipient to notify them of 
the need to halt further research and destroy specimens. 
 
6.2 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within 7 days prior to registration unless otherwise 
stated. The screening procedures include: 
• Written informed consent (within 28 days). 
• Review of inclusion and exclusion criteria. 
• Complete medical/oncology history. 
• Demographics. 
• Documentation of concomitant medications. 
• Complete physical examination, including vital signs and height. 
• Performance status assessment. 
• Laboratory tests (within 7 days; pregnancy test within 72 hours). 
• Blood collection for correlative studies. 
• Documentation of tumor staging. 
• Tumor biopsy tissue collection for correlative studies (within 28 days). 
 
7.0 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment 
and which does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention. 
 
Progression of the cancer under study or events which are unequivocally due to disease progression 
should not be reported as an AE during the study (unless it is considered to be drug related by the 
investigator). 


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7.1 
Adverse Event Monitoring 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited manner 
to allow for optimal monitoring of patient safety and care. 
 
As far as possible, each adverse event should be evaluated to determine: 
• duration (start and end dates) 
• severity (grade) 
• seriousness 
• relationship to study agent 
• action taken (i.e., none, study agent modification, medical intervention) 
• outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
Adverse events monitoring begins at the time of initiating study treatment through 90 days 
following the last administration of study treatment or study discontinuation/termination, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to IPI-549. 
 
Note: Serious adverse events must be recorded in the case report forms for this 90 day-period; 
however, non-serious adverse events need only be recorded through 28 days post last study drug 
administration. 
 
All patients experiencing an adverse event at least possibly related to study treatment will be 
monitored until: 
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 
 any clinically significant abnormal laboratory values have returned to baseline; 
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
7.2 
Severity 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v5.0 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Moderate (grade 2): Moderate; minimal, local or noninvasive intervention indicated; 
limiting age- appropriate instrumental activities of daily living (ADL). Instrumental ADL 


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refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
Severe (grade 3): Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
Life-threatening (grade 4): Life-threatening consequences; urgent intervention indicated. 
Fatal (grade 5): Death related to AE. 
 
7.3 
Seriousness 
A “serious” adverse event is defined in regulatory terminology as any untoward medical 
occurrence that: 
1. Results in death. 
 
2. Is life-threatening. 
The patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization. 
Note: The following hospitalizations are not considered SAEs: 
• A visit to the emergency room or other hospital department < 24 hours 
that does not result in admission (unless considered an important medical 
or life-threatening event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy) 
• Medical/surgical admission other than to remedy ill health and planned 
prior to entry into the study. Appropriate documentation is required in 
these cases. 
• Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention (eg, 
lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason). 
• Admission for administration of anticancer therapy in the absence of any other SAEs. 
 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event 
Any event that does not meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious adverse event. The 
event may require medical or surgical intervention to prevent one of the outcomes listed in 
the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an emergency room 


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or at home; convulsions that may not result in hospitalization; development of drug abuse 
or drug dependency. 
 
7.4 
Relationship 
Attribution categories for adverse events in relationship to protocol therapy are as follows: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.5 
Prior experience 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited reporting 
purposes only, when either the type of event or the severity of the event is not listed in the current 
known adverse events listed in the agent clinical experience section of this protocol or the current 
Investigator’s Brochure. 
 
7.6 
Reporting Requirements for Adverse Events 
 
Serious adverse events, or a follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
study treatment initiation through 90 days following cessation of treatment, or the initiation of 
new anti-cancer therapy, requires expedited reporting as described below. 
 
