Clinical trial NCT04034238
Conditions: Neoplasms With Mesothelin Expression Epithelioid Mesothelioma Cholangiocarcinoma, Extrahepatic Adenocarcinoma, Pancreatic
Keywords: Advanced Cancer Immunotoxin Antibody Based Therapeutics Mesothelin
Sponsor: National Cancer Institute (NCI)
Start date: 2019-08-29; Completion date: 2021-11-19
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

The protein mesothelin is found on many kinds of tumors. The drug LMB-100 targets cancer cells that make this protein. Researchers want to see if LMB-100 combined with another drug can help people with these tumors.

Objective:

To find a safe dose of LMB-100 plus tofacitinib in people with pancreatic cancer, bile-duct cancer, and other solid tumors that make mesothelin.

Eligibility:

People ages 18 and older with pancreatic cancer, bile-duct cancer, or any other solid tumor with mesothelin that worsened after treatment or they could not receive standard treatment

Design:

Participants will be screened with:

* Medical history
* Tumor tissue sample. If they do not have a sample, they will have a biopsy.
* Physical exam
* Blood and heart tests
* Scans and x-rays: They may have a dye injected for the scans.

Participants will take the drugs in up to three 21-day cycles. They will take tofacitinib by mouth twice a day on days 1-10 of each cycle. They will have LMB-100 injected into the blood on days 4, 6, and 8 of every cycle. Patients that do not have a medi-port may need to have a central vein access line placed.

Participants will take other drugs on the days they receive LMB-100.

Participants will repeat screening tests during the study. They may have a biopsy at the start of the first 2 cycles.

If participants must stop the study, they will have a safety visit 3-6 weeks after their last dose of the study drug. Some participants may then have visits every 6 weeks.

After treatment, participants will be contacted about once a year. They will be asked about their cancer.

Detailed description:
Background:

* Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year.
* Incidence nearly equals mortality with just 6% of participants living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early-stage disease have a long-term survival of less than 20%.
* Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the extrahepatic form yearly. The median overall survival of patients with advanced disease receiving standard of care treatment is less than 1 year.
* Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%. Similar incidence of expression has been observed in extrahepatic cholangiocarcinoma.
* In addition to pancreatobiliary tumors, many other solid tumor types also express MSLN such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, gastric and triple negative breast cancers, as well as some tumors of squamous cell origin.
* LMB-100 and a closely related immunotoxin also targeting MSLN have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
* Results from these studies showed that almost all patients formed anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making it ineffective.
* Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis.
* Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against an immunotoxin closely related to LMB-100
* Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half- life in mice and enhanced anti-tumor efficacy
* This clinical trial will investigate whether co-administration of tofacitinib with LMB- 100 can prevent or delay the formation of ADAs and thus allow patients to receive additional effective cycles of LMB-100.

Objectives:

* The primary objective of the dose escalation phase of this study is to assess the safety and tolerability of LMB-100 given in combination with tofacitinib to patients with pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-positive solid tumors
* The primary objective of the expansion phase of this study is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs through cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients with pancreatobiliary cancers.

Eligibility:

* Age \>= 18 years
* Histologically confirmed solid tumor malignancy for which no curative therapy exists
* Participants must have received at least one prior systemic treatment regimen for their disease OR be ineligible to receive available standard treatments for their disease OR refused first-line standard systemic treatments but have been treated with other anti-cancer agents.

Design:

* This is a Phase I study which will accrue up to 45 subjects total, accounting for screen failure.
* Participants will be co-treated for 3 cycles with tofacitinib given orally for the first 10 days of each 21-day cycle, and LMB-100 given on days 4, 6 and 8.
* A 3+3 dose escalation schema will be used. Two dose levels are planned. One minus dose level could be utilized if dose de-escalation is necessary.
* Following identification of an optimal dose and schedule, an expansion phase of 15 participants will be initiated at the optimal dose for patients with pancreatic adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the expansion phase must have pancreatic adenocarcinoma.
* Participants on the Dose Escalation and Dose Expansion Arms who appear to be obtaining clinical benefit from LMB-100/tofacitinib after 3 cycles of treatment may elect to receive additional cycles of therapy at the discretion of the principal investigator (PI).

Arms: arm 1: LMB-100 at escalating doses plus tofacitinib arm 2: LMB-100 at optimal dose plus tofacitinib
Interventions: intervention 1: LMB-100 intervention 2: Tofacitinib intervention 3: Mesothelin Expression
Intervention descriptions: intervention 1: Arms 1 and 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study. intervention 2: Arms 1 and 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study. intervention 3: Test for mesothelin expression in tumor tissues for study eligibility

Protocol documents:
ICF_002.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 08/10/2020
Page 1 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:    Christine Alewine, M.D., Ph.D.
STUDY TITLE:
A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in 
Combination with tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma, 
Cholangiocarcinoma and other Mesothelin Expressing Solid Tumors
STUDY SITE:  NIH Clinical Center
Cohort:                                                Standard 
Consent Version:  
8/10/20
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Christine Alewine, M.D., Ph.D.
 
Phone: 240-760-6146
Email: Christine.alewine@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). This 
section provides the information we believe is most helpful and important to you to in making your 
decision about participating in this study. Additional information that may help you make a 
decision can be found in other sections of the document. Taking part in research at the NIH is your 
choice.
You are being asked to take part in this study because you have pancreatic cancer, bile-duct cancer, 
or solid tumor that has a protein called mesothelin on the surface. Your disease has either gotten 
worse after previous treatment or you are unable to receive standard treatment. 
The purpose of this study is to find a better way to treat your cancer.  LMB-100 is an investigational 
drug, which means that it has not been approved by the U.S. Food and Drug Administration (FDA) 
to treat your cancer. LMB-100 has been given in other clinical trials, but its effect has not lasted 
for as long as we hoped. 
The purpose of this study is to test LMB-100 in combination with another drug, tofacitinib, to find 
out if the effects of the combination last longer than the effects of LMB-100 alone. We would also 
like to find a safe dose for the combination by testing different doses of LMB-100. Tofacitinib is 
a drug used for rheumatoid arthritis. It is not used in cancer and has never been tried in combination 
with LMB-100. However, the FDA has given us permission to use tofacitinib in combination with 
LMB-100 in this study.
LMB-100 targets cancer cells that make a protein called mesothelin. Most (>85%) pancreatic 
adenocarcinomas, extrahepatic cholangiocarcinomas and epithelioid-subtype mesotheliomas 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
make mesothelin, but some do not. Testing to see if your tumor makes mesothelin is not required 
before you start study treatment if you have one of these tumor types.
There are other drugs that can be used to treat your disease, and these can be prescribed/given by 
your regular cancer doctor, even if you are not in this study. For example: If you have pancreatic 
cancer, you could receive further chemotherapy with gemcitabine alone or with nab-paclitaxel, 
nanoliposomal irinotecan, fluorouracil or other standard chemotherapeutic drugs that you have not 
received before. If you have extrahepatic cholangiocarcinoma, you could receive fluorouracil 
alone or with oxaliplatin, or gemcitabine with or without cisplatin if you have not received these 
drugs before. The delivery of drugs in this study happens much the same way that the delivery of 
chemotherapy does. Some side effects from treatment are expected to be the same but others are 
different. Our current ways to treat pancreatic and bile-duct cancers have not been very effective 
at preventing it from getting worse in other patients so we are studying this new treatment 
combination. Giving the drugs together as part of this study, we can learn more about how the 
treatment affects your cancer by also collecting and studying research blood and tissue samples. If 
you would prefer other treatments over what you would receive in this study, you should consider 
not joining this trial.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

We will first do some basic tests to make sure you qualify for the trial. We will confirm your 
cancer diagnosis. Also, you must have a cancer that has started growing again after previous 
treatment.

You will take tofacitinib by mouth for 10 days in a row every 3 weeks, and LMB-100 that you 
will receive as an injection in your blood 3 times every 3 weeks. The dose of LMB-100 that 
you receive may be different (higher or lower) from what others will receive in the study 
depending on when you enroll.  

You may have side effects from taking part in this study. Some can be mild or very serious, 
temporary, long-lasting, or permanent, and may include death. Examples of some of the side 
effects that you may have include: nausea, swelling, tiredness, fever, infections, etc. Other side 
effects are described further on in this consent form.  It is important that you read these.

Your involvement is expected to last for at least three months. You will be seen regularly 
during the study. You will have clinical, laboratory, and imaging tests to see how you are doing 
and to assess your disease. We will also collect required samples from you (such as blood and 
tissue biopsy) for both clinical and research purposes.

