Clinical trial NCT04171219
Conditions: Advanced Malignant Solid Neoplasm Recurrent Malignant Solid Neoplasm
Sponsor: M.D. Anderson Cancer Center
Start date: 2020-03-19; Completion date: 2025-03-11
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of talabostat and pembrolizumab and to see how well they work for the treatment of solid cancers that have spread to other places in the body (advanced). Talabostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving talabostat and pembrolizumab may help control the disease.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate response rate per Response Evaluation Criteria in Solid Tumors (RECIST) and immune (i)RECIST in patients treated in cohort A and in patients treated in cohort B.

II. To evaluate dose-limiting toxicities (DLT) in the first 6 patients enrolled to the study.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS). II. To evaluate duration of response (DOR). III. To evaluate overall survival (OS). IV. To evaluate overall safety and tolerability.

EXPLORATORY OBJECTIVES:

I. To evaluate the quantitative and qualitative effects of talabostat (BXCL701) in combination with pembrolizumab on relevant immune effector cytokines in blood.

II. To evaluate the quantitative and qualitative effects of BXCL701 in combination with pembrolizumab on various immunological effector cells, including neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer associated fibroblast (CAF), T-cells and macrophage density in pre-dose tumor biopsies and when feasible in post-dose tumor tissues.

III. To explore the predictive value of baseline programmed death ligand 1 (PD-L1) tumor expression and tumor mutation burden (TMB) with clinical outcomes.

IV. To evaluate changes in serially collected blood circulating tumor deoxyribonucleic acid (DNA) (ctDNA) to assess for tumor response and clonal evolution.

V. To evaluate pre- and post-treatment PD-L1 positron emission tomography (PET)/computed tomography (CT) as a predictive tool for therapeutic efficacy.

OUTLINE:

Patients receive talabostat orally (PO) twice daily (BID) on days 1-14 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: Patients receive talabostat PO BID on days 1-14 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Talabostat Mesylate
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
ICF_001.pdf: 
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Informed Consent
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN 
RESEARCH WITH OPTIONAL PROCEDURES 
A Phase 2 Basket Study of BXCL701, a Small Molecule Inhibitor of 
Dipeptidyl Peptidases (DPP), Administered in Combination with 
Pembrolizumab in Patients with Advanced Solid Cancers 
2019-0748
Subtitle: BXCL701- Protocol V.10 – ICD Version 15 July 2021 
Study Chair:
Aung Naing
_________________________
_____________________
Participant’s Name
Medical Record Number 
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary.
This research has been reviewed and approved by an Institutional Review Board 
(IRB – a committee that reviews research studies).
If you are reading and signing this form on behalf of a potential participant, please 
note:  Any time the words "you," "your," "I," or "me" appear, it is meant to apply to 
the potential participant.
STUDY SUMMARY
The goal of this clinical research study is to learn if BXCL701 in combination with 
pembrolizumab (Keytruda®) can help to control advanced solid cancers. 
This is an investigational study. BXCL701 is not FDA approved or commercially 
available. It is currently being used for research purposes only. Pembrolizumab is FDA 
approved and commercially available for the treatment of many different types of 
cancers, but may not be approved for your type of cancer. It is considered 
investigational to give BXCL701 and pembrolizumab in combination to treat advanced 
solid tumors. 
The study doctor can describe how the study drugs are designed to work.


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Taking the study drugs may help to control the disease. Future patients may benefit 
from what is learned in this study. There may be no benefits for you in this study.
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment. You may not want to take part in 
this study due to the need for hospitalization.
You can read a list of potential side effects below in the Possible Risks section of this 
consent.
BXCL701 will be provided during the study at no cost to you. You and/or your 
insurance provider will be responsible for the costs of pembrolizumab.
You may receive BXCL701 and pembrolizumab for as long as the study doctor thinks 
it is in your best interest.
You may choose not to take part in this study. Instead of taking part in this study, you 
may choose to receive other investigational therapy, if available. You may choose not 
to have treatment for cancer at all. In all cases, you will receive appropriate medical 
care, including treatment for pain and other symptoms of cancer.
1. STUDY DETAILS
Screening Tests
Signing this consent form does not mean that you will be able to take part in this study. 
You will have screening tests to help the doctor decide if you are eligible. The following 
tests and procedures will be performed within 4 weeks before you can begin receiving 
the study drug:

You will have a physical exam.

Urine and blood (about 5 tablespoons) will be collected for routine tests. This 
blood draw will include a pregnancy test, if you can become pregnant. To take 
part in this study, you must not be pregnant.

You will have either a CT scan or an MRI to check the status of the disease. 

If you have had a tumor biopsy or cancer surgery in the past and leftover tumor 
tissue is available, it may be collected for biomarker testing. 

You will also have a tumor biopsy collected for biomarker testing. 
You should tell your study doctor about any drugs you take while you are in this study, 
including prescription and over-the-counter medications, vitamins, herbal remedies, 
and supplements.
The study doctor will discuss the screening test results with you. If the screening tests 
show that you are not eligible to take part in the study, you will not be enrolled. Other 
options will be discussed with you.
Up to 42 participants will be enrolled in this study. All will take part at MD Anderson.


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Study Drug Administration
Each cycle is 21 days.
You will take BXCL701 tablets by mouth on Days 1-14 of each cycle. Do not take 
BXCL701 during Days 15-21. Your study doctor or study coordinator will give you 
specific instructions on how many tablets to take. You should take your study 
medication in the morning and in the evening at the same times of day every day. 
BXCL701 should not be taken on an empty stomach.
You will be given a diary card to write down when you take each dose of BXCL701. 
You will need to bring the diary card and bottle(s) containing study drug (even if the 
bottle is empty) with you to each clinic visit. 
You will receive pembrolizumab by vein over about 30 minutes on Day 1 of each cycle.
All participants will receive the same dose of study drugs, but if you have side effects 
your dose may be lowered. This will be discussed with you.
You will no longer be able to take the study drug if the disease gets worse, if 
intolerable side effects occur, or if you are unable to follow study directions.
You may be asked to drink at least 8 cups (2 liters) of liquid a day while on treatment. 
This is to help you stay hydrated and maintain your blood pressure. You may be asked 
to drink liquids that contain potassium, chloride, and magnesium, such as sports 
drinks. You may need to drink more if you are doing strenuous activities that increase 
your heart rate or make you sweat. Your doctor may decide to give you fluids by vein 
in the clinic on Day 1 of Cycle 1. This may be repeated more often, if the doctor thinks 
it is needed.
Follow the study doctor’s instructions about maintaining/increasing fluid intake
Study Visits
At every clinic visit, you will have your vital signs measured, including temperature, 
heart rate, breathing rate, and blood pressure. At some visits, your height and/or 
weight will be measured as well.
During Cycle 1, you will also need to measure your blood pressure at home and right 
down the results 2 times a day (in the morning and afternoon/evening, before each 
dose). You will be given a blood pressure log (diary) to fill out with these at-home 
measurements. The study team will show you how to take your blood pressure at 
home. If you do not have a blood pressure cuff at home, one will be provided to you to 
use while on study. You should not take your dose of BXCL701 until after you have 
measured your blood pressure. If your systolic (upper number) pressure is below 100 
mmHg, do not take your dose of BXCL701. Instead, call your study doctor right away. 
The study team will call you regularly during the first 2 weeks of Cycle 1 to ask about 
your blood pressure measurements.  You will be asked to bring the blood pressure log 
with you to every clinic visit.


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On Day 1 of Cycle 1:

You will have a physical exam.

Blood (about 7 tablespoons total) will be drawn for immune system, biomarker, 
and/or routine testing before the BXCL701 dose and 2 times during the 24 
hours after the dose. Part of this blood sample will be banked (stored) at MD 
Anderson for immune system testing in the future.

Urine will be collected for routine tests.

If you can become pregnant, blood (about 1 teaspoon) or urine will be collected 
for a pregnancy test. 
On Day 2 of Cycle 1:

You will have physical exam

Blood (about 3 tablespoons total) will be drawn for immune system, biomarker, 
and/or routine testing before the BXCL701 dose. Part of these blood samples 
will be stored at MD Anderson for immune system testing in the future. 
On Day 4-5 (-1 day) of Cycle 1:

You will have a physical exam.

Blood (about 1½ tablespoons total) will be drawn for routine tests.
On Days 8 and 15 of Cycle 1:

You will have a physical exam. 

Blood (about 5-7 tablespoons, depending on the day) will be drawn for immune 
system, biomarker, and/or routine testing before the BXCL701 dose.
On Day 14 of Cycle 1:

Blood (about 1½ tablespoons total) will be drawn for immune system testing 
before the BXCL701 dose. Parts of this blood sample will be stored at MD 
Anderson for immune system testing in the future. 
On Day 1 of Cycle 2:

You will have a physical exam.

Urine will be collected for routine testing. 

Blood (about 7 tablespoons total) will be drawn for immune system, biomarker, 
and/or routine testing before the BXCL701 dose and 2 times during the 24 
hours after the dose. Part of this blood sample will be stored at MD Anderson 
for immune system testing in the future. 

If you can become pregnant, blood (about 1 teaspoon) or urine will be collected 
for a pregnancy test. 
On Days 2 of Cycle 2:

Blood (about 1½ tablespoons total) will be drawn for immune system testing 
before the BXCL701 dose. Parts of this blood sample will be stored at MD 
Anderson for immune system testing in the future. 


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On Days 8 and 15 of Cycle 2:

You will have a physical exam. 

Blood (about 5-7 tablespoons, depending on the day) will be drawn for immune 
system, biomarker, and/or routine testing. 

Between Day 8 and Day 14 of Cycle 2, you will have a tumor biopsy collected 
for biomarker testing. 
On Day 1 of Cycles 3 and beyond:

You will have a physical exam.

Blood (about 7 tablespoons total) will be drawn for biomarker and/or routine 
testing before the BXCL701 dose.

Urine will be collected for routine testing. 

If you can become pregnant, blood (about 1 teaspoon) or urine will be collected 
for a pregnancy test.
On Day 1 of Cycle 4 and then every 9 weeks after that, you will have either a CT 
scan or an MRI to check the status of the disease. If the study doctor thinks it is 
needed, you may have a CT scan or MRI every 6 weeks instead of every 9 weeks. 
On Day 8 and 15 of Cycles 3 and Cycle 4, blood (about 5 tablespoons total) will be 
drawn for routine testing before the BXCL701 dose.
End of Study Visit
Within 21 days after you stop receiving the BXCL701 and pembrolizumab:

You will have a physical exam. 

Blood (about 4 tablespoons) will be drawn for routine tests. 

You will have either a CT scan or MRI and bone scan to check the status of the 
disease.
Follow Up Visit
About 30 days after your last dose of BXCL701:

You will be asked about any side effects or any medication changes.

If the disease got worse, you will be asked about your health every 90 days 
by phone. The phone call be about 10 minutes long. 
2. POSSIBLE RISKS
While on this study, you are at risk for side effects. You should discuss these with the 
study doctor. The more commonly occurring side effects are listed in this form, as 
are rare but serious side effects. You may also want to ask about uncommon side 
effects that have been observed in small numbers of patients but are not listed in this 
form. Many side effects go away shortly after the study drugs are stopped, but in 
some cases side effects may be serious, long-lasting or permanent, and may even 
result in hospitalization and/or death.


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Side effects will vary from person to person, and some may occur after you have 
stopped receiving the study drugs. Tell the study staff about any side effects you 
may have, even if you do not think they are related to the study drugs/procedures.
BXCL701 and pembrolizumab may cause low blood cell counts (red, white, and/or 
platelets): 

A low red blood cell count (anemia) may cause difficulty breathing and/or 
fatigue. You may need a blood transfusion. 

A low white blood cell count increases your risk of infection (such as pneumonia 
and/or severe blood infection). Infections may occur anywhere and become life-
threatening. Symptoms of infection may include fever, pain, redness, and 
difficulty breathing.

A low platelet count increases your risk of bleeding (such as nosebleeds, 
bruising, stroke, and/or digestive system bleeding). You may need a platelet 
transfusion.
BXCL701 Side Effects
This is an early study of BXCL701, so the side effects are not well known. Based 
on studies in animals and early testing in humans, BXCL701 may cause the following 
side effects: 

fluid around the heart

swelling

low blood pressure 
(possible dizziness 
and/or fainting)

shock due to low blood 
pressure

blood clots in a vein 
(possible pain, swelling, 
and/or redness) 

dizziness

dehydration/ and/or 
bleeding

abnormal blood 
acid/base balance 
(possible organ 
damage)

fever

migraine

fatigue

difficulty sleeping

skin rash

shivering

sweating 

flushing

fainting

paleness

hair loss (partial or 
total)

low blood sugar

nausea/vomiting

diarrhea

constipation

sore throat

hoarseness

taste changes

weight gain/weight loss

nosebleed

blood in the stool

low platelet cell count

breakdown of muscle 
tissue (possible kidney 
failure)

abnormal kidney test 
(possible kidney 
damage)

muscle pain

eye inflammation

blurred vision

low oxygen level in the 
blood (possible 
lightheadedness and/or 
blue colored skin)

difficulty breathing

lung inflammation 
(possible difficulty 
breathing)

cough

infection, possibly 
severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure)
Pembrolizumab Side Effects