7.6.1 Expedited Reporting 
A. The Study Chair and Site Principal Investigator must be notified within 24 hours of learning 
of any serious adverse events (SAEs) regardless of attribution, occurring during the study or 
within 30 days of the last administration of the study drug. 
B. The UCSD Human Research Protections Program (HRPP) and Moores Cancer Center 
Data and Safety Monitoring Board (DSMB) must be notified within 10 business days of 
“any unanticipated problems involving risk to subjects or others” (UPR). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), which in the 
opinion of the Principal Investigator was unanticipated, involved risk to subjects or 
others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol that 
alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated sponsor 
safety report), interim result or other finding that indicates an unexpected change 


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to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
6. Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
C. The FDA must be notified by the Study Chair according to the following timelines: 
• within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug, and 
• within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 3) 
at least possibly related to study participation. 
7.6.2 Routine Reporting Requirements 
A. The UCSD HRPP must be notified of any adverse events that are not unanticipated problems 
involving risk to subjects or others (non-UPRs) at the time of the annual Continuing Review. 
B. The FDA must be notified by the Study Chair of all non-serious adverse events annually at the 
time of the annual report. 
 
 
 
8.0 
AGENT INFORMATION 
 
8.1 
Agent IPI-549 
Please refer to Investigator’s Brochure for more comprehensive information. 
 
Mechanism of action (or Product description): 
 
IPI-549 drug substance is a freebase, white-to-yellow solid. The IPI-549 drug product is formulated in 
2 different capsule strengths (5 mg and 30 mg) for oral delivery with excipients (diluent, disintegrant, 
and lubricant) that are listed in the FDA Inactive Ingredients Database for approved drug products 
and/or Generally Regarded as Safe. 
 
Availability: Provided by Infinity Pharmaceuticals Inc. 
 
How supplied: IPI-549 is administered as an oral capsule supplied at the dose specified per subject 
and/or cohort. 
 
Route of administration for this study: IPI-549 should be self-administered orally (approximately 
every 24 hours). IPI-549 should be swallowed whole with a glass of water (approximately 8 ounces or 
240 mL). Subjects must avoid grapefruit and grapefruit juice while on study drug. Subjects should be 
advised to avoid food and liquids other than water from 2 hours prior to dosing until 1 hour after dosing. 
 
Side effects: 
 
Adverse Reactions Based on Clinical Data 


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The following side effects have been observed in 12 people who received IPI-549 according to the 
results from a Phase 1/1b first-in-human, dose escalation study to evaluate the safety tolerability, 
pharmacokinetics, and pharmacodynamics of IPI-549 monotherapy and in combination with 
nivolumab in subjects with advanced solid tumors. 
 
Grade 3 or higher TEAEs occurred in 5 (41.7%) subjects (1 each in the 10,15, and 20mg groups and 2 
in the 30mg group.)There was 1 occurrence of each of the following Grade 3 or higher TEAEs: 
anaemia, haematochezia, small intestinal obstruction, pneumonia, lymphocyte count decreased, and 
malignant neoplasm progression. 
 
Treatment-emergent SAEs occurred in 5 (41.7%) subjects. Each subject had 1 SAE as follows: 
malignant neoplasm progression (15mg), haematochezia (20mg), periotonitis (20mg), small intestinal 
obstruction (30mg), and pneumonia (30mg). 
 
The following side effects have been observed in 56 people who received IPI-549. 
 
Blood and lymphatic system disorders: 
Anemia 
 
Gastrointestinal Disorders: 
Diarrhea 
Nausea 
Vomiting 
Abdominal pain 
 
General disorders and administration site conditions: 
Fatigue 
Fever 
Local swelling 
 
Metabolism and nutrition Disorders: 
Hypomagnesaemia 
 
Nervous system disorders: 
Headache 
 
Vascular disorders 
Hypertension 
 
Skin and subcutaneous tissue disorders: 
Rash 
Itchiness 
Dermatitis acneiform 


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Investigations: 
Increased liver enzymes 
White blood cell count decreased 
Blood bilirubin increased 
 
Respiratory, thoracic and mediastinal disorders: 
Shortness of breath 
Pleuritic pain 
 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study populations 
The efficacy population will consist of all subjects who have received 2 weeks of study drug. 
Any subject who has not received 2 weeks of study drug will be replaced. 
 