After the study treatment has ended we will contact you or your physician by telephone to ask 
about any other cancer therapies you may have started and about your survival status.
Just as we cannot predict what side effects you personally will have, we cannot know if you will 
benefit from taking part in this study. If you do not benefit, this study and the results from our 
research will help others in the future.
If you are a sexually active person with a partner capable of becoming pregnant, it is important 
that your partner not become pregnant during your participation in this study. There may be 
unknown risks to a fetus or risks we did not anticipate. You and your partner must agree to use 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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birth control during the study and for three months after treatment if you want to take part in this 
study. If you think your partner has become pregnant during your participation in this study, please 
contact a research team member identified at the top of this document as soon as possible. If you 
and your partner plan for your partner to become pregnant after your participation in this study, 
please discuss this with the study team.
You are free to stop participating in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure you are not having side effects from the treatment 
that you already received.
The remaining document will now describe more about the research study.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this research study is to find a safe dose of LMB-100 plus 
tofacitinib in patients with pancreatic, bile-duct and other solid tumors that make a protein called 
mesothelin. Mesothelin is found on many different tumors, including pancreatic and some bile-
duct tumors, but on very few non-cancer cells.
We are asking you to join this research study because you have pancreatic cancer, bile-duct cancer, 
or any other solid tumor with mesothelin. You have either received, refused, or are unable to 
receive standard therapy. If you have received standard therapy, your disease has gotten worse 
after that treatment. 
If you decide to enroll to this study and have not received standard therapy, then you are refusing 
or ineligible to receive cancer therapy with proven clinical benefit. 
LMB-100 is considered investigational, which means that it has not been approved by the U.S. 
Food and Drug Administration (FDA) to treat cancers that make mesothelin, including pancreatic 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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and bile-duct cancers. Tofacitinib is an FDA approved drug but it has never been used to treat 
these cancers. It has only been used to treat specific kinds of arthritis and bowel inflammation. 
LMB-100 is a manufactured protein that contains two parts. The first part of LMB-100 is similar 
to a toxin that some bacteria make. The toxin can only kill if it gets inside a cell but cannot enter 
cells by itself. The second part of LMB-100 directs the toxin to get into cancer cells. This is similar 
to germ-fighting proteins made by your immune system and can make LMB-100 stick to cells that 
have the mesothelin protein on their surface. LMB-100 is attracted to the mesothelin protein. After 
LMB-100 binds to the mesothelin on tumor cells, the cancer cells can bring LMB-100 inside where 
the toxin can attack and kill the cancer cell. 
Another reason for this study is to find out if using tofacitinib along with LMB-100 will allow for 
longer and more effective LMB-100 treatment. Sometimes after patients receive several doses of 
LMB-100 the patient’s body creates substances (called antidrug antibodies – ADAs) that will 
attack LMB-100 and limit how well it can work. We believe that tofacitinib could be effective at 
stopping this, and that giving it with LMB-100 could potentially make LMB-100 more effective 
at killing tumor cells. 
WHAT WILL HAPPEN DURING THE STUDY?
Before you begin the study
Before beginning the study, you will need to have tests and/or procedures to help your doctor 
verify whether you can participate. This is called screening. The exams, tests, and procedures you 
will have are part of the usual approach for your cancer. Most must be performed within 28 days 
before enrollment. Briefly, these tests, which may be performed under a separate protocol or a 
separate consent for, include:

Confirmation of diagnosis (You must provide a sample tumor tissue for formal evaluation 
by the NCI Laboratory of Pathology. The tissue may be from a previous surgery or biopsy.  
If none is available, we will ask you to have a biopsy to provide a fresh sample).  

Medical history and physical examination including weight and height

Test to measure blood oxygen levels 

Lab blood and urine tests

Pregnancy test in women who can have children. Pregnant women will not be allowed on 
study.

CT Scans and/or MRI and/or PET scan

Electrocardiogram (ECG)

Echocardiogram

Tests for certain infections
During the study
Once it is determined that you are eligible, and you have signed the consent for the study, you will 
take tofacitinib by mouth, twice a day, on days 1-10 of each cycle. Each cycle is 21 days long. 
You also will keep a pill diary. This helps you keep track of when you take your tofacitinib pills. 
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The study doctor will show you how to use this diary. Each time you visit the clinic, you must 
bring the pill diary, any remaining pills, and the pill bottle. Since pancreatic cancer or other solid 
tumors can cause blood clots, you will need to take blood thinner medications every day while you 
are taking tofacitinib and until two weeks after study treatment is finished. These medications are 
taken by mouth or by injection under the skin. 
You will also receive LMB-100 on day 4, 6, and 8 of each cycle through a mediport or central line 
(a secure IV line located in your arm).  This will last for about 30 minutes, though it may take 
longer if you have side effects. You will be monitored for side effects during all infusions. Your 
blood pressure, pulse rate, oxygen levels and temperature will be monitored before the infusions 
start, and periodically until the infusions are completed. You will be given standard pre-
medications that include an antihistamine, such as diphenhydramine (Benadryl), and also 
acetaminophen (Tylenol) and ranitidine (Zantac). If ranitidine is not available, it can be substituted 
with famotidine (Pepcid). If you develop infusion related side effects, you will also receive 
Dexamethasone. 
You will receive LMB-100 in combination with tofacitinib for three cycles unless your disease 
worsens or you have intolerable side effects. 
If you show benefits from the treatment, the study doctor may give you the option to continue to 
receive treatment beyond cycle 3 until you stop benefiting from the treatment or you show 
intolerable side effects. If you choose to continue the treatment, you may initiate it immediately 
after the end of cycle 3 or start it at a later time during which you would be allowed to take other 
anti-cancer drugs. If you choose to defer the treatment beyond 6 weeks or to have a different 
intervening therapy, you may be required to repeat some screening safety evaluations.
We will continue to follow you after you have finished taking the study drug to keep track of your 
disease status (progression), your survival status or whether you have taken any additional cancer 
therapy. The specific procedures you will have are described below.
Study Procedures
While you are taking study medication, we will perform some tests and examinations for safety 
and to test the effect of the study therapy.
During the course of the treatment, we will ask you questions to monitor your symptoms and 
perform physical exams including vital signs.  You will have routine blood and urine tests and a 
weight check. You will have a pregnancy test once per cycle if you are a woman who can have 
children. You will have scans done about every 9 weeks until your tumor starts to grow, and ECGs 
will be done twice during the first cycle that you receive LMB-100. Before starting each cycle, a 
chest x-ray will be done for patients who already have a mediport. If you don’t have a mediport, 
chest x-ray will be performed each cycle that requires new placement of a central line. 
Additional research testing
In addition to the tests that we will do to check whether you are having side effects or if you are 
responding to the study therapy, we will also collect samples from you for purposes of research 
only. The samples are being collected to find out how your body handles the drugs, how your 
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body, including your immune system, reacts to the drug and how certain side effects of the LMB-
100 might be caused. 
The samples included for these studies include:

Blood

Tumor tissue
An optional biopsy may be collected at cycle 1 day 1 and on day 3 of cycle 2.  The biopsies to be 
performed are only for research purposes and will not benefit you.  What we learn from those 
biopsy samples might help other people in the future. You will be given the opportunity to decide 
whether you want to have these samples collected at the time of each biopsy.  Please see Tumor 
Biopsies and Tumor Effusions below for the risks of a biopsy.
When you are finished taking the drugs

Safety Visit
If you need to stop participating in the study treatment for any reason (including that your disease 
has started to grow while you are receiving the treatment), then you will be asked to return to the 
NIH approximately 3 – 6 weeks after you have had last dose of study drug for a safety visit. 
The visit will include the following clinical tests:

Medical history and physical exam including weight

Routine blood and urine tests 

Pregnancy test if you are a woman who can have children

ECG

CT Scans and/or MRI 

Blood for tumor markers
The visit will include the following research tests

Research blood sample 

Long term follow up
This will be encouraged.  Only patients who are removed from study therapy for reasons other 
than disease progression will be asked to return to the NIH (about every 6 weeks) for the required 
scans and labs until disease progression.
About once a year, regardless of whether your disease has gotten worse, we will contact you or 
your physician by telephone to ask about any other cancer therapies you may have started and 
about your survival status.
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this study, your involvement is expected to last for at least three months.
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You will be seen several times during treatment. The outpatient visits during and after treatment 
usually take about 3 hours but should not take longer than 8 hours. During long term follow-up 
after the treatment, we will contact you by phone to ask about your health conditions.  
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have approximately 45 people participate in this study at the NIH. 
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
Because LMB-100 is still being tested for safety, we do not know all the possible side effects.  
However, below is a list of the most common and most serious side effects occurring on earlier 
and ongoing studies. Some of these side effects occurred at higher doses of LMB-100 than will 
be used in this study.
1
The most common side effects (some were serious) were:

Low levels of the blood protein albumin which may lead to swelling, muscle weakness 
or loss of appetite

Tiredness

Swelling of the arms and legs

Nausea

Fever

Decreased appetite

Shortness of breath

Pain in muscles 

Increased protein in the urine

Reactions during or following the infusion of the drug which may cause fever, chills, 
rash or low blood pressure
2
Less common, but serious side effects included:

Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of 
ankles. This can include swelling of the heart muscle which has led to temporary 
lowering of heart function and decreased blood pressure.  