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Common (occurring in more than 20% of patients) 

fatigue

fever

skin rash and/or itching

abnormal salts, minerals, 
and/or acids in the blood 
(possible weakness, 
swelling, fatigue, low 
blood pressure, organ 
failure, heart problems, 
changes in mental status, 
and/or seizure)

high blood sugar 
(possible diabetes)

high blood levels of fat 
(possible heart 
disease and/or stroke)

loss of appetite

nausea

constipation

diarrhea

abdominal pain

low blood cell count 
(white/red/platelets)

abnormal liver test 
(possible liver 
damage)

pain

abnormal kidney test 
(possible kidney 
damage)

cough

difficulty breathing
Occasional (occurring in 3-20% of patients) 

swelling (face/arm/leg)

inflammation of the tissue 
around the heart (possible 
chest pain)

irregular heartbeat

headache

confusion

patches of skin color

underactive thyroid gland 
(possible weight gain, 
heart failure, and/or 
constipation)


overactive thyroid 
gland (possible weight 
loss, diarrhea, mood 
swings, difficulty 
sleeping, heart rate 
changes, and/or 
sweating)

low blood sugar

weight loss

vomiting

fluid in the abdomen

blood in the urine

abnormal liver tests 
(possible yellowing of 
the skin and/or eyes)

weakness

nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function)

difficulty breathing 
(possibly due to lung 
inflammation)

flu-like symptoms

infusion reaction 
(possible dizziness, 
low blood pressure, 
nausea, pain, and/or 
difficulty breathing)
Frequency Unknown

heart failure

heart attack

build-up of fluid around 
the heart (possible 
heart failure)

abnormal connections 
or passageways 
between organs or 
vessels

bleeding in the rectum 
and/or uterus

blockage in the lung 
(possible pain and/or 
shortness of breath)

nosebleed

coughing up blood
Rare but serious (occurring in fewer than 3% of patients) 

low blood pressure 
(possible 
dizziness/fainting)

heart inflammation

hormonal deficiency 
that affects the body's 
ability to control blood 
pressure and react to 
stress

kidney failure

build-up of fluid around 
the lungs 

immune response that 
causes the body to 


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
build-up of fluid in the 
tissue around the heart

blood vessel 
inflammation (possible 
bleeding and/or 
bruising)

seizure

immune system 
damage to the nervous 
system (causing 
muscle weakness, 
numbness, and/or 
paralysis)

spinal cord 
inflammation (possible 
pain, weakness, loss of 
feeling or movement, 
and/or paralysis)

brain inflammation 
(possible paralysis 
and/or coma) 

shedding, scaling 
and/or inflammation of 
the skin (possible fatal 
loss of bodily fluids)

large skin blisters

very severe blistering 
skin disease (loss of 
large portion of skin 
and/or ulcers of the 
skin and digestive tract)

pituitary gland 
inflammation (possible 
headaches)

decreased production 
of adrenal hormones 
(possible weakness 
and/or low blood 
pressure) 

inflammation of the 
thyroid gland (possible 
tenderness in the neck)

diabetes requiring 
insulin

severe high blood 
sugar due to 
uncontrolled diabetes

inflammation of the 
pancreas (possible 
abdominal pain)

anemia due to 
destruction of red blood 
cells 

liver damage (hepatitis)

inflammation inside the 
eye (possible vision 
problems) 

kidney inflammation 
(possible kidney 
damage/failure)
attack itself (possible 
organ damage)

multi-organ disease 
causing lesions, most 
often in the lungs 
(sarcoidosis) 

immune response 
(causing muscle 
weakness)

immune system 
reaction (possible 
fever, jaundice, 
liver/spleen 
enlargement, irritability, 
and/or seizures)

severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure)

Vogt Koyanagi Harada 
syndrome -- pigmented 
tissue (possible eye 
pain/swelling and 
changes in vision, 
hearing loss, and/or 
white patches on the 
skin)
If you have a solid tumor type and you have an organ transplant, pembrolizumab may 
increase your risk for the transplant to be rejected by your body.
Pembrolizumab works by boosting the immune system. This may cause unknown side 
effects resulting from your immune system attacking your organs. This may cause 
inflammation and inflammation-related side effects in any organ or tissue. These side 
effects can affect more than one of your normal organs and tissues at the same time.
Using the study drugs together may cause side effects that are not seen when each 
is given alone. The study drug combination may also increase the frequency and/or 
severity of the side effects listed above.
Other Risks


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Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop 
an infection with redness and irritation of the vein at the site where blood is drawn. 
Frequent blood collection may cause anemia, which may create a need for blood 
transfusions. 
CT scans send x-rays through the body at many different angles. You will be exposed 
to a small dose of radiation. All radiation adds up over a lifetime and may increase the 
risk of new cancer forming. Some people may feel “closed in” while lying in the 
scanner. However, the scanner is open at both ends, and an intercom allows you to 
talk with doctors and staff. If you feel ill or anxious during scanning, doctors and/or 
radiology technicians will give comfort, or the scanning will be stopped. Solution may 
also be given by vein to make the x-ray pictures more accurate. This may cause an 
uncomfortable feeling of warmth, nausea, and/or severe allergic reactions. The 
solution injection may also cause pain, bleeding, bruising, hives, and/or itching.
During the MRI, you may feel mild vibrations throughout your body. The machine will 
produce a loud knocking noise. This is normal. You will be given earplugs to protect 
your ears. Some people, especially those who tend to feel uncomfortable in small or 
closed spaces, may feel “closed in” and become anxious while in the scanner. The 
scanner has an intercom, which will allow you to speak to the staff during the 
procedure. If you feel ill or anxious during scanning, tell the MRI staff and the scanning 
will be stopped if you wish. The MRI will require a catheter to be inserted into one of 
your veins in order to inject the MRI contrast agent. This may cause skin irritation, 
bleeding, and/or infection. You may have an allergic reaction to the contrast agent.
The magnetic field used in MRI scanning may harm you if you have certain types of 
metal in your body (as might be found in pacemakers, neurostimulators, or certain 
clips). It may cause problems with devices, such as pacemakers. If you have metal in 
your body or devices such as a pacemaker, you should discuss this with the study 
doctor.
A standard bone scan exposes you only to the radiation that comes from injecting the 
standard radioactive imaging solution for bone imaging.
Although every effort will be made to keep study data safe, there is a chance that your 
personal health information could be lost or stolen, which may result in a loss of 
confidentiality. All study data will be stored in password-protected computers and/or 
locked file cabinets and will continue to be stored securely after the study.
This study may involve unpredictable risks to the participants.
Pregnancy Related Risks
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you 
should not become pregnant, breastfeed a baby, or father a child while on this study. 
You must use 2 forms of birth control during the study and for at least 4 months 
(females) or 60 days (males) after your last dose of study drugs, if you are sexually 
active.


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Birth Control Specifications: If you can become pregnant, you must use 2 forms of 
birth control while you are on study. Acceptable forms of birth control include 
intrauterine device (IUD), hormonal birth control methods, and surgical sterilization in a 
combination with a barrier method (such as condoms).
If you are male, you must use barrier birth control (such as a condom with spermicidal 
foam/gel/film/cream/suppository). If your partner can become pregnant, they must also 
use one of the above birth control methods. 
Males: Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy.
Females: If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away.
Getting pregnant will result in your removal from this study. 
OPTIONAL PROCEDURES FOR THE STUDY 
Optional Procedure #1: If you agree, you will have a tumor biopsy performed at the 
End of Treatment visit. Some participants who agree to these optional procedures may 
have biopsies at only some of those time points. The study team will let you know how 
many biopsies you may have if you agree.
Researchers will use these samples for tests to help learn about how your body is 
responding to the study drug. The type of biopsy performed and the timing of the 
collection will depend on how easily and safely an available sample can be collected, 
and if there is any inflammation. 
You will not be compensated for any patents or discoveries that are produced by this 
research.
There are no benefits to you for taking part in the optional procedure. Future patients 
may benefit from what is learned. You may stop taking part in the optional procedures 
at any time. There will be no cost to you for taking part in the optional procedure.
Optional Procedure Risks:
Having biopsies performed may cause pain, bruising, bleeding, redness, swelling, 
and/or infection at the site of the biopsies. An allergic reaction to the anesthetic may 
occur. A scar may form at the biopsy site.
CONSENT/PERMISSION/AUTHORIZATION FOR OPTIONAL PROCEDURES
Circle your choice of “yes” or “no” for each of the following optional 
procedures:


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Optional Procedure #1: Do you agree to have a biopsy at the End of Treatment Visit?
YES
NO
3. COSTS AND COMPENSATION 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson, BioXcel Therapeutics Inc. for 
this injury. You may also contact the Chair of MD Anderson’s IRB at 713-792-6477 
with questions about study-related injuries. By signing this consent form, you are not 
giving up any of your legal rights.
Certain tests, procedures, and/or drugs that you may receive as part of this study 
may be without cost to you because they are for research purposes only. However, 
your insurance provider and/or you may be financially responsible for the cost of 
care and treatment of any complications resulting from the research tests, 
procedures, and/or drugs. Standard medical care that you receive under this 
research study will be billed to your insurance provider and/or you in the ordinary 
manner. Before taking part in this study, you may ask about which parts of the 
research-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility. You may ask that 
a financial counselor be made available to you to talk about the costs of this study.
Samples that are collected from you in this study may be used for the development 
of treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit.
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research. 
You will receive no compensation for taking part in this study. 
Additional Information 
4.
You may ask the study chair (Dr. Aung Naing, at 713-563-1930) any questions you 
have about this study. You may also contact the Chair of MD Anderson's 
Institutional Review Board (IRB - a committee that reviews research studies) at 
713-792-6477 with any questions that have to do with this study or your rights as a 
study participant.
5.
You may choose not to take part in this study without any penalty or loss of 
benefits to which you are otherwise entitled. You may also withdraw from 
participation in this study at any time without any penalty or loss of benefits. If you 
decide you want to stop taking part in the study, it is recommended for your safety 
that you first talk to your doctor. If you withdraw from this study, you can still 


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choose to be treated at MD Anderson. If you withdraw from the study, the study 
staff may ask if they can continue collecting the results of routine care from your 
medical record. 
6.
This study or your participation in it may be changed or stopped without your 
consent at any time by the study chair, BioXcel Therapeutics, Inc., the U.S. Food 
and Drug Administration (FDA), the Office for Human Research Protections 
(OHRP), or the IRB of MD Anderson.
7.
You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study, and you may be asked to sign 
another informed consent and authorization form stating your continued willingness 
to participate in this study.
8.
MD Anderson may benefit from your participation and/or what is learned in this 
study.
9. This study is supported by: BioXcel Therapeutics, Inc. 
10. In a medical emergency, you may be cared for by someone who has a financial 
interest with the study sponsor(s)/supporter. If you have any questions about this, you 
may call the IRB at 713-792-6477.
Future Research
Data
Your personal information is being collected as part of this study. These data may be 
used by researchers at MD Anderson and BioXcel Therapeutics, Inc. and/or shared 
with other researchers and/or institutions for use in future research.
Samples 
Samples (such as blood and/or tissue) are being collected from you as part of this 
study. Researchers at MD Anderson may use any leftover samples that are stored at 
MD Anderson in future research. 
Before being used or shared for future research, every effort will be made to remove 
your identifying information from any data and/or research samples. If all identifying 
information is removed, you will not be asked for additional permission before future 
research is performed.
In some cases, all of your identifying information may not be removed before your 
data or research samples are used for future research. If future research is performed 
at MD Anderson, the researchers must get approval from the Institutional Review 
Board (IRB) of MD Anderson before your data and/or research samples can be used. 
At that time, the IRB will decide whether or not further permission from you is 
required. The IRB is a committee of doctors, researchers, and community members 
that is responsible for protecting study participants and making sure all research is 
safe and ethical. 


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If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples. 
If you do not want your samples or data to be used for future research, tell the study 
doctor. You may withdraw your samples at any time by telling your study team.
Genetic Research
Research samples collected from you as part of this study may be used for genetic 
research, which may include whole genome sequencing. Whole genome sequencing 
is a type of testing in which researchers study your entire genetic makeup (DNA). 
This may help researchers learn how changes in the ordering of genes may affect a 
disease or response to treatment. If genetic research is done with your samples, 
those who have access to those samples may be able to identify you. The results of 
this research may also be able to be linked to you.
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes 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:

Health insurance companies and group health plans may not request your 
genetic information that we get from this research.

Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.

Employers with 15 or more employees may not use your genetic information 
that we get from this research when deciding to hire, promote, or fire you or 
when setting the terms of your employment.
Be aware that this federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
Nor does this federal law prohibit discrimination based on an already known genetic 
disease or disorder.
Authorization for Use and Disclosure of Protected Health Information (PHI):
A. 
During the course of this study, MD Anderson will be collecting and using your 
PHI, including identifying information, information from your medical record, and 
study results. For legal, ethical, research, and safety-related reasons, your doctor 
and the research team may share your PHI with:

Federal agencies that require reporting of clinical study data (such as the 
FDA, National Cancer Institute [NCI], and OHRP)

The IRB and officials of MD Anderson

BioXcel Therapeutics, Inc. who is a supporter of this study, and/or any future 
sponsors and/or licenses of the study technology. 

Study monitors and auditors who verify the accuracy of the information

Individuals who put all the study information together in report form


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Study sponsors and/or supporters receive limited amounts of PHI. They may also 
view additional PHI in study records during the monitoring process. MD Anderson’s 
contracts require sponsors/supporters to protect this information and limit how they 
may use it. 
You will not be identified in any presentation or publication of the results of this 
study. The results of this research may be published in scientific journals or 
presented at medical meetings, but your identity will not be disclosed.
The sponsor may transfer your study data to countries outside of the United States 
for the purposes described in this form. Please be aware that the laws in such 
countries may not provide the same level of data protection as in the US and may 
not stop your study data from being shared with others. All data that are transferred 
will be coded. The study doctor, the regulatory authorities, and the sponsor may 
keep the research records forever.
Tissue, blood, CT scans, MRI (magnetic resonance imaging) scans, and other test 
results may be submitted to a third party for review.
B.
Signing this consent and authorization form is optional but you cannot take part in 
this study or receive study-related treatment if you do not agree and sign.
C.
MD Anderson will keep your PHI confidential when possible (according to state 
and federal law). However, in some situations, the FDA could be required to reveal 
the names of participants.
Once disclosed outside of MD Anderson, federal privacy laws may no longer 
protect your PHI.
D. 
The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed 
from the study and the data collected about you up to that point can be used and 
included in data analysis. However, no further information about you will be 
collected.
 E.
 A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time.