The safety population will consist of all subjects who have received any dose of study drug. 
 
 
9.2 
Study Design/Study Endpoints 
We anticipate enrolling 15 subjects. The primary analysis will use the efficacy population. Within 
subject change from the post-treatment to the pre-treatment sample in the immune activation 
signature will be the primary endpoint. We will test the hypothesis of an increase in this signature 
using a one sided paired t-test at 5% significance level. With 15 subjects we have 80% power to 
detect a difference in the mean signature equal to 0.68 standard deviations, which is a modest effect 
size. Although we lack preliminary data on the magnitude of the standard deviation of within 
subject changes, effect sizes less than this would be unlikely to be clinically interesting. Also, the 
differences seen between the poor prognosis and good prognosis groups in Kaneda et al. [2] were 
greater than this minimal effect size. Thus the study appears to be well-powered to detect 
meaningful differences. 
 
 
 
 
Figure 1: Illustration of shift in the 
signature distribution, which would yield 
an effect size of 0.68 
 
 
 
9.3 
Sample Size and Accrual 


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We anticipate enrolling 15 subjects. Subjects who do not complete 2 weeks of IPI-549 therapy will 
be replaced. Thus far, IPI-549 in advanced cancer patients has been well tolerated without serious 
toxicity. Therefore, we anticipate being able to fully accrue this trial within one year of activation 
and the administration of IPI-549 will not interfere with planned surgery. If at any time 3 or more 
subjects have observed progression prior to the start of definitive treatment the study will be halted. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
4 
8 
12 
Ethnic Category: Total of all subjects 
(A1) 
(B1) 
(C1) 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
3 
8 
11 
Racial Category: Total of all subjects 
(A2) 
(B2) 
(C2) 
(A1 = A2) 
(B1 = B2) 
(C1 = C2) 
 
9.4 
Safety stopping rule 
The study will be stopped early in the event of excessive toxicity leading to delays in definitive 
surgery. In particular any grade 3 toxicity will result in discontinuation of IPI-549, and any 
subject who has not received 2 weeks of study drug will be replaced. If at any time 3 or more 
subjects have observed progression prior to the start of definitive treatment the study will be 
halted. In addition, if at any time 3 or more subjects have surgery delayed by one week or more 
because of adverse events at least possibly related to study drug, the study will be halted. These 
safety stopping rules will be assessed at least bi-annually in a formal safety report. 
 
9.5 
Secondary analyses 
Safety analysis: The safety analysis will use the safety population. Adverse events will be 
summarized by grade, attribution, and system organ class. 
Secondary efficacy analyses: Subjects will have clinical tumor measurement prior to initiating 
IPI-549 and after 2 weeks administration of IPI-549. Only clinical measurement of disease will 
be performed. If clinical assessment is not feasible, this will be indicated on the CRF with the 
reason. 
 
 
 
 
10.0 
STUDY MANAGEMENT 
 
10.1 
Conflict of Interest 


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Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed according to UCSD conflict of interest policy. 
 
10.2 
Institutional Review Board (IRB) Approval and Consent 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review Board (IRB) that 
complies with regulations in 21 CFR 56 must review and approve this protocol and the informed 
consent form prior to initiation of the study. The IRB should approve the consent form and protocol 
prior to any study-related activities. It is expected that the IRB will have the proper representation 
and function in accordance with federally mandated regulations. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient will 
be asked to give consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
The Principal Investigator or her associate must explain verbally and in writing the nature, 
duration, and purpose of the study and possible consequences of treatment. Patients must also be 
informed that they may withdraw from the study at any time and for any reason without 
jeopardizing their future treatment. In accordance with federal regulations (21 CFR 312), all 
patients must sign the IRB-approved consent form in the presence of a witness. Prior to the start 
of the study, a copy of the IRB-approved consent form must be submitted to the Sponsor. 
 