Abnormal heartbeat

Pain in joints

Kidney damage which may cause swelling, or could require dialysis

Heart inflammation which may cause chest pain, swelling and shortness of breath
3
Other possible side effects
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Other possible side effects discussed below are based on side effects that occurred when testing 
a similar agent, SS1P and, also in animal studies of LMB-100. It is possible that there may be 
other unexpected side-effects that occur in addition to those listed below.
LMB-100 may cause inflammation to membranes causing chest pain, shortness of breath, low 
blood pressure, and heart failure.  In animals, some mild kidney damage was seen, that is, 
increased enzymes and protein in the urine. We will check for this with regular blood and urine 
tests.
As with other drugs like LMB-100, there is a chance that the drug could cause the body to 
produce an unwanted response called ‘Anti-drug antibodies’ (ADAs).  These might not cause 
problems however there is a chance they could lead to a severe anti-drug response in the body.  
There may also be pain and swelling at the infusion site.
It is important that you contact your doctor as soon as you experience any side effects whether 
you think the treatment has caused them or not. You must also tell your doctor if you have started 
any new medication or had a change to your existing medication. This includes medications 
available without a prescription (over the counter) and alternative medicines.  If you have any 
questions or concerns about any of the information provided above, about the possible side 
effects of treatment, or the possible consequences of treatment for those side effects, please ask 
the principal investigator or the research staff for more information. 
The most important symptoms you need to report to your doctor immediately are:
o
possible infusion or allergic reactions (symptoms that start during or within a few 
hours of the infusion, e.g. wheezing, tightness in the throat or chest, rash, and 
facial swelling)
o
chest pain
o
shortness of breath
o
palpitations (fast heart beat)
o
bleeding and high fever
o
impaired brain function (e.g., dizziness, blurred vision, confusion)
If you experience any severe or dangerous side effect, you should:
1. Seek professional medical help immediately.
2. Call your study doctor.
3. If necessary, go to the nearest emergency room.
Risks and Possible Side Effects of tofacitinib.
Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive 
fungal, viral, and other opportunistic infections, lymphoma and other malignancies, 
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gastrointestinal perforations, low lymphocyte and neutrophil count, low hemoglobin levels, and 
elevation of liver enzymes and cholesterol have occurred in patients receiving tofacitinib. 
Tofacitinib treatment can increase the risk of getting blood clots in the lungs or deep veins of the 
legs.
Risks from pre-medications and medications to prevent blood clots
Acetaminophen (Tylenol) 
Acetaminophen is considered to be safe and effective in the recommended doses. However, when 
taken incorrectly acetaminophen can cause liver damage. Your risk of liver damage may be 
increased if you drink more than three alcoholic drinks every day, take more than the recommended 
dose (overdose), or if you take any additional drugs that also contain acetaminophen at the same 
time.
Diphenhydramine (Benadryl)
Drowsiness, dizziness, constipation, stomach upset, blurred vision, or dry mouth/nose/throat may 
occur when taking diphenhydramine.
Ranitidine (Zantac) 
Constipation, diarrhea, headache, nausea or upset stomach may occur when taking ranitidine.  Rare 
serious side effects include severe allergic reaction with rash, hives, itching, difficulty breathing; 
confusion, dark urine, depression, fast or slow heartbeat, unusual bruising or bleeding, yellowing 
of the eyes or skin (indicating liver damage).
Dexamethasone:  
Stomach upset, headache, dizziness, changes in your period, trouble sleeping, increased appetite, 
or weight gain may occur. Rarely patients using dexamethasone have experienced increased 
infection, bone/joint pain, thirst, increased urination, irregular heartbeat, eye pain, vision problems, 
black stools, vomit that looks like coffee grounds, puffy face, swelling of the feet and ankles, 
pain/redness/swelling of the arms or legs, tiredness, mood changes, unusual hair/skin growth, 
muscle cramps, weakness, easy bruising/bleeding, slow wound healing, thinning skin and seizures.
Enoxaparin (Lovenox), Rivaroxaban (Xarelto) and Apixaban (Eliquis)
These medications that cause thinning of the blood can increase the risk of bleeding which can be 
serious or fatal. Allergic reactions are also possible with all three drugs. Allergic reaction to 
enoxaparin (called HIT for heparin-induced thrombocytopenia) can cause increased risk of blood 
clotting and decreases in platelets, the cells that clot blood.
Risks from Study Research Procedures
The following study procedures and treatments may have risks and cause discomfort while you 
participate on this study:
Blood draws
There is the risk of slight pain, bruising or infection when your blood is drawn.  Drawing blood 
may cause some people to faint. 
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Electrocardiogram (ECGs)
The glue used to keep the electrodes in place during the ECG may irritate your skin and cause 
redness. 
Central Line Insertion

Contamination of the catheter which would result in a serious blood stream infection, 
requiring admission to the hospital and giving you antibiotics through the vein.

Collapsed lung particularly if the central line is placed in the vein under your collarbone. 
Collapsed lung is treated with a chest tube when necessary.

During the insertion of some types of central lines, the heart may be irritated by the process 
while the line travels through the blood vessels near the heart, causing an alteration in the 
heart's rhythm. This typically gets better once the line is in place but may require 
medication for some rare individuals.

Air embolism, a condition where air enters the blood stream and begins to travel through 
the body. This condition, which is very serious, is also very rare and largely preventable.
Tumor Biopsies and Tumor Effusions 
Tumor biopsies and tumor effusions: local anesthesia of the skin will be given prior to any tumor 
biopsy or effusion collection to prevent painful sensations.  However, you may still experience 
pain or discomfort at the biopsy site.  Irritation, redness, swelling and/or bleeding may also occur. 
There is a risk of abnormal healing, fever, infection or of an allergic reaction to the anesthetic 
agent used to anesthetize the skin at the biopsy site.  Once the sample has been obtained, a stitch 
may be used to close the wound and assist in healing. 
Risks for MRI 
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of the body.  We will obtain pictures of your abdomen for this study. The MRI scanner is a metal 
cylinder surrounded by a strong magnetic field.  During the MRI, you will lie on a table that can 
slide in and out of the cylinder.  It is very important for the experiment that you do not move your 
head or body inside the scanner. We will place soft padding or a coil around your abdomen to help 
keep it in place. You will be in the scanner about 45-60 minutes. You may be asked to lie still for 
up to 10-15 minutes at a time. While in the scanner you will hear loud knocking noises, and you 
will be fitted with earplugs or earmuffs to muffle the sound. You will be able to communicate with 
the MRI staff at all times during your scan, and you may ask to be moved out of the machine at 
anytime.
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
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these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks from Gadolinium 
Gadolinium is an FDA-approved medication used to improve MRI images. About 98% of patients 
receiving gadolinium have no symptoms related to the injection of this medication. Mild symptoms 
that may occur include: coldness in the arm at injection, a metallic taste, headache, and nausea. In 
an extremely small number of patients, more severe symptoms have been reported including: 
shortness of breath, wheezing, and lowering of blood pressure.
MRI contrast agents containing gadolinium can cause a rare disease known as Nephrogenic 
Systemic Fibrosis (NSF) mostly in patients with severe kidney disease. NSF has been nearly 
eliminated by screening kidney function prior to MRI. To try and avoid NSF, we do not give 
gadolinium to patients with severe kidney disease in this research study. NSF can cause tight rigid 
skin, trouble bending joints, pain, weakness, and can scar body organs. NSF is debilitating and 
may cause death.
Recent reports indicate that some gadolinium may be retained in the brain, bone, and skin. In May 
2018, the FDA stated that no harmful effects have been identified related to gadolinium in the 
brain, but it is continuing to study the issue. You will receive additional information called a 
“medication guide” about the contrast medication you will receive.
Gadolinium will be administered as clinically indicated. We will check your kidney function 
before giving you any gadolinium contrast.
What are the risks related to pregnancy?
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 3 months after you finish study treatment (the restricted period). If 
you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that we 
did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact the study team as soon as possible.
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If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period. There may be unknown risks to a fetus 
or risks we did not anticipate. You and your partner must agree to use birth control if you want to 
take part in this study. If you think your partner has become pregnant during the restricted period, 
please contact the study team as soon as possible. If you and your partner plan for your partner to 
become pregnant after the restricted period, please discuss this with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from CT scans, 
CT-guided biopsies, and chest X-rays. The amount of radiation exposure you will receive from 
these procedures is equal to approximately 7.28 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans, PET scans, CT-guided biopsies, and chest X-rays that you get in this study will 
expose you to the roughly the same amount of radiation as 23.8 years’ worth of background 
radiation. Being exposed to too much radiation can cause harmful side effects such as an increase 
in the risk of cancer.  The risk depends on how much radiation you are exposed to. Please be aware 
that about 40 out of 100 people (40%) will get cancer during their lifetime, and 20 out of 100 
(20%) will die from cancer. The risk of getting cancer from the radiation exposure in this study is 
0.7 out of 100 (0.7%) and of getting a fatal cancer is 0.4 out of 100 (0.4%). 
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time. .
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might be shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer. Because there is not much information 
about the drugs’ effect on your cancer, we do not know if you will benefit from taking part in this 
study. 
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because of the knowledge gained from 
this therapeutic intervention.
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WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could: 

get treatment or care for your cancer without being in a study, including standard options 

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care, also called 
palliative care, to relieve symptoms. This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by the cancer. It does not treat the cancer directly. 
Instead, it tries to improve how you feel. Comfort care tries to keep you as active and 
comfortable as possible.
You should discuss with your doctor your other choices and their risks and benefits.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
The results from all standard clinical test results will be reported to you. However, we will not 
return to you results from research studies conducted with your samples. 
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease worsens or comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if you become pregnant

if LMB-100 may become unavailable

if new information shows that another treatment would be better for you

if you do not follow the study rules

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
After therapy is stopped we would like to see you for a safety visit 3-6 weeks after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to collaborators or designated 
representatives.
WILL YOUR SPECIMENS OR DATA BE SAVED FOR USE IN OTHER RESEARCH 
STUDIES?
As part of this study, we are obtaining specimens and data from you. We plan to use these 
specimens and data for studies going on right now, as well as studies in the future. These studies 
may provide additional information that will be helpful in understanding pancreatic cancer, bile-
duct cancer, or other mesothelin-expressing solid tumors, or other diseases or conditions. This 
could include studies to develop other research tests, treatments, drugs, or devices, that may lead 
to development of a commercial product by the NIH and/or its research or commercial partners. 
There are no plans to provide financial compensation to you if this happens. Also, it is unlikely 
that we will learn anything from these studies that may directly benefit you. By agreeing to let 
us use your specimens and data, you give the NIH any rights you may have in the samples and 
data.
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, other 
research centers and institutions, or industry sponsors of research. 
In addition to the use and sharing of your specimens and data described above, we might remove 
any information from your samples and data that can identify you such as name, address, or 
medical record number, and then use the samples and data for additional research studies at the 
NIH or other places. If we do this, we might not contact you to ask your permission or otherwise 
inform you.
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your samples. For example, if some research with your specimens and data has 
already been completed, the information from that research may still be used. Also, for example, 
if the specimens and data have been shared already with other researchers, it might not be 
possible to withdraw the specimens and data. 
Please place your initials in the blank next to Yes or No for each of the questions below:
My specimens and data may be stored and used for future research as described above.
_____ Yes
_____ No
Initials
Initials
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My specimens and data may be shared with other researchers and used by these researchers for 
future research as described above.
_____ Yes 
_____ No
Initials
Initials
How Long Will Your Specimens and Data be Stored by the NIH?
Your samples and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
The NCI generally does not cover expenses during screening. If you are scheduled for and begin 
treatment, the NCI will cover the cost for some of your expenses. Some of these costs may be paid 
directly by the NIH and some may be reimbursed after you have paid. Someone will work with 
you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center.