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CONSENT/AUTHORIZATION
(Adult Participants Only)
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think about 
it, ask questions, and talk about it with others as needed. I give the study chair permission 
to enroll me on this study.  By signing this consent form, I am not giving up any of my 
legal rights. I will be given a signed copy of this consent document.
________________________________________
_______
SIGNATURE OF PARTICIPANT
DATE
_________________________________        
PRINTED NAME OF PARTICIPANT                
WITNESS TO CONSENT
I was present during the explanation of the research to be performed under Protocol 
2019-0748.
_____________________________________________________
_________
SIGNATURE OF WITNESS TO THE VERBAL CONSENT 
DATE
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR)
A witness signature is only required for vulnerable adult participants. If witnessing the assent of a pediatric 
participant, leave this line blank and sign on the witness to assent page instead.
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT
PERSON OBTAINING CONSENT
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits and 
risks and that the participant understood this explanation.
______________________________________________
_________
PERSON OBTAINING CONSENT 
DATE
______________________________________________
PRINTED NAME OF PERSON OBTAINING CONSENT
PARENT/GUARDIAN PERMISSION
I have read and understand the description of this research. I have had a chance to 
discuss the study and ask questions.  My questions have been answered. I give 
permission for my child or ward to take part in this study.
______________________________________________ 
_________
SIGNATURE OF PARENT/GUARDIAN
DATE
PRINTED NAME OF PARENT/GUARDIAN


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______________________________________________ 
_________
SIGNATURE OF PARENT/GUARDIAN
DATE
Signature of Other Parent (Optional, unless required by the IRB.)
PRINTED NAME OF PARENT/GUARDIAN
____The IRB has determined that the signature of both parents is required.
If not obtaining both parental signatures, please indicate reason below:
____Other parent is deceased, unknown, incompetent, or not reasonably available.
____Parent/Guardian signing above has sole legal responsibility for the care and custody 
of the child.
__X__ The IRB has determined that the signature of both parents is NOT required.
WITNESS TO PARENTAL/GUARDIAN PERMISSION
I was present during the explanation of the research to be performed under Protocol 
2019-0748. The child participant was also present.  In my opinion, the parent(s)/guardian 
provided permission for the child to participate in the research.
___________________________________________________
_________
SIGNATURE OF WITNESS TO THE PARENTAL/GUARDIAN 
DATE
PERMISSION (OTHER THAN PARENT/GUARDIAN OR 
MEMBER OF THE STUDY TEAM)
PRINTED NAME OF WITNESS TO THE PARENTAL/GUARDIAN
PERMISSION
ASSENT OF MINOR
(Entire section must be completed if the participant’s intellectual age is at least 7 
and less than 18 years. Participants with an intellectual age of 7 - 12 are not 
required to sign.)
If written assent is not obtained on an age-appropriate participant, check reason why not:
____ 1.) The participant’s intellectual age is less than seven.


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____ 2.) The participant dissented, but the participant's parent(s)/guardian felt that the 
intervention(s) or procedure(s) involved in the research hold out the possibility of a direct 
benefit that is important to the health and/or well being of the participant and is available 
only in the context of this research study.
____ 3.) Other:   
I have been told what I will be asked to do in this study.
I have been told that I do not have to be in this study.  If I decide not to be in this study, 
no one will be mad at me.  I may quit at any time, but if I do, I may need to take a 
different treatment.
I have had a chance to talk about the study and ask the study doctor questions. All of my 
questions have been answered.  I agree to be in this study and do what I am asked to do 
so long as I want to stay in this study.  I agree that the study doctor can put me on this 
study. By signing this paper, I am not giving up any of my legal rights. I have been given 
a copy of this document.
___________________________________________________
_________
SIGNATURE OF MINOR (Age 13-17)
DATE
_____________________________________________________
PRINTED NAME OF MINOR
WITNESS TO ASSENT
I was present during the explanation of the research to be performed under Protocol 
2019-0748.  The child participant was also present.  In my opinion, the child assented to 
participate in the research. (Note: If obtaining assent, a witness signature is required.)
__________________________________________________
_________
SIGNATURE OF WITNESS TO THE ASSENT (OTHER THAN 
DATE
PARENT/GUARDIAN OR MEMBER OF THE STUDY TEAM)
PRINTED NAME OF WITNESS TO THE ASSENT
TRANSLATOR
I have translated the above informed consent as written (without additions or 
subtractions) into
and assisted the people
(Name of Language)
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant.


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_____________________       _______________________________   ___________
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR
DATE
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line below.)
____________________________________________________
___________
SIGNATURE OF WITNESS TO THE VERBAL TRANSLATION 
DATE 
(OTHER THAN TRANSLATOR, PARENT/GUARDIAN, 
OR STUDY CHAIR)
_____________________________________________________
PRINTED NAME OF WITNESS TO THE VERBAL TRANSLATION

Prot_SAP_002.pdf: 
Protocol 2019-0748 
08 Apr 2022 
Page 1 of 44 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0748 
Protocol Title 
A Phase 2 Basket Study of BXCL701, a Small Molecule Inhibitor 
of Dipeptidyl Peptidases (DPP), Administered in Combination 
with Pembrolizumab in Patients with Advanced Solid Cancers 
Protocol Version 
11 
Version Date 
04/08/2022 
Protocol PI 
Aung Naing, MD 
Department 
Investigational Cancer Therapeutics 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
146664 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 2 of 44 
 
TITLE: A Phase 2 Basket Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl 
Peptidases (DPP), Administered in Combination with Pembrolizumab in Patients with 
Advanced Solid Cancers  
 
PROTOCOL NUMBER: 
 
 
STUDY DRUG: 
BXCL701 (Talabostat) 
 
IND: 
146664 
 
INSTITUTION: The University of Texas MD Anderson Cancer Center 
 
 
Support provided by:  
BioXcel Therapeutics, Inc. 
555 Long Wharf Drive 
New Haven 
CT 06511 | USA 
 
DATE OF FINAL PROTOCOL:   08 Apr 2022 
 
 
 
 
 
 
 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 3 of 44 
 
 
 
Table of Contents 
1 
INTRODUCTION ............................................................................................ 7 
 
BXCL701 Mechanism of Action .................................................................. 7 
 
Preclinical Pharmacology ............................................................................. 7 
 
Clinical Experience....................................................................................... 9 
1.3.1 
Healthy Volunteers ....................................................................................... 9 
1.3.2 
Phase 1 Studies in Patients ........................................................................... 9 
1.3.3 
Phase 2 studies ............................................................................................ 10 
1.3.4 
Phase 3 Studies ........................................................................................... 10 
1.3.5 
Clinical Pharmacokinetics .......................................................................... 10 
2 
STUDY OBJECTIVE(S)................................................................................. 11 
 
Primary Objectives ..................................................................................... 11 
 
Secondary Objectives ................................................................................. 11 
 
Exploratory Objectives ............................................................................... 11 
3 
STUDY DESIGN ............................................................................................ 11 
 
Justification for Dose .................................................................................. 15 
4 
STUDY POPULATION .................................................................................. 16 
4.1. 
Eligibility Criteria ....................................................................................... 16 
4.1.1 
Inclusion Criteria ........................................................................................ 16 
4.1.2 
Exclusion Criteria ....................................................................................... 18 
5 
STUDY METHODOLOGY ............................................................................ 19 
5.1. 
Concomitant Medications ........................................................................... 19 
5.1.1 
Permitted Medications/Therapies ............................................................... 19 
5.1.2 
Prohibited Medications/Therapies .............................................................. 19 
5.2. 
Efficacy Assessments ................................................................................. 19 
5.3. 
Safety Assessments .................................................................................... 19 
5.3.1. 
Non-Serious Adverse Events ...................................................................... 19 
5.3.2. 
Reporting Serious Adverse Events ............................................................. 21 
5.4. 
Adverse Event Follow-Up .......................................................................... 22 
5.5. 
Pharmacokinetic Assessments .................................................................... 23 
5.6. 
Pharmacodynamic Assessments ................................................................. 23 
5.7. 
Removal of Patients from the Study ........................................................... 23 
5.8. 
Study Completion ....................................................................................... 23 
6 
STUDY MEDICATION ................................................................................. 23 
 
BXCL701 Dosage and Administration ....................................................... 24 
 
Dose Adjustments of BXCL701 Secondary to Toxicity ............................ 24 
 
Monitoring of Patient Compliance with BXCL701 Study Medication ...... 25 
 
BXCL701 Description and Storage ............................................................ 26 
 
Pembrolizumab Administration, Dose Modifications and Discontinuation
 .................................................................................................................... 26 
7 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................. 26 
 
Safety Analyses .......................................................................................... 28 
 
Clinical Laboratory Analyses ..................................................................... 28 
8 
INVESTIGATOR REQUIREMENTS ............................................................ 28 
 
Protocol Adherence .................................................................................... 28 
 
Study Monitoring Requirements ................................................................ 29 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 4 of 44 
 
 
Drug Accountability ................................................................................... 29 
 
Retention of Records .................................................................................. 29 
 
Study Discontinuation ................................................................................ 29 
8.5.1 
Discontinuation/Withdrawal Criteria.......................................................... 29 
9 
ETHICAL CONSIDERATIONS .................................................................... 30 
10 
LIST OF ABBREVIATIONS ......................................................................... 31 
11 
REFERENCES ................................................................................................ 34 
12 
APPENDIX A: Study Schedule of Assessments ............................................. 36 
13 
APPENDIX B: RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) VERSION 1.1 .......................................................... 40 
 
Measurability of tumor at baseline ............................................................. 40 
 
Response criteria ........................................................................................ 40 
 
Evaluation of best overall response ............................................................ 41 
 
Duration of response ................................................................................... 41 
14 
APPENDIX C: RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS for IMMUNe-based therapies (iRECIST) ................................. 42 
 
Comparison of response evaluation criteria in solid tumors (RECIST) 1.1 
and modified response evaluation criteria in solid tumors for immune-
based therapies (iRECIST) ......................................................................... 42 
 
Assessment of timepoint response using modified response evaluation 
criteria in solid tumors for immune-based therapies (iRECIST) ................ 43 
 
 
 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 5 of 44 
 
SUMMARY 
 
Summary of rationale: 
 
Development of immune checkpoint inhibitors revolutionized treatment of many hard to 
treat cancers such as melanoma, non-small cell lung cancer, urothelial cancers, kidney 
cancers, MSI-high colorectal cancers and others. Nevertheless, reported response rates 
typically range from 13% to 30% for PD1/PD-L1 antibodies and up to 50% for 
combination of CTLA-4 antibody ipilimumab and PD1 antibody nivolumab.[1-8] In 
addition, a number of cancers such as MSS colorectal cancer, most of soft tissue sarcoma, 
prostate cancer, pancreatic cancer and others do not respond to immunotherapy.[9-13] 
Resistance to immune therapy can be driven by exclusion of CD8+ T-cells and other 
immune cells or absence of immune cells (immune desert).[14] Activation of innate 
immunity can activate type I interferon response and increase sensitivity to immune 
checkpoint inhibitors.[15] We hypothesize that BXCL701 (Talabostat) is a competitive 
inhibitor of DPPs that can induce innate immune reaction and tumor inflammation, leading 
to synergistic anticancer activity when combined with the immune checkpoint PD1 
targeted antibody pembrolizumab. 
 
Summary of the Study Design: 
 
This is an open-label, single-institution, Phase 2 study to determine the response rate of 
BXCL701 administered orally and daily, combined with pembrolizumab, in patients with 
advanced solid cancers. The study will also assess other efficacy parameters, such as 
progression free survival (PFS), overall survival (OS) and (DOR), as well as the safety the 
combined treatment. Bayesian optimal phase 2 (BOP2) design will be adopted to monitor 
efficacy. The study will consist of 2 stages: 
1. Lead-in Stage (first 6 patients enrolled) - in which the safety and tolerability of the 
combination of BXCL701 administered orally daily on Days 1 to 14 of a 21-day 
cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 
21 days will be assessed and confirmed in patients with advanced solid cancers. 
The dose of BXCL701 will be 0.6 mg in two doses (0.3 mg twice a day).  
2. Efficacy Stage (BOP2 Stage) - in which patients with advanced solid cancers will 
be treated with BXCL701 combined with pembrolizumab. Patients enrolled to the 
Lead-in Stage will be also evaluated in the efficacy stage. Starting from Protocol 
version 7, new patients enrolled  will be administered BXCL701at the starting dose 
of 0.2 mg orally twice a day for the first 7 days. If well tolerated and in the absence 
of signs and symptoms of clinically significant hypotension the dose will be 
escalated to 0.3 mg orally twice a day. 
 
Summary of the Study Objectives 
 
Primary objectives 
• To evaluate response rate per RECIST and iRECIST in patients treated in cohort A 
and in patients treated in cohort B.[19, 20] Tumor measurements will be in QIAC.   


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 6 of 44 
 
• To evaluate dose-limiting toxicities (DLT) in the first 6 patients enrolled to the 
study. 
 
 
Secondary objectives 
• To evaluate progression-free survival (PFS), overall survival (OS), duration of 
response, and overall safety and tolerability. 
Exploratory objectives 
• To evaluate the quantitative and qualitative effects of BXCL701 in combination 
with pembrolizumab on relevant immune effector cells and cytokines in tumor 
tissues and blood, respectively.  
• To explore the predictive value of baseline PD-L1 tumor expression and tumor 
mutation burden (TMB) with clinical outcomes 
• To evaluate changes in serially collected blood circulating tumor DNA (ctDNA) to 
assess for tumor response and clonal evolution 
• To evaluate pre- and post-treatment PD-L1 PET/CT as a predictive tool for 
therapeutic efficacy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 7 of 44 
 
1 INTRODUCTION 
Development of immune checkpoint inhibitors revolutionized treatment of many hard to 
treat cancers such as melanoma, non-small cell lung cancer, urothelial cancers, kidney 
cancers, MSI-high colorectal cancers and others. Nevertheless, reported response rates 
typically range from 13% to 30% for PD1/PD-L1 antibodies and up to 50% for 
combination of CTLA-4 antibody ipilimumab and PD1 antibody nivolumab.[1-8] In 
addition, a number of cancers such as MSS colorectal cancer, most of soft tissue sarcoma, 
prostate cancer, pancreatic cancer and others do not respond to immunotherapy.[9-13] 
Resistance to immune therapy can be driven by exclusion of CD8+ T-cells and other 
immune cells or absence of immune cells (immune desert).[14] Activation of innate 
immunity can activate type I interferon response and increase sensitivity to immune 
checkpoint inhibitors.[15] We hypothesize that BXCL701 is a competitive inhibitor of 
DPPs that can induce innate immune reaction and tumor inflammation, leading to 
synergistic anticancer activity when combined with the immune checkpoint PD1 targeted 
antibody pembrolizumab.        
 