10.3 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
 
10.4 
Data and Safety Monitoring/Auditing 
In addition to adverse event monitoring and clinical oversight by the Study Chair and co- 
investigators, quality assurance of the study will be performed by the UCSD Moores Cancer Center 
Clinical Trials Office internal monitor. Monitoring intervals will be dependent upon the number 
of patients enrolled and the complexity of the study. 
 
This study will also use the UCSD Moores Cancer Center Data Safety and Monitoring Board 


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(DSMB) to provide oversight in the event that this treatment approach leads to unforeseen 
toxicities. Data from this study will be reported and will include: 
 
1) 
the protocol title, IRB protocol number, and the activation date of the study. 
2) 
the number of patients enrolled to date 
3) 
the dates of patient enrollment 
4) 
a summary of all adverse events regardless of grade and attribution 
5) 
a response evaluation for evaluable patients when available 
6) 
a summary of any recent literature that may affect the ethics of the study. 
 
10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, investigators are required to conduct their 
research according to the plans reviewed and approved by the IRB. 
 
10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Study Chair. It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent form 
might be required. 
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation. 
 
10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two years 
after the last approval of marketing application in an International Conference on Harmonization 
(ICH) region. In all other cases, study documents should be kept on file until three years after the 
completion and final study report of this investigational study. 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The 
Principal Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 


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guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring 
visits will be conducted and the Principal Investigator will provide access to his/her original 
records to permit verification of proper entry of data. At the completion of the study, all case report 
forms will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
11.0 
Ethical considerations 
 
11.1 
Ethical Conduct of Study 
This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical 
Practices (GCP) guidelines. The Principal Investigator or qualified designees are responsible for 
reporting to the authorities and IRB amendments, safety updates and protocol violations that 
impact subject safety. 
 
11.2 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
subjects who have provided written informed consent must also sign a subject authorization to 
release medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 


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12.0 
REFERENCES 
 
1. 
Kaneda, M.M., et al., Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma 
Progression. Cancer Discovery, 2016. 6(8): p. 870. 
2. 
Kaneda, M.M., et al., PI3Kγ is a molecular switch that controls immune suppression. 
Nature, 2016. 539(7629): p. 437-442. 
3. 
De Palma, M. and Claire E. Lewis, Macrophage Regulation of Tumor Responses to 
Anticancer Therapies. Cancer Cell, 2013. 23(3): p. 277-286. 
4. 
Gabrilovich, D.I., S. Ostrand-Rosenberg, and V. Bronte, Coordinated regulation of 
myeloid cells by tumours. Nat Rev Immunol, 2012. 12(4): p. 253-268. 
5. 
Schmid, M.C., et al., Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate 
myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and 
progression. Cancer cell, 2011. 19(6): p. 715-727. 
6. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer, 2009. 45(2): p. 228-247. 


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13.0 
APPENDICES 
 
Appendix A. Performance Status 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully 
active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on 
normal activity or to do active 
work 
2 
In bed < 50% of the time. 
Ambulatory and capable of 
all self-care, but unable to 
carry out any work activities. 
Up and about more than 50% 
of waking hours. 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care 
3 
In bed > 50% of the time. 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent 
4 
100% bedridden. 
Completely disabled. 
Cannot carry on any self- 
care. Totally confined to bed 
or chair 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 


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5 
Dead. 
0 
Dead. 


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Appendix B: Patient Pill Diary [be sure to bring this diary and pill bottles with you to your 
next study visit. 
 
Study #: 
Patient ID: 
Patient name: 
Patient Signature: 
Date: 
Day Number 
Day of the week 
Date 
IPI-549 (mg) 
Comments 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 


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Appendix C: Medications or foods known to inhibit or induce CYP3A 
 
The following list provides medications known to induce or inhibit CYP3A activity. Note that 
this 
is not a comprehensive list of all medications which may modulate CYP3A activity. Additional 
information can be found at: 
 
• http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ 
ucm292362.pdf 
 
Note: Subjects receiving IPI-549 are prohibited from concomitant use of medications or foods 
that are known to be strong inhibitors or inducers of CYP3A. 
 