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
are expected to follow these guidelines or the guidelines of their home institution, but they do not 
need to report their personal finances to the NIH.
The National Institutes of Health and the research team for this study have developed a drug being 
used in this study. This means it is possible that the results of this study could lead to payments to 
NIH. By law, the government is required to share such payments with the employee inventors. 
You will not receive any money from the development of LMB-100.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release any 
information about your research involvement without your written permission. However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
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File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
insurance company information from your medical record. This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens and data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);
3. is for other research;
4. is disclosed with your consent 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research.
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act. In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


PATIENT IDENTIFICATION
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File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Christine 
Alewine, Christine.alewine@nih.gov, 240-760-6146. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 19C0128
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020

Prot_SAP_000.pdf: 
1 
Abbreviated Title: LMB100 + tofacitinib in PDA 
Version Date: 08/19/20 
 
Abbreviated Title: LMB100 + tofacitinib in PDA 
CC Protocol #:19C0128 E 
Version Date: August 19, 2020 
NCT Number: NCT04034238 
 
Title: A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with 
Tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma 
and other Mesothelin Expressing Solid Tumors. 
 
NCI Principal Investigator: 
Christine Alewine, M.D., Ph.D. 
Laboratory of Molecular Biology (LMB), CCR, NCI 
Building 37, Room 5116 
9000 Rockville Pike 
Phone: 240-760-6146 
Email: Christine.alewine@nih.gov 
Investigational Agents:     
Drug Name: 
LMB-100 (formerly 
RO6927005) 
Tofacitinib (Xeljanz) 
Mesothelin 
Expression 
Testing 
IND Number: 123332 
123332 
NSR device 
Sponsor: 
Center for Cancer Research 
(CCR), NCI, NIH 
Center for Cancer Research 
(CCR), NCI, NIH 
CCR, NCI, 
NIH 
Manufacturer 
Selecta Biosciences 
Pfizer 
NCI 
Laboratory of 
Pathology 
 
Commercial Agents: none 


2 
Abbreviated Title: LMB100 + tofacitinib in PDA 
Version Date: 08/19/20 
 
PRÉCIS 
Background: 
• Pancreatic cancer is the fourth most common cause of cancer death in the United States, 
claiming more than 40,000 lives each year. 
• Incidence nearly equals mortality with just 6% of participants living five years beyond 
their diagnosis. Most patients are diagnosed at an advanced stage, but even patients 
with early stage disease have a long-term survival of less than 20%. 
• Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the 
extrahepatic form yearly. The median overall survival of patients with advanced 
disease receiving standard of care treatment is less than 1 year. 
• Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has 
been examined in several published studies and ranges from 86 to 100%. Similar 
incidence of expression has been observed in extrahepatic cholangiocarcinoma. 
• In addition to pancreatobiliary tumors, many other solid tumor types also express 
MSLN such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, 
gastric and triple negative breast cancers, as well as some tumors of squamous cell 
origin. 
• LMB-100 and a closely related immunotoxin also targeting MSLN have been studied 
in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.  
• Results from these studies showed that almost all patients formed anti-drug-antibodies 
(ADAs) that neutralized subsequent injection of the product making it ineffective.  
• Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for 
the treatment of rheumatoid arthritis and ulcerative colitis. 
• Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs 
against an immunotoxin closely related to LMB-100 
• Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half-
life in mice and enhanced anti-tumor efficacy 
• This clinical trial will investigate whether co-administration of tofacitinib with LMB-
100 can prevent or delay the formation of ADAs and thus allow patients to receive 
additional effective cycles of LMB-100. 
Objectives: 
• The primary objective of the dose escalation phase of this study is to assess the safety 
and tolerability of LMB-100 given in combination with tofacitinib to patients with 
pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-
positive solid tumors  
• The primary objective of the expansion phase of this study is to determine whether co-
administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs 


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through cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients 
with pancreatobiliary cancers. 
Eligibility: 
• Age ≥ 18 years 
• Histologically confirmed solid tumor malignancy for which no curative therapy exists  
• Participants must have received at least one prior systemic treatment regimen for their 
disease OR be ineligible to receive available standard treatments for their disease OR 
refused first-line standard systemic treatments but have been treated with other anti-
cancer agents. 
Design: 
• This is a Phase I study which will accrue up to 45 subjects total, accounting for screen 
failure. 
• Participants will be co-treated for 3 cycles with tofacitinib given orally for the first 10 
days of each 21 day cycle, and LMB-100 given on days 4, 6 and 8. 
• A 3+3 dose escalation schema will be used. Two dose levels are planned. One minus 
dose level could be utilized if dose de-escalation is necessary.  
• Following identification of an optimal dose and schedule, an expansion phase of 15 
participants will be initiated at the optimal dose for patients with pancreatic 
adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the 
expansion phase must have pancreatic adenocarcinoma. 
• Participants on the Dose Escalation and Dose Expansion Arms who appear to be 
obtaining clinical benefit from LMB-100/tofacitinib after 3 cycles of treatment may 
elect to receive additional cycles of therapy at the discretion of the PI. 
 


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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION .................................................................................................................. 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 25 
2.1 
Eligibility Criteria .......................................................................................................... 25 
2.2 
Screening Evaluation...................................................................................................... 28 
2.3 
Participant Registration and Status Update Procedures ................................................. 29 
2.4 
Treatment Assignment Procedures................................................................................. 30 
3 
STUDY IMPLEMENTATION ............................................................................................ 30 
3.1 
Study Design .................................................................................................................. 30 
3.2 
Drug Administration ...................................................................................................... 34 
3.3 
Dose Modifications ........................................................................................................ 39 
3.4 
Study Calendar ............................................................................................................... 43 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 47 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 47 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 48 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 48 
5.2 
Sample Collection schedule ........................................................................................... 53 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION ........................................... 54 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 56 
6.1 
Data Collection ............................................................................................................... 56 
6.2 
Data Sharing Plans ......................................................................................................... 57 
6.3 
Response Criteria ........................................................................................................... 57 
6.4 
Toxicity Criteria ............................................................................................................. 65 
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN............ 65 
7.1 
Definitions ...................................................................................................................... 65 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 66 
7.3 
NCI Clinical Director Reporting .................................................................................... 66 
7.4 
NIH required Data and Safety Monitoring Plan............................................................. 66 


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8 
SPONSOR SAFETY REPORTING ..................................................................................... 67 
8.1 
Definitions ...................................................................................................................... 67 
8.2 
Assessment of Safety Events.......................................................................................... 68 
8.3 
Reporting of Serious Adverse Events ............................................................................ 69 
8.4 
Reporting Pregnancy ...................................................................................................... 69 
8.5 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 70 
9 
CLINICAL MONITORING ................................................................................................. 70 
10 STATISTICAL CONSIDERATIONS.................................................................................. 71 
10.1 Statistical Hypothesis ..................................................................................................... 71 
10.2 Sample Size Determination ............................................................................................ 71 
10.3 Populations for Analyses ................................................................................................ 72 
10.4 Statistical Analyses ........................................................................................................ 73 
11 HUMAN SUBJECTS PROTECTIONS ............................................................................... 75 
11.1 Rationale For Subject Selection ..................................................................................... 75 
11.2 Participation of Children ................................................................................................ 75 
11.3 Participation of Subjects Unable to Give Consent ......................................................... 75 
11.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 75 
11.5 Consent Process and Documentation ............................................................................. 77 
12 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION .............. 77 
12.1 LMB-100 (IND # 123332) ............................................................................................. 77 
12.2 Tofacitinib ...................................................................................................................... 80 
13 REFERENCES ..................................................................................................................... 82 
14 APPENDICES ...................................................................................................................... 87 
14.1 Appendix A- Performance Status Criteria ..................................................................... 87 
14.2 Appendix B-Model chemotherapy note ......................................................................... 88 
14.3 Appendix C- Patient Medication Diary .......................................................................... 89 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives 
• For dose escalation cohort: To assess the safety and tolerability of LMB-100 with 
tofacitinib in patients with pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma 
and other mesothelin-positive solid tumors  
• For dose expansion cohort: To determine whether co-administration of tofacitinib delays 
the formation of neutralizing anti-LMB-100 ADAs through cycle 2 of treatment (as 
measured by LMB-100 serum drug levels) in patients with pancreatobiliary cancers. 
1.1.2 Secondary Objectives 
• For the dose escalation cohort: To determine whether co-administration of tofacitinib 
delays formation of neutralizing anti-LMB-100 ADAs through cycle 2 of treatment (as 
measured by LMB-100 serum drug levels) 
• For the expansion cohort: To assess the safety and tolerability of the combination in 
patients with pancreatobiliary cancer 
• For both cohorts: To define the effect of tofacitinib on the pharmacokinetic characteristics 
of LMB-100  
• For both cohorts: To determine the percentage of patients who have delayed formation of 
neutralizing anti-LMB-100 ADAs through cycle 3 of treatment (as measured by LMB-100 
serum drug levels) when co-administered tofacitinib 
1.1.3 Exploratory Objectives 
• To obtain preliminary assessment of activity including change in appropriate serum tumor 
markers with treatment, objective response rate (ORR), disease control rate after 3 cycles 
(~9 weeks) of treatment (DCR), progression free survival (PFS) and overall survival (OS) 
• Evaluate association between anti-LMB-100 antibody titer and peak serum drug level 
• To examine the relationship between MSLN expression and response to treatment  
• To evaluate changes in the tumor microenvironment following treatment with LMB-100 
plus tofacitinib 
• To assess changes in circulating immune cell and cytokine levels caused by the treatment 
• For treatment extension: To determine whether tofacitinib can continue to prevent ADA 
formation beyond 3 cycles of treatment regardless of whether patients had another 
intervening therapy or not. 