BXCL701 Mechanism of Action 
BXCL701 is a competitive inhibitor of DPPs, including DPP4 (CD26), DPP8, and DPP9, 
members of the postprolyl-cleaving protease family. By inhibiting DPP8 and DPP9, 
BXCL701 treatment results in robust immunostimulation via several mechanisms. One 
such mechanism is by inhibiting DPP8 and DPP9 in macrophages in the tumor 
microenvironment and lymph nodes, which, in turn, release interleukin (IL)-1β, a potent 
activator of immune effector cells that release numerous other cytokines and chemokines 
that contribute to anti-tumor activity. 
BXCL701 has also been shown to inhibit FAP, which has previously been described as a 
type II membrane protein with DPP and gelatinase activity. Studies of FAP have reported 
that FAP expression is induced in fibroblasts associated with the stroma of malignant 
epithelial tumors. These reports suggest that FAP does not appear to be expressed 
constitutively in most healthy tissues of the adult animal; however, experiments have 
demonstrated the expression of FAP in bone marrow and lymphoid tissue from both 
healthy and tumor-bearing mice. FAP, as well as DPP8 and 9, are expressed and activated 
in a wide range of malignancies, especially CRPC, that emerge following treatment of 
CRPC with second generation anti-androgen (enzalutamide) or cytochrome P450 (CYP)17 
(abiraterone) inhibitors. Resistance to androgen ablation therapy also results in the 
expression of programmed death-ligand 1 (PD-L1), and there is robust correlation between 
the expression of PD-L1 and the targets of BXCL701, particularly FAP, DPP8 and DPP9. 
In animal models with fully intact immune systems, BXCL701 and programmed cell 
death 1 (PD-1) inhibitors resulted in synergistic anti-cancer activity. To date, BXCL701 
has been administered to more than 700 individuals, including 585 cancer patients. 
 
Preclinical Pharmacology 
In a purified enzyme system, BXCL701 inhibits DPP4/CD26 and FAP activity with half 
maximal inhibitory concentration (IC50) values of 1.0 and 32.0 nM, respectively, while 
inhibiting DPP8 and DPP9 with IC50 values of 2.7 and 3.2 nM, respectively. DPP4/CD26 
is a serine protease expressed on a variety of tissues, including T-lymphocytes, endothelial 


Protocol 2019-0748 
08 Apr 2022 
 
 
Page 8 of 44 
 
and epithelial cells, and has been shown to play an important role in tumor progression. It 
has been found to be expressed in non-small cell lung cancer (NSCLC), chronic 
lymphocytic leukemia (CLL), lymphoma, and melanoma. In 1 series, 93% of all cases of 
lung adenocarcinomas were positive for aberrant DPP4/CD26 activity (see Investigators 
Brochure).[16] 
FAP is a type II integral membrane glycoprotein belonging to the serine protease family. 
It is a 95-kD cell surface glycoprotein expressed by tumor stromal fibroblasts. FAP is well 
expressed by reactive stromal fibroblasts in more than 90% of human epithelial carcinomas 
(breast, lung, colorectal, ovary) as determined by immunohistochemistry. In an evaluation 
of a series of malignant tumors, FAP was expressed in the stroma of all 13 lung tumor 
samples that were examined. Neural and lymphoid cells, as well as surrounding normal 
tissue, do not express FAP. FAP expression in normal tissue has only been observed in a 
subset of pancreatic endocrine cells, bone marrow stromal cells, and transiently in healing 
wounds. Epithelial carcinoma cells are also FAP-negative, making FAP an attractive target 
for the study of tumor stromal cell biology. Stromal cells residing in colorectal adenomas 
are also predominantly FAP-negative, suggesting that malignancy is required for effective 
FAP induction. Some bone and soft-tissue sarcomas are also known to express FAP, 
consistent with FAP’s mesenchymal origin. Thus, FAP is selectively expressed by tumor 
stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells or normal 
fibroblasts.[17] 
DPP8 and DPP9 are expressed widely in a number of tissues, but notably in monocytes 
and macrophages, where their inhibition with BXCL701 has been compared to the action 
of an immune checkpoint inhibitor through the activation of an immunogenic cell death 
called pyroptosis.[18] Current checkpoint inhibitor based therapies largely target T-cells, 
members of the adaptive immune system, while monocytes and macrophages belong to the 
innate immune system. Thus, it is an attractive approach to target the cells of the innate 
immune system, using BXCL701 as a single agent, or even more compelling to use 
BXCL701 in combination with checkpoint inhibitors targeting the adaptive immune 
system. 
In syngeneic mouse models utilizing the WEHI 164 fibrosarcoma cell line, BXCL701 
significantly inhibited tumor growth, both as single agent and in combination with 
chemotherapies. BXCL701 also significantly inhibited the growth of a human 
osteosarcoma, SK-ES-01, in mouse xenografts (see Investigators Brochure). A study 
conducted in a mouse model of metastases using a sarcoma cell line at the National Cancer 
Institute showed that BXCL701 substantially reduced the number of lung metastases in 
mice (see Investigators Brochure). The supporter has further demonstrated potent activity 
of BXCL701 in combination with other immune modulating agents including adaptive 
immune cell checkpoint inhibitors (e.g., anti-PD-1) in several other models. Notably, in 
these animal models, tumor response was complete and durable, resulting in the generation 
of a functional memory T-cell response. This is the case because challenge with the same 
cancer cells resulted in the failure of a subsequent tumor to form in animals that had 
generated a durable response. 
Thus, preclinical data from the literature and generated by the supporter support the use of 
BXCL701 as a multimodal DPP inhibitor targeting distinct, yet complimentary, 
mechanisms in the biology of a cancer. 


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Clinical Experience 
BXCL701 has been administered to more than 700 human subjects in Phase 1, 2, and 3 
clinical trials. Edema and fatigue were the most common adverse events (AEs) seen in 
these trials. 
1.3.1 Healthy Volunteers 
Two placebo-controlled Phase 1 studies were conducted in 120 healthy male volunteers 
(out of which 90 received BXCL701). BXCL701 was well tolerated at single daily doses 
up to 2.4 mg and when administered as a single daily dose for 7 days at doses up to 1.8 mg. 
In the single-dose tolerance study, the most frequently occurring AEs in BXCL701 treated 
subjects were: sensation of temperature change (12/54, 22.2%), tachycardia (11/54, 
20.4%), dizziness (8/54, 14.8%) versus 11.1%, 0%, and 0%, respectively, in the placebo 
group. There were no serious adverse events (SAEs). In the multiple-dose tolerance study, 
the most frequently occurring AEs in BXCL701 treated subjects were: headache (18/36, 
50.0%); temperature change sensation (13/36, 36.1%); myalgia (8/36, 22.2%); nausea 
(6/36, 16.7%); vomiting (5/36, 13.9%); peripheral swelling (5/36, 13.9%); and sore throat 
(4/36, 11.1%) versus 41.7%, 0%, 16.7%, 0%, 8.3%, 8.3%, and 0, respectively in the 
placebo group.  
In both studies, BXCL701 significantly increased plasma IL-6 and inhibited plasma DPP-4 
activity at single doses ≥1.2 mg. Plasma levels of BXCL701 in the multiple-dose study 
suggest a multi-compartmental distribution. The initial distribution phase was 
approximately 12 hours. Maximum plasma concentration (Cmax) appeared to be 
dose-proportional. Time to maximum plasma concentration ranged from 1 to 2 hours 
postdose. The plasma half-life was not calculated due to a prolonged elimination phase 
extending past Day 7. It is thought that BXCL701 binds irreversibly to plasma proteins and 
that this binding is responsible for the long half-life. 
1.3.2 Phase 1 Studies in Patients 
BXCL701 was evaluated in 2 Phase 1 studies: in combination with myelosuppressive 
chemotherapy in 34 patients with chemotherapy-induced neutropenia at doses up to 
1.2 mg/day and in combination with rituximab in 20 patients with B-cell malignancies 
(non-Hodgkin’s lymphoma [NHL] or CLL) at doses up to 0.8 mg/day. 
Overall, BXCL701 was well tolerated in both the studies. Edema was the most common 
AE in both studies (45% and 41%). Other AEs when BXCL701 was administered in 
combination with myelosuppressive chemotherapy included hypotension (including 
orthostatic) 10/34 (29%) versus 4/41 (10%); anorexia 5/34 (15%) versus 2/41 (5%); and 
hypovolemia 4/34 (12%) versus 0. In the B-cell malignancy study with BXCL701 
administered in combination with rituximab, other AEs included nausea and fatigue (each 
in 9 patients, 45%); dizziness (8 patients, 40%); constipation and vomiting (each in 
6 patients, 30%); and pyrexia, rigors, and thrombocytopenia (each in 5 patients, 25%). 
Efficacy results revealed a relatively consistent 1-day reduction in the total number of days 
of Grade 4 neutropenia at doses from 0.2 to 0.8 mg, whereas no consistent changes in the 
median or mean number of days of Grade 3 neutropenia were observed. In the B-cell 
malignancy study, 2/20 (10%) patients were considered to have a partial response (PR). 


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1.3.3 Phase 2 studies 
BXCL701 was evaluated in 6 Phase 2 studies: 54 patients in combination with rituximab 
in advanced CLL at daily doses of 0.6 mg, as a single agent in 42 patients with metastatic 
melanoma at doses up to 0.8 mg/day, 55 patients with NSCLC in combination with 
docetaxel at doses up to 0.6 mg/day, 74 patients with metastatic melanoma in combination 
with cisplatin at doses up to 0.8 mg/day, 68 patients with pancreatic adenocarcinoma in 
combination with gemcitabine at doses up to 0.6 mg/day, and in 28 patients with metastatic 
colorectal cancer at doses up to 0.8 mg/day. 
Edema, fatigue, nausea, dizziness and fever were the most common AEs seen these 
6 Phase 2 studies. Most of these AEs were either Grade 1 or 2 in nature. Most common 
Grade 3/4 AEs included dyspnea, neutropenia, fatigue and hypotension. None of the deaths 
in any of these studies were attributed to BXCL701. 
Antitumor activity was shown by an objective response of PR in 7/54 patients in advanced 
CLL patients. Two objective responses (1 complete response [CR] and 1 PR) were reported 
in 33 evaluable patients, for a response rate of 6.1% (2/33) in advanced melanoma. The 
response rate was 9.1% (5/55) in advanced NSCLC patients in combination with docetaxel. 
Response rate was 8.1% (6/74) in advanced melanoma patients in combination with 
cisplatin and 5.9% in advanced pancreatic cancer patients. 
1.3.4 Phase 3 Studies 
Two Phase 3 studies were conducted with BXCL701, both in advanced NSCLC patients, 
in combination with docetaxel and pemetrexed respectively. In both these studies, 
BXCL701 0.2-mg tablets were administered orally twice daily. 
Similar to the AE profile seen in Phase 1 and 2 studies, edema and fatigue were the most 
common AEs seen in these 2 Phase 3 studies and were Grade 1 or 2 in nature. 
Thrombocytopenia and febrile neutropenia were the most common SAEs seen. A few cases 
of cardiac tamponade were also seen in both the trials. In the study with docetaxel, there 
was a significant difference with respect to efficacy between the 2 treatment groups in favor 
of placebo. In the study with pemetrexed, there was no significant difference in the 
2 treatment arms with respect to efficacy. No deaths were attributed to BXCL701 during 
these trials. 
1.3.5 Clinical Pharmacokinetics 
BXCL701 has negligible protein binding in vitro. It is not metabolized to any appreciable 
extent and does not inhibit any of the pharmacologically relevant CYP enzymes tested in 
standard in vitro models. In humans, Cmax of BXCL701 is achieved approximately 1 to 
1.5 hours after oral dosing. Cmax and area under the plasma concentration-time curve 
(AUC) tend to increase proportionally with increasing dose. Co-administration of 
BXCL701 with a high-fat meal resulted in approximately a 30% decrease in mean plasma 
levels (Cmax). 
1.4. Pembrolizumab 
Pembrolizumab is a humanized monoclonal antibody that binds to the PD-1 receptor with 
high affinity, thereby blocking the PD-1 receptor-ligand interaction and boosting the 
immune response against tumor cells. Pembrolizumab was initially approved for the 


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treatment of refractory melanoma in 2014 (United States Food and Drug Administration 
[FDA]) and 2015 (European Medicines Agency). Subsequent approvals have included 
subsets of non-small cell lung cancer, squamous cell carcinoma of the head and neck, 
classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial 
carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell 
carcinoma, and any unresectable or metastatic solid tumor with certain genetic anomalies 
(mismatch repair deficiency or microsatellite instability-high). The safety profile of 
pembrolizumab includes adverse events (AE) related to increase immune activation and 
include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction. Full details are 
available in pembrolizumab Prescribing Information. 
2 STUDY OBJECTIVE(S) 
 
Primary Objectives 
• The primary objectives of the study are: 
• To evaluate response rate per RECIST and iRECIST in patients treated in cohort A 
and in patients treated in cohort B.[19, 20]  Tumor measurements will be in QIAC.  
• To evaluate dose-limiting toxicities (DLT) in the first 6 patients enrolled to the 
study. 
 
Secondary Objectives 
• The secondary objectives of the study for cohort A and cohort B include: 
• To evaluate progression-free survival (PFS) 
• To evaluate duration of response  
• To evaluate overall survival (OS) 
• To evaluate overall safety and tolerability 
 
Exploratory Objectives 
• To evaluate the quantitative and qualitative effects of BXCL701 in combination 
with pembrolizumab on relevant immune effector cytokines in blood  
• To evaluate the quantitative and qualitative effects of BXCL701 in combination 
with pembrolizumab on various immunological effector cells, including 
neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer 
associated fibroblast (CAF),  T-cells and macrophage density in pre-dose tumor 
biopsies and when feasible in post-dose tumor tissues.  
• To explore the predictive value of baseline PD-L1 tumor expression and tumor 
mutation burden (TMB) with clinical outcomes 
• To evaluate changes in serially collected blood circulating tumor DNA (ctDNA) to 
assess for tumor response and clonal evolution 
• To evaluate pre- and post-treatment PD-L1 PET/CT as a predictive tool for 
therapeutic efficacy. 
 