Classification of In Vivo Inhibitors of CYP3A 
 
Strong Inhibitors(1) 
Moderate inhibitors(2) 
Weak inhibitors(3) 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice,(5) indinavir, 
itraconazole, ketoconazole, 
lopinavir/ritonavir, 
mibefradil,(6) 
nefazodone, nelfinavir, 
posaconazole, ritonavir, 
saquinavir, 
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice, 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, (4) 
goldenseal,(4) 
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 area under the 
curve (AUC) of a substrate for that CYP by equal or more than 5-fold or > 80% decrease in 
clearance (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. Herbal product. 
5. 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 (eg, high- dose, double-strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (eg, low-dose, single- 
strength). 
6. Withdrawn from the United States market because of safety reasons. 


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Protocol IPI-549-01 
Infinity Pharmaceuticals, Inc. 
IPI-549 
 
Classification of In Vivo Inducers of CYP3A 
 
Strong Inducers ≥ 80% 
decrease in AUC 
Moderate Inducers 50-80% 
decrease in AUC 
Weak Inducers 20-50% 
decrease in AUC 
Avasimibe,(1) 
carbamazepine, phenytoin, 
rifampin, St. John’s Wort(2) 
Bosentan, efavirenz, 
etravirine, modafinil, nafcillin 
Amprenavir, aprepitant, 
armodfinanil, Echinacea,(3) 
pioglitazone, prednisone, 
rufinamide 
1. Not a marked drug. 
2. The effect of St. John’s Wort varies widely and is preparation-dependent. 
3. Herbal product. 


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Appendix D: Medications associated with prolongation of the QTC and/or with torsades de 
pointes 
 
Medications that prolong the QT interval and/or have a risk of inducing Torsades de Pointes are 
listed below. Below, these drugs are divided into two groups based on their known or perceived 
risk of causing Torsades de Pointes. These lists show examples only, and are not comprehensive. 
 
Medications from Group 1 are prohibited throughout the trial. Medications from Group 2 may be 
allowed in selected circumstances after consultation with the medical monitor. 
 
Additional 
information 
can 
be 
found 
at: 
http://www.azcert.org/medical-pros/drug- 
lists/bycategor.cfm 
 
Group 1 Drugs: Generally Accepted to Have a Risk of Causing Torsades de Pointes 
 
Amiodarone 
Arsenic trioxide 
Bepridil 
Chlorpromazine 
Chloroquine 
Cisapride 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Halofantrine 
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine Methadone 
Moxifloxacin 
Pentamidine Pimozide 
Probucol 
Procainamide 
Quinidine 
Sotalol 
Sparfloxacin 
Thioridazine 
Vandetanib 


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Group 2 Drugs: Drugs That in Some Reports May be Associated with QTc Prolongationand/or 
Torsades de Pointes, but Lack Substantial Evidence of Causing Torsades dePointes 
 
Alfuzosin 
Amantadine 
Atazanavir 
Azithromycin 
Chloral hydrate 
Clozapine 
Dolasetron 
Dronedarone 
Escitalopram 
Felbamate 
Flecainide 
Foscarnet 
Fosphenytoin 
Gatifloxacin 
Gemifloxacin 
Granisetron 
Indapamide 
Isradipine 
Lapatinib 
Levofloxacin 
Lithium 
Moexipril/HCTZ 
Nicardipine 
Nilotinib 
Octreotide 
Ofloxacin 
Ondansetron 
Oxycodone 
Paliperidone 
Quetiapine 
Ranolazine 
Risperidone 
Roxithromycin 
Sertindole 
Sunitinib 
Tacrolimus 
Tamoxifen 
Telithromycin 
Tizanidine 
Vardenafil 
Venlafaxine 
Voriconazole 
Ziprasidone 


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Appendix E: CYP2C8 OR CY2C9 SUBSTRATES 
 
The following lists provide known sensitive CYP2C8 or CYP2C9 substrates. 
 