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1.2 
BACKGROUND AND RATIONALE 
1.2.1 Background on disease 
Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming 
more than 40,000 lives each year. Incidence nearly equals mortality with just 6% of patients living 
five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even 
patients with early stage disease have a long term survival of less than 20%.(1) Combination 
chemotherapy with FOLFIRINOX provides the greatest survival advantage for patients who have 
advanced disease, but the median overall survival (OS) for this regimen does not reach one year 
and most pancreatic cancer patients are not fit enough to tolerate it.(2) Gemcitabine with NAB-
paclitaxel is an alternative regimen and extends median overall survival to 8.5 months from 6.7 
months with gemcitabine alone. The response rate (RR) to this regimen in the first-line is 23% 
with less than 1% of patients achieving a complete response (CR).(3) Prospective and retrospective 
cohort studies have estimated a 17% RR to this regimen when given in second-line to good 
performance status patients following FOLFIRINOX.(4,5) Single agent gemcitabine remains the 
recommended treatment for patients with poor performance status. Erlotinib is the only targeted 
therapy with efficacy against this disease and extends median OS by approximately 10 days when 
added to gemcitabine at the expense of significant toxicity.(6) Median survival of patients able to 
receive second line therapy is approximately 3-6 months.(7) New paradigms for the effective 
treatment of pancreatic cancer are sorely needed.  
Cholangiocarcinoma is a rare cancer type which originates in the biliary tract. Extrahepatic 
cholangiocarcinoma refers to biliary tract tumors that arise in the bile ducts outside the gallbladder 
and the liver parenchyma. For the purposes of this study, this includes patients with hilar and 
periampullary carcinoma. Approximately 3,000 cases of extrahepatic cholangiocarcinoma are 
diagnosed in the United States each year.(1) Patients with advanced disease are treated with 
combination chemotherapy using gemcitabine and cisplatin. The Phase III randomized ABC-02 
trial demonstrated a median OS of 11.7 months for patients treated with the combination as 
compared to 8.1 months for gemcitabine alone. The rate of tumor control (objective response and 
stable disease for 24 weeks) was 81.4% for the combination.(8) Based upon Phase II data, 
combination 5-FU based chemotherapy regimens may also be administered. Improved treatment 
options for this disease would be advantageous to patients. 
1.2.2 Mesothelin (MSLN) as a therapeutic target 
MSLN is a cell surface glycoprotein that is a differentiation antigen for mesothelial cells; 
expression in normal tissues is confined to the pleura, pericardium and peritoneum. The normal 
function of MSLN is unknown. Strong and frequent expression of MSLN has been noted in many 
solid tumors, but is especially notable in mesothelioma, pancreatic, ovarian, lung and biliary tract 
malignancies as shown in Table 1 (adapted from (9)). MSLN expression is also associated with 
more aggressive disease in pancreatic cancer, cholangiocarcinoma, lung, ovarian and breast 
cancers (10-14). In pancreatic cancer cell lines, overexpression of MSLN increases proliferation, 
motility and invasion and decreases survival of mice bearing tumors grown from these cells (15). 
Similar effects have been seen with other tumor cell types (16-18). These properties make MSLN 
an attractive target for anti-neoplastic therapies, and more than five anti-MSLN agents are 
currently undergoing clinical testing. 


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Table 1. Prevalence of MSLN expression by tumor type(9) 
1.2.3 Recombinant Immunotoxins (RITs) that target MSLN 
1.2.3.1 Mechanism and structure of RITs 
RITs are antibody-based therapeutics that carry a toxin payload. RITs that target MSLN contain a 
genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-binding 
domain of PE is replaced by the MSLN-binding antibody fragment. In this way, the RIT binds 
specifically to MSLN on the cell surface and gets internalized through endocytic processes. In the 
cytosol, PE catalyzes an irreversible, inactivating modification of eukaryotic elongation Factor-2 
(eEF-2). This prevents the elongation step of protein synthesis halting production of new cellular 
proteins, a stressor that triggers apoptosis. This mechanism of action results in cytotoxicity to both 
proliferating and non-dividing cells, therefore proper targeting is critical to the safety profile (19). 
SS1P was the first MSLN-targeted RIT tested in patients. Phase I studies established a maximum 
tolerated dose (MTD) of 45 mcg/kg given every other day for three total doses per cycle. Dose 
limiting toxicities (DLTs) were pleuritis, an expected on-target off-tumor toxicity caused by SS1P-
induced inflammation of the normal pleura, and capillary leak syndrome (CLS). Clinical trials 
have demonstrated that efficacy of SS1P is limited by its immunogenicity. Anti-RIT neutralizing 


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antibodies (Nabs) form after one cycle in ~90% of patients preventing effective drug exposure in 
subsequent cycles (20). When SS1P was administered with a lymphocyte-depleting conditioning 
regimen of pentostatin and cyclophosphamide, this delayed the development of anti-RIT 
antibodies in most patients. In a pilot study, three of ten patients with chemotherapy refractory 
mesothelioma achieved durable major responses with this regimen (21). These results provide a 
proof of principle that RITs can have meaningful clinical efficacy in patients with advanced solid 
tumors.  
         Figure 1. RIT Structure 
 
1.2.4 Rationale for the development of LMB-100 
LMB-100 (previously RO6927005 and RG7787) is a next generation anti-MSLN RIT developed 
in NCI’s Laboratory of Molecular Biology in collaboration with Roche (         Figure 1). The anti-
MSLN targeting region of LMB-100 uses a humanized Fab fragment instead of the smaller dsFv 
fragment used in SS1P. In addition, LMB-100 contains a newly engineered PE fragment that has 
similar or improved activity against most cancer cell lines in vitro, and is also much less toxic than 
SS1P in pre-clinical models while maintaining or improving upon efficacy seen with SS1P in most 
models (22-25). The new PE contains modifications specifically designed to reduce 
immunogenicity of the molecule. This includes deletion of a 14 kD sequence that precedes the 
catalytic domain and 7 point mutations within the catalytic domain itself. These changes ablate the 
major human B cell epitopes within the molecule and also the most antigenic T cell epitope (26,27).  
1.2.5 Nonclinical Studies of LMB-100  
1.2.5.1  Nonclinical Pharmacology  
In vitro LMB-100 inhibited viability of a variety of mesothelin-positive cancer cell lines at 
effective concentrations typically around 14 pM (~1 ng/mL). The cytotoxic potency of LMB-100 
varied between 0.35 ng/mL in primary mesothelioma cells (RH21) and 15.7 ng/mL in an adeno-


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squamous lung carcinoma cell line (H596). Binding studies showed that while the Fab fragment 
did not bind to mouse or rat mesothelin, the binding affinities to cynomolgus and human 
mesothelin were identical. In agreement with this, LMB-100 induced apoptosis in mesothelin-
positive primary cynomolgus pericardial cells and significantly impaired viability of HEK293 cells 
transfected with human mesothelin, but not of rat mesothelin transfected or un-transfected 
HEK293 cells. In addition, control experiments showed that free PE24 was 100−1000 fold less 
potent on mesothelin-positive target cell lines, confirming low cytotoxic potential of PE24 lacking 
a targeting moiety.  
Animal studies demonstrated that a single cycle of LMB-100 treatment given at an optimal dose 
of approximately 2 mg/kg, 3 × per week, every other day (QOD) achieved tumor regressions in 
subcutaneous xenografts of adeno-squamous lung carcinoma (H596) in severe combined 
immunodeficient (SCID) beige mice. Three consecutive treatment cycles, given with 1 week 
breaks in between, led to massive shrinkage of large tumors with an average initial volume of 600 
mm3. Tumor regressions in monotherapy were also achieved when treating subcutaneous 
xenografts of mesothelioma (NCI-H226), gastric (MKN-28), and triple negative breast (HCC70) 
cancer cell lines in athymic nude mice. Highly synergistic antitumor efficacy was observed in 
combination therapy with paclitaxel when treating subcutaneous xenografts of the recombinant 
high mesothelin expressing A431H9 cell line or the pancreatic cancer cell line KLM1. These 
results support evidence that LMB-100 may provide clinical benefit to participants with cancer. 
1.2.5.2 Pharmacokinetics in Animals  
The pharmacokinetics (PK) of LMB-100 were tested in cynomolgus monkeys following single IV 
administration at doses ranging from 0.03 mg/kg to 0.3 mg/kg. Two different enzyme-linked 
immunosorbent-based formats were used for analyzing plasma levels of LMB-100; free and total 
drug assay (where the total drug assay was the sum of free LMB-100 and LMB-100 complexed 
distribution at steady-state similar to the plasma volume). Within the dose range tested, non-linear 
PK was observed for free drug with an extended half-life at higher doses (mean terminal half-life 
approximately 0.6 hours at 0.3 mg/kg compared to 0.3 hours at 0.03 mg/kg) suggesting saturation 
of MSLN-mediated clearance pathways. Clearance of total drug was consistently lower than that 
for free drug implying the presence of soluble binding partners such as soluble mesothelin and 
ADAs. Induction of anti-drug antibodies (ADA) responses was frequently detectable in all dose 
groups tested. Overall, given the limited predictive value of immunogenicity reactions in animals 
to human, a risk for immunogenicity in humans cannot be excluded. Toxicokinetics after repeated 
IV dosing in cynomolgus monkeys demonstrated an increase in total exposure in a dose 
proportional manner between 0.1 mg/kg and 3.0 mg/kg. No accumulation was observed over 5 
consecutive days of treatment or over two dosing cycles with 3 × per week dosing. Almost all 
monkeys developed ADAs upon treatment, while induction of high ADA levels impaired the 
exposure of free drug. In some cases, the induction of ADAs may have induced a slight increase 
in exposure  
The relationship between systemic drug exposure and anti-tumor activity of LMB-100 was 
investigated on human lung cancer NCI-H596 xenograft growth in female SCID beige mice. Free 
and total drug profiles were similar in mice. Modeling estimated a plasma concentration of 6800 
ng/mL (± 36%) to trigger a half maximal rate of tumor regression. Concentrations of LMB-100 
above this level resulted in potent tumor regression after dosing. Normalized for exposure, SS1P 
was found to be ~3-fold more potent than LMB-100 in terms of tumor growth inhibition.  