3 STUDY DESIGN 
This is an open-label, single-institution, Phase 2 study to determine the response rate of 
BXCL701 administered orally and daily, combined with pembrolizumab, in patients with 


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advanced solid cancers. The study will also assess other efficacy parameters, such as PFS, 
OS and DOR, as well as the safety the combined treatment. Bayesian optimal phase 2 
(BOP2) design will be adopted to monitor efficacy. The study will consist of 2 stages: 
1) Lead-in Stage (first 6 patients enrolled) - in which the safety and tolerability of the 
combination of BXCL701 administered orally twice a day on Days 1 to 14 of a 21-
day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 
every 21 days will be assessed and confirmed in patients with advanced solid 
cancers. The dose of BXCL701 will be 0.6 mg divided in two doses (0.3 mg twice 
a day).  
2) Efficacy Stage (BOP2-Stage) - in which patients with advanced solid cancers will 
be treated with BXCL701 combined with pembrolizumab. Patients enrolled to the 
Lead-in Stage will be also evaluated in the efficacy stage. Starting from Protocol 
version 7, new patients enrolled will be administered BXCL701 at the starting dose 
of 0.2 mg orally twice a day for the first 7 days. If well tolerated and in the absence 
of signs and symptoms of clinically significant hypotension the dose will be 
escalated to 0.3 mg orally twice a day.  
During the Lead-in Stage, patients will be observed for dose-limiting toxicity (DLT) during 
Cycle 1. Six patients will be treated initially with 0.3 mg BXCL701 twice a day (Days 1 to 
14) plus pembrolizumab 200mg: 
• If > 1 of the 6 original patients has a DLT in Cycle 1, the dose will be considered 
above the maximum tolerated dose (MTD) and additional 6 patients will be treated 
at the 0.4 mg BXCL701 daily Days 1 to 14 dose level.  
o 
If < 1 of the patients experience a DLT, the Efficacy Stage can commence 
o 
If > 1 of the patients experience a DLT, a discussion will be held between the 
investigators and supporters as to how to proceed 
 
The study schema is presented in Figure 1. 


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Figure 1  
Study Schema   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose-limiting toxicity; pembro = pembrolizumab; PR, partial response; CR, complete response  
 
All safety data from all patients, who received at least one dose of study drug will be 
included in safety analysis. Unless doses were held because of DLT, a patient must have 
9-34 (Evaluable) Patients 
< 1 DLTs 
Efficacy Stage  
Lead-in Stage  
0.3 mg BID 
BXCL701 + pembro 
(6 patients) 
> 1 PR or CR 
BOP2 Stage 1: 9 patients 
Lead-in Stage  
0.2 mg BID 
BXCL701 + pembro 
(6 patients) 
>1 DLT 
If < 1 DLT 
If > 1 DLT 
Discussion about next steps 
Efficacy Stage  
Cohort A: PD1/PDL1 or CTLA-4 naïve 
Cohort B: PD1/PDL1 or CTLA-4 pretreated 
BOP2 Stage 1: 9 patients 
BOP2 Stage 2: 8 patients 
BOP2 Stage 2: 8 patients 


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received >70% of their BXCL701 in Cycle 1 (i.e., ≥30 of 42 planned doses) with 
pembrolizumab dosed on Day 1 of Cycle 1 to be eligible for DLT assessment. 
Toxicities will be assessed by the investigator using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 5. The relationship of an 
AE to combination therapy (i.e., attribution to BXCL701 and/or pembrolizumab) is to be 
assessed by the investigator using the criteria in the protocol (Section 5.3.1). 
A DLT is defined as any of the following AEs occurring during Cycle 1, regardless of 
investigator attribution to study treatment, unless the AE can be clearly and 
incontrovertibly attributed to an extraneous cause (e.g., disease progression) by the 
Principal Investigator: 
• Any Grade 4 laboratory abnormality, regardless of duration. 
• Any Grade 3 laboratory abnormalities if associated with clinical symptoms 
regardless of duration 
• Any Grade ≥3 non-hematologic AE, with the exceptions of Grade ≥3 nausea, 
vomiting, diarrhea, constipation, and fatigue, that resolves to Grade ≤1 within 72 
hours with optimal medical management and/or supportive measures. 
• Grade ≥3 thrombocytopenia with Grade >1 bleeding or requirement for platelet 
transfusion. 
• Grade ≥3 febrile neutropenia. 
• Grade ≥3 fever. 
• Grade ≥3 skin rash. 
• Laboratory abnormalities meeting Hy’s law criteria (aspartate aminotransferase 
[AST] or alanine aminotransferase [ALT] >3 × upper limit of normal [ULN] with 
concomitant total bilirubin >2 × ULN). 
• Any toxicity resulting in ≥30% held/skipped doses of BXCL701 during Cycle 1. 
• Delay of Cycle 2 by ≥14 days due to toxicity. 
• Any other significant toxicity considered by the investigator and supporter’s 
medical representatives to be dose-limiting. 
Efficacy Stage: 
After assessment of the safety and confirmation of the BXCL701/pembrolizumab2 dose 
schedule to be used in the subsequent stage, the Efficacy Stage will begin. Eligible patients 
will receive oral BXCL701 daily on Days 1 to 14 of a 21-day cycle plus pembrolizumab 
200 mg administered IV on Day 1 every 21 days. 
Study Design Features (Both Stages): 
In both Lead-in and Efficacy Stages, patients will be screened for study eligibility within 
28 days before the first study drug dose after provision of written informed consent. 
Patients who are determined to be eligible, based on Screening assessments, will be 
enrolled in the study on Cycle (C)1, Day (D)1 (Baseline, before the first dose of 
BXCL701). 
During treatment, patients will attend study center visits and have study evaluations 
performed as detailed in the Schedule of Assessments (Appendix A). All study visits will 


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be conducted on an outpatient basis but may be conducted on an inpatient basis per the 
investigator’s judgement. 
All patients must have pre-treatment (prior to study treatment dosing) imaging (computed 
tomography [CT] scan of chest/abdomen/pelvis or magnetic resonance imaging [MRI] for 
baseline tumor measurements, as well as bone scintigraphy [BS, if deemed necessary]). 
Patients with skin, subcutaneous or lymph node metastases may also have tumor 
evaluations (including measurements, with a ruler) by means of physical examination. 
Patients with a history of central nervous system (CNS) malignant involvement or CNS 
symptoms should have either CT or MRI imaging of the brain performed to assess active 
CNS malignancy. 
Tumor measurements and disease response assessments (CT or MRI; BS) are also to be 
performed at the end of Cycle 3 (approximately 9 weeks after the first study treatment 
dose), and then approximately every 9 weeks thereafter until development of progressive 
disease (PD). Intervals can be shortened to 6 weeks if clinically necessary per treating 
physician. For patients with evidence of disease control (stable disease or better) at Week 
27, tumor measurements and disease response assessments may be performed less 
frequently (approximately every 12 weeks) thereafter. Tumor measurements and disease 
response assessments also are to be performed at the End of Treatment (EOT) visit. 
Study procedures are listed in Appendix A. 
 
Justification for Dose 
In a previously conducted multiple dose clinical study by Point Therapeutics with single 
agent BXCL701 (CA168-002), there was a dose dependent increase in plasma IL-6 in 
subjects receiving daily doses of BXCL701 from 0.3 to 1.2 mg when measured on Day 7. 
At doses ≥0.1 mg, pronounced inhibition of plasma CD26/DPP-IV activity to ≤20% of 
baseline was apparent within 1 hour of dosing, and at doses of ≥0.3 mg, CD26/DPP-IV 
activity was almost completely inhibited (>95%) within 30 minutes of the first dose on 
Day 1. These pharmacologic data suggest that daily doses of 0.4 to 0.6 mg BXCL701 
provide maximum pharmacodynamic inhibition, as measured by inhibition of plasma 
CD26/DPP-IV while also providing significant cytokine (IL-6 and G-CSF) upregulation 
over baseline.   
BioXcel has considered the clinical AE profile of each therapeutic, BXCL701 and 
pembrolizumab, to clinically combine them. Based upon results from completed clinical 
trials, single agent BXCL701 is associated with AEs that are generally mild, manageable, 
and reversible. The most frequently observed AEs that appear to be characteristic of 
BXCL701 are edema/peripheral swelling, hypotension, dizziness, and hypovolemia. These 
events, including edema, tend to be manageable and reversible and usually resolve 
following a drug hold. The most common AEs associated with pembrolizumab include 
anemia, fatigue, hyperglycemia, hyponatremia, itching, cough, and nausea. A comparison 
of the safety profiles of BXCL701 and pembrolizumab does not indicate clinically 
significant overlapping potential toxicities. Given the lack of overlapping toxicities when 
the 2 agents are combined, it is expected that there will be no more toxicity than the sum 
of the individual toxicities observed at the maximum tolerated dose of each agent. 
Nonetheless, the starting dose for BXCL701 in combination with pembrolizumab is 


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proposed to be 0.6 mg daily, i.e., the previously identified recommended Phase 2 dose. The 
dose will be divided into two doses (0.3 mg twice a day) to minimize the risk of 
hypotension. Based on a review of emerging data from the BXCL701 program, the dosing 
schedule in the Efficacy Stage will be modified to implement a step-up dosing schedule 
during Cycle 1. The intent of step-up dosing is to immediately address a potentially serious 
side effect of hypotension that appears most likely to occur during the first week of 
treatment in Cycle 1. BioXcel has evaluated BXCL701 0.4 mg total daily dose with 
pembrolizumab during Phase 1b of the prostate cancer study and it was well-tolerated, with 
no DLTs experienced. In the Phase 1b cohort, none of the three patients experienced 
adverse events consistent with cytokine activation considered related to BXCL701. 
Therefore, the Bioxcel program is incorporating a one-week lead-in dosing period of 0.2 
mg BID to potentially mitigate the effects of cytokine activation, including hypotensive 
events, which seem to predominantly occur during the first week of treatment in patients 
starting with 0.3mg BID. Escalation to 0.3 mg BID in patients demonstrating tolerance 
after one week of treatment is important since it is the dose that was previously associated 
with objective responses during prior development of BXCL701. Therefore, starting from 
Protocol version 7, new patients enrolled will be administered BXCL701 at the starting 
dose of 0.2 mg orally twice a day for the first 7 days. If well tolerated and in the absence 
of signs and symptoms of clinically significant hypotension the dose will be escalated to 
0.3 mg orally twice a day.  
 
4 STUDY POPULATION 
Approximately 6 to 12 and 24 to 48 patients who fulfill the eligibility criteria of the protocol 
will be enrolled during Lead-in and Efficacy Stages of the protocol, respectively. Patients 
enrolled to the Lead-in Stage will be evaluated and used for the efficacy stage.  
4.1. Eligibility Criteria 
All patients must satisfy the following inclusion and exclusion criteria to be eligible for 
entry into the trial.  
4.1.1 Inclusion Criteria 
1. Patient with a histology or cytology proven solid advanced cancer, which failed or is 
intolerant of standard therapies known to offer survival benefit unless standard therapies 
include PD1 or PD-L1 antibodies. 
a. Lead-in stage: patient with advanced cancers meeting the criteria above with or 
without prior treatment with PD1/PDL1 and/or CTLA-4 targeted therapies. 
Patients with prior treatment with PD1/PDL1 targeted therapies should be 
relapsed. 
b. Efficacy stage cohort A: patients with advanced cancers not previously treated with 
PD1/PDL1 and/or CTLA-4 targeted therapies. 
c. Efficacy stage cohort B: patients with advanced cancers which have relapsed or 
progressed with PD1/PDL1 and/or CTLA-4 targeted therapies   
2. Patient with a life expectancy of more than 3 months, in the opinion of the investigator. 
3. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 
0-2. 


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4. Patient is ≥12 years of age. Patients < 18 years of age have to weigh > 40 kgs. 
5. Patients must have measurable disease by RECIST 1.1 and iRECIST. Disease amenable 
to a biopsy is not mandatory. However, pre and post treatment biopsies (see Appendix A) 
are mandatory if deemed medically safe and feasible for arms, which advanced to Stage 2 
of Efficacy Stage (BOP2). 
6. Patient’s acute toxic effects of previous anticancer therapy have resolved to 
≤Grade 1 except for Grade 2 peripheral neuropathy or any grade of alopecia. 
7. Patient has adequate baseline organ function, as demonstrated by the following: 
a. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or 
calculated creatinine clearance >40 mL/min; 
b. Serum albumin ≥2.5 g/dL; 
c. Total bilirubin ≤1.5 × ULN (for patients with known Gilbert syndrome < 3 x 
ULN); 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 
3 × institutional ULN (patients with hepatic metastases must have AST/ALT 
≤5 × ULN). 
8. Patient has adequate baseline hematologic function, as demonstrated by the 
following: 
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L. 
b. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 7 days. 
c. Platelet count ≥75 × 109/L. 
9. Women of childbearing potential must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within 14 days prior to the initiation of treatment and/or 
postmenopausal women must be amenorrheic for at least 12 months to be 
considered of non childbearing potential. Women of childbearing potential must 
agree and commit to the use of 2 highly effective methods of birth control 
throughout the duration of the study until at least 4 months following the last dose 
of study drug. Acceptable methods are defined as those that result, alone or in 
combination, in a low failure rate (ie, less than 1% per year) when used consistently 
and correctly, such as surgical sterilization, an intrauterine device, or hormonal 
contraception in combination with a barrier method. It is currently unknown 
whether BXCL701 or pembrolizumab may reduce the effectiveness of systemically 
acting hormonal contraceptives; therefore, women using systemically acting 
hormonal contraceptives should add a barrier method. In certain countries (if 
permitted by law), WOCBP may agree to abide by heterosexual sexual abstinence 
during the time of participation in this study. 
10. Male patients and their female partners of childbearing potential must agree and 
commit to use a barrier contraception (eg, condom with spermicidal 
foam/gel/film/cream/suppository) throughout the duration of the study until at least 
60 days following the last dose of study drug, in addition to their female partners 
using either an intrauterine device or hormonal contraception and continuing until 
at least 4 months following the last dose of study drug. This criterion may be waived 
for male patients who have had a vasectomy > 6 months before signing the ICF. 
11. Patient has signed informed consent prior to initiation of any study-specific 
procedures or treatment. 