Medications that are metabolized via CYP2C8 or CYP2C9 should be used with caution. Those 
with a narrow therapeutic range are prohibited during the trial. 
 
Additional information can be found at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm2 
92362.pdf. 
 
CYP2C8 Substrates 
paclitaxel 
cerivastatin 
torsemide 
rosiglitazone 
amodiaquine 
repaglinide 
pioglitazone 
CYP2C9 Substrates 
celecoxib 
Warfarin* 
Phenytoin* 
glipizide 
*Substrates with a narrow therapeutic range are prohibited throughout the trial 


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CONFIDENTIAL 
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Protocol Date: January 15, 2021 
Page 44 of 45 
 
 
 
 
 
 
 
 
 
 
Appendix F: P-GP Substrates and medications that are inhibitors of P-GP 
 
The following list provides medications that are substrates or inhibitors of P-gp. Substrates of P- 
gp should be used with caution during treatment with IPI-549. Inhibitors of P-gp are prohibited 
during treatment with IPI-549. Note that this is not a comprehensive list of all medications which 
may be substrates of P-gp or may modulate P-gp activity. 
 
P-gp Substrates 
Amitriptyline 
Loperamide 
Amiodarone 
Losartan 
Atorvastatin 
Lovastatin 
Cefoperazone 
Methadone 
Chlorpromazine 
Methotrexate 
Cimetidine 
Methylprednisolone 
Ciprofloxacin 
Morphine 
Clarithromycin 
Nadolol 
Colchicine 
Norfloxacin 
Cyclosporine 
Nortriptyline 
Dexamethasone 
Ondansetron 
Digoxin 
Omeprazole 
Diltiazem 
Pantoprazole 
Erythromycin 
Phenytoin 
Estradiol 
Pravastatin 
Fentanyl 
Propranolol 


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Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
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Protocol Date: January 15, 2021 
Page 45 of 45 
 
 
 
Fexofenadine 
Quinidine 
Hydrocortisone 
Ranitidine 
Intraconazole 
Sirolimus 
Lansoprazole 
Tacrolimus 
Levofloxacin 
Timolol 
Lidocaine 
Trimethroprim 
Verapamil 


UCSD Moores Cancer Center 
Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
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Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 46 of 45 
 
 
 
 
 
 
 
 
 
P-gp Inhibitors 
Amiodarone 
Lovastatin 
Amitriptyline 
Mefloquine 
Carvedilol 
Nicardipine 
Chlorpromazine 
Nifedipine 
Clarithromycin 
Ofloxacine 
Cortisol 
Omeprazole 
Cyclosporine 
Pantoprazole 
Desipramine 
Progesterone 
Diltiazem 
Propafenone 
Dipyridamole 
Propranolol 
Doxepin 
Quinidine 
Erythromycin 
Rifampicin (Rifampin) 
Felodipine 
Saquinavir 
Fluphenazine 
Simvastatin 
Grapfruite juice 
Sirolimus 
Haloperidol 
Tacrolimus 
Itraconazole 
Testosterone 
Ketoconazole 
Verapamil 
Source: Atkinson AJ et al. Principles of Clinical Pharmacology, 2nd ed. Academic Press, 
Massachusetts, 2007. 


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Phase 2 Window Study of IPI-549 in Locally Advanced HNSCC 
CONFIDENTIAL 
UCSD IIT Cohen 172058 
Protocol Version: 5.0 
Protocol Date: January 15, 2021 
Page 47 of 45 
 
 
Appendix G: Pharmacodynamic changes observed in peripheral blood of MARIO3 TNBC 
patients after 15 day treatment with eganelisib in combination with atezolizumab + nab- 
paclitaxel 
 
Source: Infinity