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1.2.5.3 Toxicology and Safety Pharmacology  
The toxicological profile of LMB-100 was assessed after repeated intravenous administration to 
cynomolgus monkeys, the only relevant species, for a maximum of 5 daily doses for one week or 
2 cycles with QOD × 3 dosing, separated by a 9-day dosing free period. Four daily doses of 3 
mg/kg exceeded the maximum tolerated dose with animals being found in moribund condition, 
indicated by clinical signs of hypoactivity, hunched posture, ataxia, and tremors. There were no 
histopathological changes to account specifically for the deteriorating physical condition of these 
animals. Histopathological findings such as kidney tubular degeneration/regeneration and changes 
at serosal-lining tissues were observed at lower doses as well. In general, administration of LMB-
100 resulted in both on- and off-target toxicities.  
On-target effects were observed on serosal-lining tissues, consistent with high expression of 
mesothelin. Mesothelium hypertrophy accompanied by sub pleural cellular hypertrophy and 
serosal fibrin exudate was observed in the lung at doses ≥ 1 mg/kg. Mesothelium hypertrophy also 
occurred in heart (epicardium), spleen, and stomach. Off-target or non-specific toxicity included 
degeneration/regeneration of kidney tubular epithelium after repeated doses of ≥ 0.3 mg/kg. Local 
inflammatory findings at the injection sites were observed after administration of LMB-100 in 
several studies. Clinically, reddening of the skin, swelling, and skin being warm to touch or flaky 
injection sites were reported. In the 2-cycle GLP study (3 intermittent doses over a 5-day period, 
9-days apart), impaired movement of animals from all dose groups was likely related to injection 
site findings and an overall inflammatory profile. One female at 1 mg/kg was sacrificed early on 
Day 4 after 2 doses due to severe clinical signs most likely attributed to inflammatory changes at 
injection sites, resulting in moribundity of the animal. Clinically, inflammatory changes correlated 
with histopathological changes such as hemorrhages and/or acute inflammation at the injection 
sites and clinical pathology changes consistent with an overall inflammatory profile (increases in 
monocytes, neutrophils, CRP, and haptoglobin) were observed. Microscopic changes reversed 
completely after the 4-week recovery period in the 2-cycle GLP study. The Highest Non-Severely 
Toxic Dose (HNSTD) in this study was 0.3 mg/kg, which resulted in a mean AUC for total drug 
of 16.0 mcg/h/mL (study day 1, preliminary data). In a subsequent 1 cycle GLP study (QOD × 3 
dosing), markedly reduced injection site findings were observed after administration of a batch 
with reduced levels of product related modifications of LMB-100. In this study, the HNSTD was 
1 mg/kg, resulting in an AUC for total drug of 27.4 and 23.6 mcg/h/mL after the first and third 
dose (preliminary data).  
The potential of LMB-100 to induce off-target vascular leak in lungs was assessed in female Wistar 
rats. Mild perivascular edema was reported microscopically but did not correlate with macroscopic 
or serum chemistry findings consistent with VLS. Ultrasound evaluation in the NHP GLP study 
revealed minimal accumulation of pericardial fluid with limited biological significance at the 
highest dose of 1 mg/kg. No appreciable accumulation of pleural fluid was observed at necropsy.  
In vitro evaluation of LMB-100 in human whole blood assay indicated a low risk for cytokine-
mediated infusion related reaction (IRR)/cytokine release syndrome (CRS) upon first 
administrations. LMB-100 caused no hemolysis when added to human peripheral blood up to the 
highest concentrations of 0.5 mg/L. 


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1.2.6 Rationale for starting dose of LMB-100:  
In prior Phase I study, the MTD of LMB-100 was determined to be 140 mcg/kg given as a 30-
minute infusion every other day x3. For this combination study, we will decrease the dose of LMB-
100 to 100 mcg/kg for initial combination testing. Rationale for limitation to 3 cycles of treatment 
for Dose Escalation (Arm 1) and Expansion (Arm 2)  
Infusion-related reaction (IRR) upon LMB-100 administration is associated with the presence of 
ADAs. For participant safety, treatment will be limited to 3 cycles to lower risk of IRR if tofacitinib 
co-treatment is unsuccessful at limiting or delaying ADA development.  
1.2.7 Rationale for starting dose and schedule of tofacitinib  
Tofacitinib is FDA approved for the treatment of ulcerative colitis at a dose of 10 mg (immediate 
release formulation) given orally twice daily on a continuous schedule. Tofacitinib will be given 
at the same dose on this protocol, which is the highest dosage approved by FDA for any indication. 
For our purpose- diminishing ADA formation- we anticipate that immunosuppression by 
tofacitinib will only be necessary during the time which immune cells are potentially exposed to 
LMB-100. Therefore, tofacitinib will not be given continuously. Instead, dosing will be limited to 
days 1 through 10 of each cycle. This provides immunosuppression throughout the three doses of 
LMB-100, a lead-in for 3 days before to establish physiologic effect before the first LMB-100 
administration, and then continued tofacitinib for 2 days after last administration of LMB-100 for 
the cycle while the drug is eliminated from the body. Intermittent dosing is anticipated to reduce 
the risk of infection caused by tofacitinib-mediated immune suppression and hypothetical risk of 
inhibiting anti-tumor immune response. 
1.2.8 Clinical testing of LMB-100 
1.2.8.1 Previous Roche study 
Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in 
human trial (NCT02317419). The primary objective of the Phase I study was to define the safety 
and tolerability (including the MTD) and pharmacokinetics of the drug in participants with MSLN-
expressing metastatic or locally advanced solid tumors for whom no standard therapy was 
available. Secondary objectives included determination of the RP2D and schedule, exploration of 
preliminary anti-tumor activity by assessing objective response rate (ORR) and disease control 
rate (DCR), and assessment of pharmacodynamic effects.  
A total of 15 participants were enrolled onto the study before termination. Median age of 
participants was 60.8 years and 53.3% were female. All participants had received prior anti-cancer 
therapy for their tumors. Enrolled participants had advanced mesothelioma (7), ovarian cancer (3), 
pancreatic cancer (3), and gastroesophageal cancer (2). Tumors from 13 of the 15 treated 
participants had moderately to strongly positive MSLN expression as measured by central IHC 
analysis.  
LMB-100 was administered intravenously on Days 1, 3 and 5 of a 21-day treatment cycle. No pre-
medications were given. Treatment was initiated at the MTD of SS1P, 45 mcg/ kg. Five different 
dose levels were tested (see Table 2). Dose limiting toxicity (DLT) was reached at 250 mcg/kg, 
with 2 of 4 participants treated at this dose level experiencing vascular leak syndrome (grade 2 and 
grade 4). Additional toxicities were associated with this toxic dose level. At this point, a sixth 


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cohort receiving 200 mcg/kg of study drug was enrolled, however, the study was terminated by 
the company before the two accrued participants completed cycle 1 of therapy. Therefore, the 
single agent MTD was not determined. 
Table 2. LMB-100 Dose escalation study- NCT02317419 
Dose (mcg/kg) 
Number of patients 
Patients with DLT 
45 
1 
0 
65 
1 
0 
100 
3 
0 
170 
4 
0 
200 
2 
NE 
250 
4 
2 
DLTs were vascular leak syndrome and proteinuria 
NE, Study terminated before DLT assessment period was complete and patients 
only received single dose of RG7787 
1.2.8.1.1 LMB-100 Adverse Events  
Overall, 14 participants (93.3%) experienced at least one AE. The most common AEs were 
hypoalbuminemia (60.0%), fatigue (53.3%), peripheral edema (53.3%), nausea (46.7%), pyrexia 
(40.0%), decreased appetite (33.3%), dyspnea (33.3%), and myalgia (33.3%). SAEs included 
vascular leak syndrome, pyrexia, atrial flutter, infusion related reaction, arthritis, 
glomerulonephritis minimal lesion and dyspnea. No participants experienced an AE that led to 
withdrawal of study treatment. Four participants experienced a total of 8 infusion-related reactions 
that were independent of drug dose level. All of these AEs were non-serious and resolved within 
approximately 1 hour of onset. Pre-medication for infusion reaction was administered to these 
participants prior to subsequent doses of LMB-100. Two suspected Type III hypersensitivity 
reactions were observed. These consisted of arthritis (1) and rash with fever (1), both of which 
were fully reversible. When other AEs attributed to the study drug are presented by dose level of 
drug, it becomes clear that toxicity was strongly associated with the 250 mcg/kg dose level at 
which DLT was reached (see Table 3 and Table 4) which are adapted from Roche Final Study 
Report, “Summary of Adverse Events Related to Study Medication, Safety-Evaluable Patients 
Protocol: BP29387”). Two of four patients treated at 250 mcg/kg experienced serious VLS which 
manifested with hypotension, respiratory compromise, serosal membrane reaction and 
hyponatremia as well as the hypoalbuminemia and edema that can be seen with mild VLS. Other 
symptoms associated with the DLT dose were fatigue, nausea, vomiting, decreased appetite and 
mild elevation of transaminases. In summary, safety and tolerability of LMB-100 were as 
expected. 