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12. Patient is able to adhere to the study visit schedule and other protocol requirements. 
4.1.2 Exclusion Criteria 
1. Patient cannot swallow oral medication. 
2. Patient is on gliptins. 
3. Patient has active central nervous system (CNS) metastases not controlled by prior 
surgery or radiotherapy (patient must be off steroids). Patients with signs or 
symptoms suggestive of brain metastasis are not eligible unless brain metastases 
are ruled out by brain MRI/CT. 
4. Patient has received external-beam radiation or another systemic anticancer therapy 
within 14 days or 5 half-lives, whichever is shorter, prior to study treatment. 
5. Patient has received treatment with an investigational systemic anticancer agent 
within 14 days prior to study drug administration. 
6. Patient has an additional active malignancy that may confound the assessment of 
the study endpoints. Patients with the following concomitant neoplastic diagnoses 
are eligible: non-melanoma skin cancer and carcinoma in situ (including 
transitional cell carcinoma, anal carcinoma, and melanoma in situ). Patients with 
simultaneous cancers, which are not active and do not require treatment may be 
eligible contingent on discussion with the PI and supporter. 
7. Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any 
New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled 
angina, history of myocardial infarction, unstable angina or stroke within 6 months 
prior to study entry, uncontrolled hypertension or clinically significant arrhythmias 
not controlled by medication). 
8. Patients with a history of clinically significant hypotension within past 3 months. 
9.  Patients, who are unable to maintain adequate hydration of > 2 liters per day. 
10. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy at a prednisone equivalent dose of >10 mg daily for at least 1 week or other 
form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 (C1D1). 
11. Patient has uncontrolled intercurrent illness including, but not limited to, 
uncontrolled infection, disseminated intravascular coagulation, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
12. Patient has known positive status for human immunodeficiency virus active or 
chronic Hepatitis B or Hepatitis C. Patients with history of hepatitis B or C and 
undetectable viral load are eligible. Screening is not required. 
13. Has a clinically significant upper gastrointestinal obstruction, abnormal 
physiological function or malabsorption syndrome that may affect the absorption 
of the study medication. 
14. Patient has any medical condition which, in the opinion of the investigator, places 
the patient at an unacceptably high risk for toxicity. 
15. Patient is pregnant or breast-feeding 
 
 
 
 
 


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5 STUDY METHODOLOGY 
5.1. Concomitant Medications 
5.1.1 Permitted Medications/Therapies 
The use of growth factors (e.g., granulocyte-colony stimulating factor [G-CSF]) is allowed 
as clinically indicated for the treatment of Grade ≥3 cytopenias.  
Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the 
use of oral or IV treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each AE, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care.  
5.1.2 Prohibited Medications/Therapies 
Enrolled patients may not receive investigational or approved anticancer agents including 
cytotoxic chemotherapy agents, anticancer tyrosine kinase inhibitors, or therapeutic 
monoclonal antibodies. 
Concurrent radiation is not permitted with the exception of palliative radiation of limited 
number of isolated solitary lesions.  
Preclinical studies have demonstrated a low potential for BXCL701 to inhibit the following 
major human liver CYP isoenzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
and CYP3A4. Further, relevant concentrations of BXCL701 did not induce CYP3A4 or 
CYP1A2. Therefore, there are no prohibited medications based on CYP isoenzymes.   
5.2. Efficacy Assessments 
Efficacy will be assessed during treatment using the RECIST 1.1 and iRECIST every 9 
weeks (every 3 cycles). Intervals can be shortened to 6 weeks (every 2 cycles) if clinically 
necessary per treating physician. Details on RECIST and iRECIST are described in 
Appendix B and C. [19, 20] Tumor measurements will be in QIAC. 
5.3. 
Safety Assessments 
5.3.1. Non-Serious Adverse Events 
An Adverse Event is defined as any untoward medical occurrence in a patient regardless 
of its causal relationship to study treatment. An AE can be any unfavorable and unintended 
sign (including any clinically significant abnormal laboratory test result), symptom, or 
disease temporally associated with the use of the study treatment, whether or not it is 
considered to be study drug(s) related. Included in this definition are any newly occurring 
events and any previous condition that has increased in severity or frequency since the 
administration of study therapy. Investigators should assess for AEs at each visit. All AEs, 
including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the eCRF. Each AE is to be evaluated for duration, intensity, and causal relationship 


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with the study treatment or other factors. MOCLIA will be used for eCRF in this study. 
Department (Investigational Cancer Therapeutics) database team will create the CRF based 
on protocol requirement and IND monitor will review and approve it once ready. 
The investigator is responsible for monitoring the safety of patients who have entered the 
study. All AEs occurring during the treatment period and/or occurring within 30 days of 
the last dose of BXCL701 and or pembrolizumab (investigational products, IPs) will be 
followed to the end of the study or until resolution. AEs will be graded according to the 
revised NCI CTCAE, Version 5.0, (see http://ctep.cancer.gov/reporting/ctc.html). AEs 
occurring 30 days after the last dose of IPs do not need to be reported unless the investigator 
considers the event to be related to IPs. 
Clinical laboratory data are to be collected in this study, and toxicity trends will be analyzed 
utilizing objective toxicity criteria. Abnormal laboratory findings considered clinically 
significant by the investigator and outside the expected deviation for a patient with IPs 
should be reported as AEs. Wherever possible, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the investigator and 
recorded on the eCRF. Clinical syndromes associated with laboratory abnormalities are to 
be recorded as such (e.g., diabetes mellitus instead of hyperglycemia). However, if an 
observed or reported sign or symptom is not considered a component of a specific disease 
or syndrome by the investigator, it should be recorded as a separate AE on the eCRF. 
PD should not be reported as an AE (see Section 5.7) unless the patient dies solely due to 
PD within 30 days of the last dose of IPs. 
The relationship of each AE to each study drug (BXCL701 and/or pembrolizumab) will be 
evaluated by the investigator using the following definitions: 
• Not related: The AE is clearly not related to the study drug(s). The AE can be 
explained to be likely related to other factors such as concomitant medications or 
the patient’s clinical state. 
• Possibly related: The AE may be related to the investigational agent(s). A plausible 
temporal sequence exists between the time of administration of the investigational 
product and the development of the AE, and it follows a known response pattern to 
the investigational product. The reaction may have been produced by the patient’s 
clinical state or other concomitant therapies or interventions. 
• Related: The AE is clearly related to the investigational agent(s). A plausible 
temporal sequence exists between the time of administration of the investigational 
product and the development of the AE, and it follows a known response pattern to 
the investigational product. The occurrence of this AE can be confirmed with a 
positive re-challenge test or supporting laboratory data. 
The causality criteria of related and possibly related will be considered “related” to the 
study drug(s) for regulatory reporting requirements. 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events 
for subjects enrolled. 
 


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Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
5.3.2. Reporting Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
the investigator, it results in any of the following outcomes: 
  
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
  


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• Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND supporter, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Serious 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug or earlier if the participant 
withdraws consent or starts a new anti-cancer therapy. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have returned 
to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
  
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND supporter (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
  
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the supporter’s guidelines, and Institutional Review Board policy.  
5.4. 
Adverse Event Follow-Up 
Patients are to be monitored for AEs throughout the treatment period and for a minimum 
of 30 days after their last dose of BXCL701. Longer AE follow-up is required, if necessary, 
to document recovery from AEs considered related to study medication. For patients who 
discontinue study medication due to an AE, repeated observations of that AE (or laboratory 
abnormality) must be made at intervals not exceeding 30 days until recovery is 
documented. 
No further reporting of new AEs is required after the initiation of any subsequent 
chemotherapy or more than 30 days following the last dose of study medication, unless the 
study medication is considered to have contributed to the new AE. 


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5.5. 
Pharmacokinetic Assessments 
Pharmacokinetic (PK) testing is not planned for this study since PK profiles of both 
agents are well known 
5.6. 
Pharmacodynamic Assessments 
Tumor biopsies (optional for Lead-in Stage and Stage 1 of Efficacy Stage [BOP1]; 
mandatory for Stage 2 of Efficacy Stage [BOP2]) will be collected at the time points 
described in Appendix A (Section 12) and the Laboratory Manual. Examples of biomarker 
analysis of tumor biopsies include immunohistochemistry, RNA sequencing or Nanostring. 
Whole blood samples (optional for Lead-in Stage and Stage 1 of Efficacy Stage [BOP1]; 
mandatory for Stage 2 of Efficacy Stage [BOP2]) will be collected at the time points 
described in Appendix A (Section 12) and Laboratory Manual. Examples of analysis 
include relevant immune effector cytokines, target engagement, testing of circulating 
tumor DNA (ctDNA). 
5.7. 
Removal of Patients from the Study 
Every effort within the bounds of safety and patient choice should be made to have each 
patient complete the treatment period of the study. Patients who have treatment 
discontinued due to PD may be treated with any additional therapy deemed appropriate by 
the investigator. Patients with disease progression per RECIST and/or iRECIST can 
continue on therapy for clinical benefit if deemed appropriate by the investigator. 
Patients may be discontinued from the study for any of the following reasons: 
• Investigator recommends discontinuation and documents the reason(s) 
• There is a need for any treatment not allowed by the protocol  
• Patient’s decision to withdraw consent or discontinue for any reason 
• There is an unacceptable AE thought to be related to study medication 
 
Any patient who discontinues during the treatment period should return to complete safety 
and disease assessments (see Appendix A]). 
5.8. 
Study Completion 
The study will be considered complete when all patients have been followed to disease 
progression; are lost to follow-up, death, or withdrawal due to toxicity; patient’s request; 
or investigator’s discretion; and have completed all end-of-study treatment procedures.  
6 STUDY MEDICATION 
Study medication will be administered in 21-day cycles. Either BXCL701 or 
pembrolizumab may be administered first. However, on Cycle 1 Day 1, it is recommended 
that pembrolizumab be administered first and that ≥1 hour should elapse before the 
administration of BXCL701 so that it will be easier to determine the relatedness of any 
AEs to study drug. 


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BXCL701 Dosage and Administration 
BXCL701 tablets contain valine-proline boronic acid formulated as the methanesulfonate 
salt. Current dosage strengths include 0.1 mg and 0.05 mg tablets for oral administration. 
BXCL701 will be administered orally as 0.1 mg and 0.05 mg tablets. BXCL should not be 
taken on an empty stomach. For a dose of 0.3 mg, patients will take 3 x 0.1 mg tablets and 
together. Patients will take 0.3 mg of the study drug twice a day, on days 1 to 14 of each 
cycle, for a total daily dose of 0.6 mg. BXCL701 will be continued until disease progression 
or unacceptable toxicity. Starting from Protocol version 7, newly enrolled patients will be 
administered BXCL701 at the starting dose of 0.2 mg (2 x 0.1 mg) orally twice a day. If 
well tolerated and in the absence of signs and symptoms of clinically significant 
hypotension the dose will be escalated to 0.3 mg (3 x 0.1 mg) orally twice a day. 
To minimize risk of hypotension, patients should be advised to maintain adequate 
hydration while on-treatment, such as drinking at least 2 liters of fluids per day, including 
fluids with electrolytes. Factors such as strenuous exercise, heat, humidity, fever, 
gastrointestinal disturbance may increase hydration needs. Administration of at least 1L of 
IV fluids is recommended if not medically contraindicated at Cycle 1 Day 1. It is at the 
investigator’s discretion to provide IV hydration during in-person clinic visits beyond 
Cycle 1 Day 1.  
 
On days when pharmacodynamic studies are being performed, BXCL701 should be 
administered at the study center, and should be administered at (approximately) the same 
time of day on each treatment day in the cycle. In cycles in which pharmacodynamics are 
not evaluated, BXCL701 also should be administered at (approximately) the same time of 
day on each treatment day in the cycle, preferably 0800 hours. If the patient forgets to take 
study medication the dose will be skipped.  
 
Dose Adjustments of BXCL701 Secondary to Toxicity 
BXCL701 dose modifications (other than recommended in the protocol) within a treatment 
cycle are discouraged in Cycle 1 unless required by AE and/or DLT. In Cycle ≥2, dose 
modifications within a treatment cycle will be at the discretion of the investigator. Doses 
held because of AEs should not be made up on subsequent days within or following a cycle. 
A dose that is missed for reasons other than an AE (i.e., the patient forgets to take a dose) 
may be administered on days subsequent to scheduled doses; any such adjustments should 
be discussed with the Investigator. Under no circumstances should missed doses be made-
up on a day when the patient is already taking a planned dose (i.e., no “doubling-up” to 
account for missed doses). 
Recommendations for BXCL701 dose modifications are: 
• Do not administer BXC701 if systolic blood pressure obtained before dosing is less 
than 100 mmHg 
• Grade 2 or higher AEs of edema/peripheral swelling, hypotension, dizziness, and 
hypovolemia: 


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o For Grade 3 AEs, hold/interrupt BXCL701until resolution of these AEs to ≤ 
Grade 1 or baseline. Thereafter, restart BXCL701 at a dose reduced by 0.2 mg 
(reduction of 0.1 mg twice day to 0.2 mg twice a day; 1 dose level reduction). 
o For Grade 2 AEs, hold/interrupt BXCL701 until resolution of these AEs to ≤ 
Grade 1 or baseline. Thereafter, resume at the full dose or at a dose reduced by 
0.2 mg (reduction of 0.1 mg twice day to 0.2 mg twice a day; 1 dose level 
reduction) at the discretion of the investigator. 
o For any Grade 3 or higher edema or Grade 2 edema that has not improved within 
7 days, restart BXCL701 at a dose reduced by 0.2 mg (reduction of 0.1 mg 
twice day to 0.2 mg twice a day; 1 dose level reduction) after resolution of the 
edema to ≤ Grade 1 or baseline.  
• For other Grade 2 or higher AEs deemed related to BXCL701: 
o Hold BXCL701 until resolution of these AEs to ≤ Grade 1 or baseline.  
o For Grade 2 AEs, restart BXCL701 at the full dose or at a dose reduced by 
0.2 mg (reduction of 0.1 mg twice day to 0.2 mg twice a day; 1 dose level 
reduction) at the discretion of the Investigator. 
o For Grade 3 AEs, restart BXCL701 at a dose reduced by 0.2 mg (reduction of 
0.1 mg twice day to 0.2 mg twice a day; 1 dose level reduction). 
• Once BXCL701 dose has been de-escalated, it may not be re-escalated. 
• A maximum of 2 dose reductions per participant will be permitted for 
BXCL701-related AEs, after which the study drug will be permanently 
discontinued. 
• Adverse events deemed related to BXCL701 not recovering to ≤ Grade 1 or 
baseline within 6 weeks from onset will require permanent discontinuation of 
BXCL701. 
• Discontinue BXCL701 for any life-threatening AE. 
 
If an SAE thought to be related to BXCL701 occurs during the Treatment Period, dosing 
of BXCL701 should be interrupted in that patient until the SAE resolves. If the Investigator 
wishes to continue the patient on BXCL701, the supporter should be contacted to discuss 
continuing BXCL701 at the same or reduced dose.  
If BXCL701 is discontinued due to an AE, all termination from treatment procedures and 
assessments must be performed. 
 
Monitoring of Patient Compliance with BXCL701 Study Medication  
All BXCL701 dosing containers must be returned to the clinic at each visit. Patients should 
be queried regarding their compliance with the dosing regimen and medication containers 
should be reviewed at each visit to determine if any doses of BXCL701 have been missed, 
and the number of missed doses recorded. Patients must be at least 70% compliant with 
taking BXCL701 in Cycles 1 and 2 in order to be included in the per-protocol efficacy 
analyses.  


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BXCL701 Description and Storage  
BXCL701 is supplied as 0.1 mg and 0.05 mg tablets in high-density polyethylene bottles 
with desiccant and child-resistant caps. 90 tablets will be provided in each bottle of 0.1 mg 
and 0.05 mg tablets. Supplies of BXCL701 will be appropriately labeled for clinical trial 
material. BXCL701 should be stored under refrigerated conditions between 2°C to 8°C 
(36°F to 46°F). 
 
Pembrolizumab Administration, Dose Modifications and Discontinuation 
Pembrolizumab will be prepared, stored, and administered according to the current full 
Prescribing Information. Pembrolizumab will be obtained from commercial supplies and 
will be administered 200 mg intravenously over 30 minutes through a 0.2 to 5 micron 
sterile, nonpyrogenic, low-protein binding online or add-on filter. No other medication will 
be infused through the infusion line. Infusion will be interrupted and slowed for grade 1 or 
2 infusion-related reactions and permanently discontinued for grade 3 or 4 infusion-related 
reactions. Pembrolizumab will be administered until disease progression, unacceptable 
toxicity, or withdrawal of consent. 
AEs associated with pembrolizumab exposure may be immune-mediated. Immune-related 
AEs may occur any time after pembrolizumab administration and may affect multiple body 
systems. Early recognition and treatment are important to reduce complications. Most 
immune-related AEs are reversible and can be managed with discontinuation of 
pembrolizumab and initiation of steroids.  Refer to the current regional pembrolizumab full 
Prescribing Information for recommended dose modifications for the management of 
toxicities (including immune-mediated reactions and infusion-related reactions) 
considered related to pembrolizumab. Patients who require a dose hold of pembrolizumab 
of ≥ 42 days will be discontinued from the study. 
 
Pembrolizumab should not be used in conjunction with other immunosuppressive agents 
other than corticosteroids administered for control of immune reactions considered related 
to pembrolizumab. Refer to the current regional pembrolizumab full Prescribing 
Information for further details. 
 
7 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
This is a phase 2, single center, basket study of oral BXCL701 daily on days 1-14 in 
combination with intravenous PD1/PDL1 antibody on day1 of 21-day cycle in subjects 
with advanced and refractory malignancies. Lead-in cohort will enroll 6 patients. Only the 
6 patients treated at the selected dose during safety lead-in will be assigned to Cohort A or 
B as appropriate. That is, if there is a dose de-escalation during safety lead-in, then the 6 
patients treated at the higher dose will not be assigned to the phase II cohorts. Cohorts A 
and B will enroll 9 to 17 patients. Response assessments with CT and/or MRI will be done 
every 9 weeks (3 cycles) following RECIST and iRECIST criteria.[19, 20] Intervals can 
be shortened to 6 weeks (2 cycles) if clinically necessary per treating physician. 
The study will follow the BOP2 design with the following operating characteristics.  
Power:  
0.80 


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Type I error:  0.05 
P0: 
 
0.05 
P1: 
 
0.25 
Each cohort will enroll 9 patients. If there is no complete (CR) or partial response (PR) in 
the first 9 patients the enrolment to that cohort will stop. If there > 1 PR or CR in the first 
9 patients the enrollment will continue to enroll total of 17 patients. PR or CR does not 
require confirmation. The treatment will be considered promising for further exploration if 
> 3 CRs or PRs are observed in 17 patients. The expected Sample Size will range from 9 
(if terminated after safety lead in) to 34 patients. Accounted for ~ 20% of patients not being 
evaluable for efficacy, the actual number of patients to be recruited for the trial will range 
from 11 to 42. 
Operating characteristics:  
Scenarios 
(PA, PB) 
Pr(reject H0 for 
cohort A) 
Pr(reject H0 for 
cohort B) 
Average sample size 
for cohort A 
Average sample size 
for cohort B 
(0.05,0.05) 
0.046 
0.046 
12.0 
12.0 
(0.05,0.25) 
0.046 
0.813 
12.0 
16.4 
(0.25,0.25) 
0.813 
0.813 
16.4 
16.4 
(0.05,0.15) 
0.046 
0.455 
12.0 
15.1 
(0.15,0.15) 
0.455 
0.455 
15.1 
15.1 
(0.15,0.25) 
0.455 
0.813 
15.1 
16.4 
Note: PA is the response rate for cohort A, PB is the response rate for cohort B.  
The Investigator is responsible for completing toxicity/efficacy summary reports and 
submitting them to the IND office Medical Affairs and Safety Group for review.  These 
should be submitted as follows:  
• 
Lead-In Stage: 
After the first 6 evaluable patients, complete cycle 1 of study treatment. IND Office 
approval must be obtained prior to advancing to the efficacy stage. 
• 
Efficacy Stage: 
After the first 9 evaluable patients per cohort, complete 9 weeks of study treatment, and 
after a total of 17 patients per cohort have completed 9 weeks of study treatment. A copy 
of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”.  
Toxicity monitoring is also performed in this stage. If the empirical DLT rate > 33%, we 
will suspend accrual for safety and discussions for the next step will be made.  


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Safety Analyses 
All patients in the safety population will be included in the final summaries and listings of 
safety data for the lead-in patients. Summaries of AEs and other safety parameters will be 
provided as appropriate. Emphasis in the analysis of AEs will be placed on those that are 
treatment-emergent through 30 days after last dose of BXCL701 with pembrolizumab 
Frequencies of patients experiencing at least 1 AE will be displayed by body system and 
preferred term according to Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. Detailed information collected for each AE will include: a description of the 
event, duration, whether the AE was serious, nature of the event (single episode versus 
multiple episode), intensity (i.e., NCI CTCAE version 5 grade), relationship to study drug, 
action taken, clinical outcome, and whether the AE resulted in surgery or alternate 
procedures. Intensity (severity) of the AEs will be graded according the NCI CTCAE. The 
latest version of MedDRA and NCI CTCAE will be used. 
Summary tables will be prepared to show the number of patients reporting AEs, the 
frequency of patient reports, and corresponding percentages. Percentages will be calculated 
using the number of patients in the safety population as the denominator. Within each table, 
the AEs will be categorized by MedDRA body system and preferred term. Additional 
subcategories will be based on event intensity and relationship to study drug. AE data will 
be presented across all cycles and for each cycle. The denominator for each cycle is those 
patients available at the start of the cycle who received a dose of BXCL701 for that cycle.  
To the extent possible, AE relationship to either BXCL701 or pembrolizumab will be 
identified. 
Individual patient listings will be prepared for all AE data. 
Vital signs and ECOG performance status will be summarized by visits/cycles, using 
descriptive statistics applicable to continuous or categorical measures of these additional 
safety data.  Summaries for the Lead-in and Efficacy Stages will be presented.   
 
Clinical Laboratory Analyses 
All clinical laboratory values will be listed individually and tabulated in a manner to 
identify safety concerns on a per-patient basis. Listing tables will be prepared for each 
laboratory measure and will be structured to permit review of the patient data as they 
progress on treatment. The tables will list the cycle of treatment, BXCL701 dose for 
Lead-in data, and the associated NCI CTCAE grade. Descriptive summary statistics will 
be generated per laboratory parameter.  
Summary tables will be prepared to examine the distribution of these toxicities per cycle. 
Graphic displays and shift tables may be provided to illustrate results over time on study. 
Assessment of cumulative toxicities may be made. 
8 INVESTIGATOR REQUIREMENTS 
 
Protocol Adherence 
Each investigator must adhere to the protocol as detailed in this document and agree that 
any intended departures from the protocol must be approved by the Principal Investigator 


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or her/his designee prior to seeking approval from the IRB. Each investigator will be 
responsible for enrolling only those patients who have met protocol eligibility criteria. 
 
Study Monitoring Requirements 
Site visits will be conducted by the sponsor or sponsor’s representative to inspect study 
data, patients’ medical records, and other documents in accordance with current Food and 
Drug Administration (FDA) Good Clinical Practices (GCP), the International Council for 
Harmonisation (ICH) guidelines, and the respective local and national government 
regulations and guidelines. The investigator will permit the sponsor and/or authorized 
representatives of the sponsor, the FDA, and the respective national or local health 
authorities to inspect his or her facility and records relevant to this study. 
 
Drug Accountability 
Inventory control of all BXCL701 must be maintained throughout the duration of the study. 
Any discrepancies that are noted between drug-dispensing records and drug inventory must 
be reported. Medication-dispensing records are provided to the investigative site. All study 
medication used during the study must be accounted for on the appropriate form. All 
unused study medication must be returned by the patient to the site for completion of their 
drug accountability record. All unused study medication will be disposed of in biohazard 
containers in accordance with the policies of the institution by site personnel.  
 
Retention of Records 
Records and documents pertaining to the conduct of this study, including screening logs, 
source documents, consent forms, laboratory test results, medication inventory records and 
other documents must be retained according to the local standard operating procedures and 
institutional and/or IRB policies.  
 
Study Discontinuation 
A discontinuation occurs when an enrolled patient ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol. The investigator 
must determine the primary reason for discontinuation. The investigator or study 
coordinator must notify the supporting company immediately when a subject/patient has 
been discontinued/ withdrawn due to an adverse experience (telephone or FAX). When a 
subject/patient discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation.  
 
8.5.1 Discontinuation/Withdrawal Criteria 
 
• A patient may be withdrawn by the investigator or the supporting company if he/she 
violates the study plan or for administrative and/or other safety reasons.  
• The patient withdraws consent at any time after agent administration. Every effort 
will be made to determine why any subject withdraws from the study prematurely. 


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• The patient is lost to follow-up. A genuine effort must be made to determine the 
reason(s) why a patient fails to return for the necessary visits. If the subject is 
unreachable by telephone, a registered letter, at the minimum, should be sent 
requesting him/her to contact the clinic. 
• Disease progression. RECIST 1.1 and iRECIST will be used for assessment of 
tumor response for the purposes of managing patients on protocol treatment and 
decision making for discontinuation of study therapy due to disease progression. 
Response assessments with CT and/or MRI will be done every 9 weeks (3 cycles) 
following RECIST and iRECIST criteria (intervals can be shortened to 6 weeks if 
clinically necessary per treating physician). Patients with disease progression per 
RECIST and/or iRECIST can continue on therapy for clinical benefit if deemed 
appropriate by the investigator. 
• The patient starts a new anti-cancer therapy  
• There is a need for any treatment not allowed by the protocol 
• Any life-threatening AE. 
 
Any adverse experiences that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 5.3 
Safety Assessments.  
Patients who discontinue study treatment who have not shown disease progression and 
have not withdrawn consent will continue to be followed for disease progression and 
survival. 
 
9 ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with current FDA regulations, GCP, the ICH 
guidelines, the ethical principles that have their origins in the Declaration of Helsinki, and 
local ethical and legal requirements. 
 
 


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10 LIST OF ABBREVIATIONS  
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase  
AUC 
Area under the plasma concentration-time curve 
AUC0-last 
Area under the plasma concentration time curve for the last 
measurable concentration 
BID 
Twice daily 
BS 
Bone scintigraphy 
BUN 
Blood urea nitrogen 
C 
Cycle 
Ca 
Calcium 
CAF 
Cancer associated fibroblast 
CI 
Confidence interval 
Cl 
Chloride 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
Cr 
Creatinine 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTC 
Circulating tumor cells 
ctDNA 
Circulating tumor DNA 
CTLA-4 
Cytotoxic T-lymphocyte–associated antigen 4 
CYP 
Cytochrome P450 
D 
Day 
DKA 
Diabetic ketoacidosis 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DPP 
Dipeptidyl peptidase 
DSRC 
Data Safety Review Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
FAP 
Fibroblast activation protein 


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FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-colony stimulating factor 
IC50 
Half maximal inhibitory concentration 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria In Solid Tumors 
ITT 
Intent-to-Treat  
IV 
Intravenous 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LHRH 
Luteinizing hormone-releasing hormone 
MDSC 
Myeloid derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
Na 
Sodium 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NEPC 
Neuroendocrine prostate cancer 
NHL 
Non-Hodgkin’s lymphoma 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed death-ligand 1 
PD-L2 
Programmed death-ligand 2 
PFS 
Progression-free survival 
PR 
Partial response 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
RECIST 
Response Evaluation Criteria In Solid Tumors 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 


Protocol 2019-0748 
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SJS 
Stevens-Johnson syndrome 
TEN 
Toxic epidermal necrolysis 
T1DM 
Type 1 diabetes mellitus 
tmax 
Time of maximum observed concentration 
ULN 
Upper limit of normal 
US 
United States 


Protocol 2019-0748 
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11 REFERENCES 
 
1. 
Robert, C., et al., Pembrolizumab versus Ipilimumab in Advanced Melanoma. N 
Engl J Med, 2015. 372(26): p. 2521-32. 
2. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl 
J Med, 2013. 369(2): p. 122-33. 
3. 
Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. 
N Engl J Med, 2015. 372(21): p. 2018-28. 
4. 
Reck, M., et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-
Small-Cell Lung Cancer. N Engl J Med, 2016. 375(19): p. 1823-1833. 
5. 
Ferris, R.L., et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head 
and Neck. N Engl J Med, 2016. 375(19): p. 1856-1867. 
6. 
Chow, L.Q.M., et al., Antitumor Activity of Pembrolizumab in Biomarker-
Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous 
Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J 
Clin Oncol, 2016. 34(32): p. 3838-3845. 
7. 
Bellmunt, J., et al., Pembrolizumab as Second-Line Therapy for Advanced 
Urothelial Carcinoma. N Engl J Med, 2017. 376(11): p. 1015-1026. 
8. 
Rosenberg, J.E., et al., Atezolizumab in patients with locally advanced and 
metastatic urothelial carcinoma who have progressed following treatment with 
platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet, 
2016. 387(10031): p. 1909-20. 
9. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody 
in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
10. 
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 
11. 
Royal, R.E., et al., Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for 
locally advanced or metastatic pancreatic adenocarcinoma. J Immunother, 2010. 
33(8): p. 828-33. 
12. 
Beer, T.M., et al., Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus 
Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic 
Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol, 2017. 
35(1): p. 40-47. 
13. 
Maki, R.G., et al., A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients 
with Synovial Sarcoma. Sarcoma, 2013. 2013: p. 168145. 
14. 
Mariathasan, S., et al., TGFbeta attenuates tumour response to PD-L1 blockade by 
contributing to exclusion of T cells. Nature, 2018. 554(7693): p. 544-548. 
15. 
Chiappinelli, K.B., et al., Inhibiting DNA Methylation Causes an Interferon 
Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell, 2015. 
162(5): p. 974-86. 
16. 
Enz, N., et al., CD26/DPP4 - a potential biomarker and target for cancer therapy. 
Pharmacol Ther, 2019. 198: p. 135-159. 
17. 
Mhawech-Fauceglia, P., et al., Stromal Expression of Fibroblast Activation Protein 
Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with 
Epithelial Ovarian Cancer. Cancer Microenviron, 2015. 8(1): p. 23-31. 