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Table 3. Grade 3 or 4 Adverse Events Attributed to LMB-1001 
Dose (mcg/kg) 
45 
65 
100 
170 
250 
ALL 
# of patients treated 
1 
1 
3 
4 
4 
13 
Vascular leak (gr 4) 
- 
- 
- 
- 
1 
1 
Hyponatremia (gr 3) 
- 
- 
- 
- 
1 
1 
Anemia (gr 3) 
- 
- 
- 
1 
- 
1 
Decreased lymphocytes (gr 3) 
- 
- 
- 
- 
1 
1 
Dyspnea (gr 3) 
- 
- 
- 
- 
1 
1 
Infusion-related reaction (gr 3) 
- 
- 
1 
- 
- 
1 
Arthritis (gr 3) 
- 
- 
1 
- 
- 
1 
1 adapted from Clinical Study Report No 1066017 from Roche dated December 2015, “Summary 
of Adverse Events Related to Study Medication, Safety-Evaluable Patients Protocol: BP29387” 
See pages 175-193 of the report. 
 
Table 4. Adverse Events attributed to LMB-1001 
Dose (mcg/kg) 
45 
65 
100 
170 
250 
ALL 
# of patients treated 
1 
1 
3 
4 
4 
13 
Vascular Leak 
- 
- 
1 
1 
2 
4 
Grade 3 or 4 vascular leak 
- 
- 
- 
- 
1 
1 
Hypotension 
- 
- 
- 
- 
2 
2 
Hypoalbuminemia 
- 
1 
3 
2 
3 
9 
peripheral edema 
1 
1 
3 
2 
4 
11 
Facial edema 
- 
1 
2 
- 
1 
4 
Weight gain 
- 
- 
1 
- 
1 
2 
Hyponatremia 
- 
- 
- 
- 
3 
3 
Hypophosphatemia 
- 
- 
- 
- 
1 
1 
Dyspnea 
- 
1 
- 
- 
2 
3 
Infusion related reaction 
- 
- 
2 
- 
2 
4 
Constitutional  
 
 
 
 
 
 
Fatigue 
- 
- 
- 
1 
4 
5 


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Dose (mcg/kg) 
45 
65 
100 
170 
250 
ALL 
# of patients treated 
1 
1 
3 
4 
4 
13 
Asthenia 
- 
- 
3 
- 
- 
3 
Fever 
1 
- 
2 
1 
2 
6 
Musculoskeletal 
 
 
 
 
 
 
Myalgia 
- 
- 
1 
1 
2 
4 
Arthralgia 
1 
- 
- 
- 
1 
2 
Arthritis 
- 
- 
1 
- 
- 
1 
Muscle spasm 
- 
- 
- 
1 
- 
1 
Cardiac 
 
 
 
 
 
 
Pericardial effusion 
- 
- 
- 
- 
1 
1 
Atrial flutter 
- 
- 
- 
1 
- 
1 
Renal Disorders 
Glomerulonephritis minimal 
- 
- 
- 
1 
- 
1 
Proteinuria 
- 
- 
- 
1 
1 
2 
Creatinine increase 
- 
- 
- 
- 
2 
2 
Gastrointestinal 
 
 
 
 
 
 
Decreased appetite 
- 
1 
- 
1 
2 
4 
Nausea 
1 
- 
1 
1 
4 
7 
Abdominal pain 
- 
1 
- 
1 
1 
3 
Diarrhea 
1 
- 
1 
- 
- 
2 
Vomiting 
- 
- 
- 
- 
2 
2 
Abdominal distension 
- 
1 
- 
- 
- 
1 
Constipation 
- 
- 
- 
1 
- 
1 
Dyspepsia 
- 
- 
- 
1 
- 
1 
AST increase 
- 
- 
- 
- 
2 
2 
Hematologic 
 
 
 
 
 
 
Anemia 
- 
- 
- 
1 
- 
1 
Decreased lymphocytes 
- 
- 
- 
- 
1 
1 
Total Grade 3 or greater 
- 
- 
2 
1 
2 
5 
Orange highlighting indicates that one of the patients experienced a grade 3 or 4 toxicity in this category. Please 
note that there was only 1 patient who experienced a high-grade toxicity of each type. 
1 adapted from Clinical Study Report No 1066017 from Roche dated December 2015, “Summary of Adverse Events 
Related to Study Medication, Safety-Evaluable Patients Protocol: BP29387” See pages 175-193 of the report.” 


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1.2.8.1.2 Anti-Drug Antibodies (ADAs) and LMB-100 Drug Levels  
Twelve participants were evaluable for efficacy. The best confirmed overall response was stable 
disease in 3 participants. A Roche-developed ELISA test was used to retrospectively assess anti-
drug antibody (ADA) titers. 5 of 15 participants had detectable ADAs at study enrollment while 
the remaining participants did not. However, the remaining participants developed detectable 
ADAs by the end of Cycle 2. Immunogenicity of LMB-100 did affect serum drug levels. These 
data are summarized in Figure 2.  
All evaluable participants achieved expected serum drug levels during the first cycle of treatment. 
Six of 7 participants without pre-existing ADAs achieved effective drug levels during the second 
cycle, while 0 of 2 participants with pre-existing ADAs did so. One of 3 participants that received 
a third cycle of treatment also achieved effective drug levels during this cycle. A positive test for 
ADAs did not definitively predict poor blood levels in the subsequent cycle (see patient 1101 in 
Table 5) In summary these data show that the mere presence of ADAs as measured by the Roche 
ELISA test is not predictive of ability to achieve measurable LMB-100 concentration in the serum, 
which is the most important parameter for drug efficacy. However, high titers of ADAs as 
measured by this test are predictive of diminished LMB-100 serum drug levels, while intermediate 
or low titers may or may not impact drug levels. 
Figure 2. LMB-100 ADAs and Blood Levels 
 
 


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Table 5. LMB-100 drug levels and ADAs in patients WITHOUT pre-existing ADAs 
Cycle 1 
Cycle 2 
Cycle 3 
Patien
t  
Dose 
(mcg/kg) 
ADA 
(Day1) 
Cmax 
(ng/ml) 
ADA 
(Day1) 
Cmax 
(ng/ml) 
dC1/dC 
(%) 
ADA 
(Day1) 
Cmax 
(ng/ml) 
dC1/dC 
(%) 
1002 
65 
0 
1150 
8100 
711 
-38 
- 
- 
- 
1401* 
100 
0 
1790 
0 
1610 
-10 
24300 
267 
-85 
1402 
100 
0 
1650 
0 
1360 
-18 
8100 
0 
-100 
1101* 
170 
0 
2760 
300 
3950 
43 
900 
3490 
26 
1202 
170 
0 
3040 
0 
1940 
-36 
- 
- 
- 
1301 
170 
0 
3430 
72900 
527 
-85 
- 
- 
- 
1403 
170 
0 
1930 
900 
1550 
-20 
- 
- 
- 
1102* 
250 
0 
5480 
0 
4770 
-13 
- 
- 
- 
1302 
250 
0 
4340 
- 
- 
- 
- 
- 
- 
* Patient’s treatment stopped due to study closure 
ADA data are from Roche "Bioanalytical Report (ADA) for Clinical Study BP29387“with ADA time 
point codes translated as specified in the BP29837 Lab Manual Version 1.0. Cmax data were taken from 
the Roche final study report. 
 