Protocol 2019-0748 
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18. 
Okondo, M.C., et al., DPP8 and DPP9 inhibition induces pro-caspase-1-dependent 
monocyte and macrophage pyroptosis. Nat Chem Biol, 2017. 13(1): p. 46-53. 
19. 
Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol, 2017. 18(3): p. e143-e152. 
20. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 APPENDIX A: STUDY SCHEDULE OF ASSESSMENTS 
Screen/Cycle Day (D): 
Screen 
Period 
 
Cycle 1 
Cycle 2 
>Cycle 2 
EOT 
Visita 
FU     
Visitb 
D-28 to 
D-1 
D1i 
D2 
D5t 
D8r D14 D15 r D1c D2 D8 r D14 
D15 
r 
D1c D8 D14 D15 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
cancer treatment history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor collectionl  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging and Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
Tumor assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
Xd 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BXCL701 administration 
 
 
Day 1-14 
 
Day 1-14 
 
Day 1-14 
 
 
 
Ambulatory monitoring of blood 
pressure before each dose of 
BXCL701 
 
 
Day 1-14 
 
Day 1-14 
 
Day 1-14 
 
 
 
Oral hydration monitoring 
 
 
Day 1-14 
 
Day 1-14 
 
Day 1-14 
 
 
 
Daily safety telephone calls 
 
 
Day 3-4, Day 6-14 
 
 
 
 
 
 
 
Pembrolizumab administrationj 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
Medical history/current medical 
conditions 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 


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Screen/Cycle Day (D): 
Screen 
Period 
 
Cycle 1 
Cycle 2 
>Cycle 2 
EOT 
Visita 
FU     
Visitb 
D-28 to 
D-1 
D1i 
D2 
D5t 
D8r D14 D15 r D1c D2 D8 r D14 
D15 
r 
D1c D8 D14 D15 
 
 
Vital signs (BP, HR, body 
temperature, RR, O2 saturation) 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
Height  
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
Weight 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
Clinical Laboratory Testsq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (CBC plus 
differential [5-part or auto-
analyzer]) 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Xv 
 
Xv 
X 
 
Serum chemistrye 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Xv 
 
Xv 
X 
 
Liver function testsf 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Xv 
 
Xv 
X 
 
T3, FT4, TSH 
Xu 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
 
 
Xu 
 
Cytokine-12 panel 
 
X X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Serum collectiong 
 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
Whole blood collection for 
immune parametersk 
 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
Tumor biopsiesm 
Xm 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
Xm 
 
Blood collection for ctDNAs 
 
Xh 
Xh 
 
Xh 
 
X 
Xh 
 
 
 
 
Xh 
 
 
 
X 
 
Pregnancy test 
Xn 
Xo,p 
 
 
 
 
 
Xo 
 
 
 
 
Xo 
 
 
 
 
 
 
Abbreviations: BP = blood pressure; CxDx = Cycle (number) Day (number); CBC = complete blood count; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; FU = follow-up; HR = heart rate; MRI = magnetic resonance 
imaging; RR = respiratory rate.  
a. After discontinuation of study drugs, patients will complete an EOT visit within 21 days after the last study drug dose. 


Protocol 2019-0748 
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b. A Safety Follow-up Visit is to be conducted 30 days (±7 days) after the last dose of study drug and later if drug-related AEs have 
not resolved at that time. Thereafter, patients without documented disease progression (PD) will be followed every 90 days for 
disease assessments until documentation of PD. After documentation of PD, patients will be followed every 90 days for survival 
status; such follow-up will likely be conducted by telephone. 
c. Day 1 of Cycle 2 and all subsequent cycles will be 21 days (±3 days) after the previous dose of study drug was administered. 
d. Tumor assessment must include cross-sectional imaging (MRI or CT scanning with intravenous contrast whenever possible) of the 
chest/abdomen/pelvis plus whole-body bone scan. Other body sites (e.g., neck) to be included as clinically indicated. Tumor 
assessment to be performed at Screening, C4D1 (±7 days), C7D1 (±7 days), C10D1 (±7 days), and Day 1 (±7 days) of every 3rd 
cycle thereafter and at EOT. Intervals for scans can be shortened to 6 weeks (e.g. C3D1, C5D1 etc.) if clinically necessary per 
treating physician. 
e. Serum chemistry to include: sodium (Na), potassium (K), chloride (Cl), bicarbonate, calcium (Ca), magnesium (Mg), phosphate, 
blood urea nitrogen (BUN)/creatinine (Cr), and lactate dehydrogenase (LDH). 
f. Liver function tests include aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and albumin. 
g. Serum will be collected if feasible predose (within 1 hour ± 30 minutes) and then 6 hours (± 1 hour) and 24 hours (±3 hours) postdose 
on C1D1. It will be also collected on C1D14 (± 1 days) and C2D1 (± 1 day) with the same daily schedule as C1D1 (pre-dose, 6 and 
24 hours post-dose). The C1D1 and C2D1 24-hour samples will be collected prior to the D2 doses. C1D14 24-hour samples will be 
collected on C1D15. There will not be predose or 6-hour postdose serum collection on C2D14. Instead, there will be only one time 
24-hour postdose collection on C2D15. Details about collection and processing are in the Laboratory Manual. 
h. Samples should be collected before dosing. 
i. If Cycle 1 Day 1 occurs <72 hours after Screening, physical examinations and clinical laboratory tests do not need to be repeated. 
j. Either BXCL701 or pembrolizumab may be administered first. However, on Cycle 1 Day 1, it is recommended that pembrolizumab 
will be administered first and that ≥1 hour should elapse before the administration of BXCL701 so that it will be easier to determine 
the relatedness of any AEs to study drug. It is s recommended to administer at least 1L of IV fluids if not medically contraindicated 
at Cycle 1 Day 1.  It is at the investigator’s discretion to provide IV hydration during in-person clinic visits beyond Cycle 1 Day 1.   
k. Whole blood will be collected on C1D1, C1D15 (±1 day), C2D1, C2D15 (±1 day), and at EOT for assessment of leukocytes by flow 
cytometry and other studies. Details about collection and processing are in the Laboratory Manual.  
l. Archival tissue will be collected if available. Details about collection and processing are in the Laboratory Manual. 
m. Optional tumor biopsies will be obtained during screening and between Day 8 and Day 14 of cycle 2, and at EOT.  Pre and post 
treatment biopsies will be mandatory if medically feasible in cohorts advancing to BOP2 stage. Details about collection and 
processing are in the Laboratory Manual.  


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n. Pregnancy tests will be only for women with child bearing potential. Only whole blood will be collected for the pregnancy test that 
will be performed in the screening period (D -28 to D -1) 
o. Additional pregnancy tests will be performed D1 of each cycle only for women with child bearing potential. Whole blood or urine 
can be collected for the test. 
p. Pregnancy test for the D1 of the 1st cycle can be skipped if the test for the screening period is performed close to the 1st cycle.  
q.  Laboratory assessment for immune-related toxicities will be added as per patient’s toxicity and as needed upon the investigator’s 
discretion. 
r. Days 8 and 15 of Cycles 1 and 2 can have a window of ± 2 days. These visits can be also preformed using the telehealth in case of 
unanticipated events such as COVID-19 pandemics if in agreement with applicable regulations.  
s. Details about collection and processing are in the Laboratory Manual.  
t. C1D5 visit has a window of -1 day and can happen on C1D4. 
u. T3, FT4 and TSH testing will performed at baseline, C4D1 (±7 days), C7D1 (±7 days), C10D1 (±7 days), and Day 1 (±7 days) of 
every 3rd cycle thereafter and at EOT. 
v.  Hematology (CBC plus differential [5 part or auto-analyzer]), serum chemistry and liver function tests will not be performed on 
Days 8 and 15 after Cycle 4 (at Cycle 5 and beyond) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2019-0748 
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13 APPENDIX B: RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) VERSION 1.1 
 
Adopted from the bibliographic reference [20]. 
 Measurability of tumor at baseline 
 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 
as follows. Measurable lesions must be accurately measured in at least 1 dimension 
(longest diameter in the plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥10 to <15 mm short axis), as well as non-
measurable lesions.  
 
 Response criteria 
 
Response 
criteria 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to <10 
mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
SD 
Neither sufficient shrinkage from the baseline study to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the 
smallest sum diameters while on study. 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 


Protocol 2019-0748 
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 Evaluation of best overall response 
 
Time point response: At each protocol specified time point, a response assessment should 
occur. Table below provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
 
Table: Response in patients with target disease 
 
Target lesions  
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated  
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
 
 Duration of response 
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded 
on study).  
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, 
this is the reference for calculation of PD). 
 
 
 
 
 
 
 
 
 
 


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14 APPENDIX C: RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS FOR IMMUNE-BASED THERAPIES (iRECIST) 
  
Adopted from the bibliographic reference [19]. 
 
 Comparison of response evaluation criteria in solid tumors (RECIST) 1.1 and 
modified response evaluation criteria in solid tumors for immune-based 
therapies (iRECIST) 
 
 
RECIST 1.1. 
iRECIST 
Definitions of 
measurable and non-
measurable disease; 
numbers and site of 
target disease 
Measurable lesions are ≥10 
mm in diameter (≥15 mm for 
nodal lesions); maximum of 
5 lesions (2 per organ); all 
other disease is considered 
non-target (must be ≥10 mm 
in short axis for nodal 
disease) 
No change from RECIST 
1.1; however, new lesions 
are assessed as per 
RECIST 1.1 but are 
recorded separately on the 
case report form (but not 
included in the sum of 
lesions for target lesions 
identified at baseline) 
Complete response, 
partial response, or 
stable disease 
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease 
Can have had iUPD (one 
or more instances), but not 
iCPD, before iCR, iPR, or 
iSD 
Confirmation of 
complete response or 
partial response 
Only required for non-
randomized trials 
As per RECIST 1.1 
Confirmation of stable 
disease 
 
Not required 
As per RECIST 1.1 
 
New lesions 
Result in progression; 
recorded but not measured 
Results in iUPD but iCPD 
is only 
assigned on the basis of 
this category if at next 
assessment additional new 
lesions appear or an 
increase in size of new 
lesions is seen (≥5 mm for 
sum of new lesion target or 
any increase in new lesion 
non-target); the appearance 
of new lesions when none 
have previously been 
recorded, can also confirm 
iCPD 


Protocol 2019-0748 
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Independent blinded 
review and central 
collection of scans 
Recommended in some 
circumstances - eg, in some 
trials with progression-based 
endpoints planned for 
marketing approval 
Collection of scans (but not 
independent review) 
recommended for all trials 
Confirmation of 
progression 
Not required (unless 
equivocal) 
Required 
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is 
considered when deciding 
whether treatment is 
continued after iUPD 
“i” indicated immune responses assigned using iRECIST. 
Abbreviations: iCPD=confirmed progression; iCR=complete response; iPR=partial response; iSD=stable 
disease; iUPD=unconfirmed progression; RECIST=Response Evaluation Criteria in Solid Tumors 
 
 Assessment of timepoint response using modified response evaluation criteria 
in solid tumors for immune-based therapies (iRECIST) 
 
Target 
lesions 
Non-target 
lesions 
New 
lesions 
Timepoint 
response 
with no 
previous 
iUPD in 
any 
category 
Timepoint response with previous 
iUPD in 
any categorya 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change, 
or with a 
decrease 
from last 
timepoint 
iUPD with no 
change, or 
decrease from 
last timepoint 
Yes 
Not 
applicable 
New lesions confirm iCPD if new 
lesions were previously identified 
and they have increased in size 
(≥5 mm in sum of measures for 
new lesion target or any increase 
for new 
lesion non-target) or number; if no 
change is seen in new lesions 
(size or number) from last 
timepoint, assignment remains 
iUPD 
iSD, iPR, 
iCR 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 


Protocol 2019-0748 
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increase in the size of non-target 
disease (does not need to meet 
RECIST 1.1 criteria for 
unequivocal progression) 
iUPD 
Non-iCR/non-
iUPD, or iCR 
No 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in sum of measures ≥5 
mm; otherwise, assignment 
remains iUPD 
iUPD 
iUPD 
no 
iUPD 
Remains iUPD unless iCPD is 
confirmed based on a further 
increase in previously identified 
target lesion iUPD in sum of 
measures ≥5 mm or non-target 
lesion iUPD (previous assessment 
need not have shown unequivocal 
progression) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in previously identified 
target lesion iUPD sum of 
measures ≥5 mm, previously 
identified non-target lesion iUPD 
(does not need to be unequivocal), 
or an increase in the size or 
number of new lesions previously 
identified 
Non-iUPD 
Or 
progression 
Non-iUPD or 
progression 
Yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of an 
increase in the size or number of 
new lesions previously identified 
a Previously identified in assessment immediately before this timepoint. 
Abbreviations: iCPD=confirmed progression; iCR=complete response; iPR=partial response; iSD=stable 
disease; iUPD=unconfirmed progression; non-iCR/non-iUPD=criteria for neither CR nor PD have been 
met; RECIST=Response Evaluation Criteria in Solid Tumors.