1.2.8.1.3 Comparison of toxicity and immunogenicity of LMB-100 to SS1P  
In the Roche Phase 1 trial, LMB-100 was safely administered to four patients at 170 mcg/kg 
without DLT. This is nearly four times the maximum tolerated dose (MTD) of SS1P. Most patients 
without pre-existing ADAs were able to achieve effective drug levels of LMB-100 for 2 cycles, 
unlike what has been seen previously with SS1P (see Figure 3).  
Figure 3: LMB-100 vs SS1P Cycle 2 Blood Levels 
 
 


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1.2.8.2 NCI trials of LMB-100 
1.2.8.2.1 Mesothelioma, short infusion 
Single agent LMB-100 has been tested in two additional ongoing Phase I studies. A 30-minute 
infusion given on days 1, 3 and 5 of a 21-day cycle was given to 10 mesothelioma patients 
(NCT02798536). At 170 mcg/kg, multiple patients experienced reversible acute kidney 
dysfunction which prolonged hospitalization. For this reason, single agent MTD of 140 mcg/kg 
was established. Toxicities and peak drug levels were similar to the Roche study (manuscript in 
preparation).   
1.2.8.2.2 Combination of LMB-100 with nab-paclitaxel 
The LMB-100 has also been tested in both mesothelioma (NCT02798536) and pancreatic cancer 
patients (NCT02810418) in combination with nab-paclitaxel. In mesothelioma patients, nab-
paclitaxel was given at a dose of 100 mg/m2 on Days 1 and 8. MTD of LMB-100 was found to be 
100 mcg/kg/day given over 30 minutes on days 1, 3 and 5 of each 21-day cycle. In pancreatic 
adenocarcinoma patients, nab-paclitaxel was given at a dose of 125 mg/m2 on Days 1 and 8. At 
100 mcg/kg, DLT of grade 3 myalgia was observed in 2/6 patients. A reduced dose of 65 
mcg/kg/day was subsequently tested. DLT of grade 3 edema associated with vascular leak was 
observed in 1/6 evaluable patients making this the MTD of LMB-100 for the combination. At the 
MTD, 1/14 patients experienced a partial response as their best response following the maximum 
2 cycles of treatment. Grade 4 vascular leak associated with ventricular dysfunction was observed 
in one patient and the study was closed to further accrual. ADA development is shown in Table 
6, and was similar to the Roche trial of single agent LMB-100. Evaluation of this combination 
continues in pancreatic adenocarcinoma patients (manuscripts in preparation).  
Table 6: ADA development during LMB-100 treatment 
Number of patients with expected serum LMB-100 level 
Treatment 
Study Tumor Type 
C2 
C3 
single agent 
Roche 
MSLN(+) 
6 of 9 
1 of 3 
single agent 
NCI 
mesothelioma 
5 of 10 
0 of 9 
+NAB-paclitaxel 
NCI 
mesothelioma 
3 of 10 
0 of 0 
+NAB-paclitaxel 
NCI 
PDAC 
5 of 10 
1 of 3 
TOTAL 
19 of 39 
1 of 13 
49% 
8% 
 
 
 
 
 
1.2.8.2.3 Pancreatic cancer and other MSLN-expressing malignancies, long infusion 
Since some pre-clinical studies suggested that duration of exposure to LMB-100 may be more 
important to anti-tumor activity than peak drug levels (data not shown), a new study was initiated 
to investigate the safety and efficacy of LMB-100 given in a long infusion format to patients with 
pancreatic cancer and other mesothelin-positive solid tumor malignancies (NCT02810418). As of 


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August 2018, 15 participants were enrolled on this study (12 with pancreatic adenocarcinoma, 1 
with ampullary cancer, 1 with pleural mesothelioma, 1 with rectal cancer). For this study, patients 
received only two cycles of study drug by design. Neither toxicity nor efficacy were observed in 
the 3 patients treated at the initial dose level of 65 mcg/kg/day given over 48 hrs starting on Day 
1 of each 21-day cycle. Pharmacokinetic measurements were erratic, likely secondary to inability 
of the syringe pumps to deliver such small volumes of drug, or due to presence of pre-existing 
anti-PE antibodies that acted as a drug sink in some patients. In subsequent dose levels, participants 
were treated with an initial 40 mcg/kg loading dose over 30 minutes prior to the start of the long 
infusion. Single agent MTD of 100 mcg/kg/day x48hrs preceded by 40 mcg/kg loading dose 
was established. DLT of grade 3 proteinuria was noted in 1/6 patients treated at this dose level. 
3/6 patients at this dose level developed non-dose-limiting VLS that included weight gain >5kg, 
as well as hypotension (grade 2). The dose escalation was halted at this point to consider a more 
tolerable alternative schedule. Subsequently, a dose of 100 mcg/kg/day x24hrs preceded by 40 
mcg/kg loading dose given on days 1 and 4 was tested. Two patients receiving this dose 
experienced no drug-related toxicity. One additional patient required hold of the D4 dose due to 
transient grade 2 rise in creatinine, which was considered an investigator-specified DLT. Three 
additional patients were unable to receive the D4 dose due to medical complications related to 
their cancer. These 3 patients receiving only the D1 dose also experienced no drug-related DLT or 
VLS.  
Of note, just 1 of 9 patients receiving continuous infusion achieved detectable blood levels of drug 
with cycle 2 treatment, suggesting that giving LMB-100 in the long infusion format is more 
immunogenic than the short infusion format. However, 0 of 15 patients have experienced IRR, 
suggesting that the long infusion reduces the incidence of these reactions. 
1.2.8.2.4 Pharmacokinetics of LMB-100 
Data from ongoing clinical studies have demonstrated a serum half-life of 61 minutes for LMB-
100 as compared to 466 minutes for SS1P (20). It is not known what factors contribute to the 
longer half-life in circulation of SS1P. In NCI-sponsored studies both with and without nab-
paclitaxel, C1 Cmax at 65 mcg/kg, 100 mcg/kg, 140 mcg/kg, and 170 mcg/kg were found to be 
similar to the values reported during the original Roche Phase I study (Figure 4). 
Figure 4- Patients with pancreatic adenocarcinoma receiving LMB-100 over 30 minutes with 
125 mg/m2 of nab-paclitaxel on NCT02810418 
 
1 0 0
6 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
L M B -1 0 0  d o s e  (m c g /k g )
C m a x  (n g /m L )
C 1 D 1
C 2 D 1


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1.2.9 Administration of tofacitinib for the Prevention of Anti-Drug Antibodies (ADAs) 
The development of ADAs against LMB-100 limits the number of effective cycles of RIT that can 
be administered to 2 or less in almost all patients. The pentostatin + cyclophosphamide (P+C) 
conditioning regimen represents one clinically validated means to suppress anti-RIT antibody 
formation, but this strategy has some drawbacks. First, treatment with P+C produces a numeric 
depletion of lymphocytes that frequently requires months to reverse. This renders patients 
ineligible for future immunotherapy trials and requires prolonged treatment with prophylactic 
antibiotics while lymphocyte populations recover. Secondly, nausea and renal dysfunction caused 
by P+C can reduce patient fitness to tolerate immunotoxin. Thirdly, ADA prevention by co-
administration of P+C allows for administration of only one additional effective cycle in most 
patients (21). Therefore, consideration of other ADA-prevention strategies is warranted. 
Tofacitinib is an oral inhibitor of Janus kinases (JAKs) with FDA approved indications for the 
treatment of rheumatoid arthritis (28), psoriatic arthritis and ulcerative colitis (29). JAKs are non-
receptor tyrosine kinases that are activated by cytokine receptors upon cytokine binding. Activated 
JAKs phosphorylate Signal Transducer and Activator of Transcription (STAT) transcription 
factors inducing STAT translocation to the nucleus and initiation of new transcriptional programs. 
Tofacitinib binds and inhibits JAK1, JAK2 and JAK3 with nanomolar affinity resulting in 
suppression of lymphocyte signaling (30,31). This immunosuppression is rapidly reversible upon 
drug discontinuation since it does not cause lymphocyte depletion. The most common side effect 
of tofacitinib is increased risk of viral infection resulting higher incidences of rhinosinusitis and 
headache and increased cholesterol, which typically begins after 8 weeks of continuous treatment 
(28,29). 
Preclinical data from the LMB immunotoxin group has demonstrated that tofacitinib can prevent 
anti-SS1P antibody formation in mice repeatedly immunized with this immunotoxin (32). 
Specifically, continuous administration of tofacitinib to immune-competent mice by osmotic pump 
infusion (25 ug/h for 28 days) minimized the development of ADAs to repeat immunization with 
SS1P [Figure 5, copied from (32)]. These data support the hypothesis that tofacitinib could 
suppress development of ADAs in patients treated with LMB-100, allowing patient to receive an 
increased number of effective cycles of iTox treatment. 
Figure 5 
 


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1.2.10 Tofacitinib increases serum half-life, delivery to tumor and anti-tumor efficacy of co-
administered immunotoxin 
In addition to tofacitinib increasing the number of effective cycles of LMB-100 that can be given 
by limiting ADA formation, we also hypothesize that co-treatment with tofacitinib may increase 
the efficacy of each individual cycle of LMB-100 treatment. In fact, pre-clinical anti-tumor 
experiments using the KLM-1 pancreatic cancer and MDA-MB-468 breast cancer murine models 
showed that co-administration of tofacitinib enhanced anti-tumor efficacy of LMB-100 and also 
of the anti-transferrin receptor immunotoxin HB21-PE40 in mouse models (Figure 6), although 
anti-tumor activity in cultured tumor cells was not changed.  
 
Figure 6: Tofacitinib increased LMB-100 anti-tumor efficacy.  
Athymic nude mice bearing subcutaneous KLM1 pancreatic or MDA-MB-468 breast cancer were treated 
with immunotoxin LMB-100 (2.5 mg/kg) or HB21-PE40 (0.1 mg/kg) at time points indicated by arrows with 
or without tofacitinib (5 mg/kg BID).  Ns = no significance; ***p < 0.001, D. Fitzgerald lab, in press (JCI 
Insight) 
Further studies in mice demonstrated that co-administration of tofacitinib increased delivery of 
fluorescently-labeled immunotoxin to tumor cells (Figure 7) and altered immunotoxin 
pharmacokinetics to prolong serum half-life and increase immunotoxin exposure (Figure 8). The 
mechanism responsible for these changes is under investigation. 


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Figure 7: Tofacitinib increased immunotoxin delivery to cancer cells.  
Athymic nude mice bearing subcutaneous KLM1 or MDA-468 tumors were treated with the indicated 
Alexa-labeled immunotoxin (IT, 2.5 mg/kg) with or without tofacitinib (tofa). Tumors were harvested 3 
hours later, cancer cells were dissociated and incorporation of Alexa label was measured by flow 
cytometry. *p < 0.05. D. Fitzgerald lab, in press (JCI Insight) 
 
 
Figure 8: Tofacitinib prolonged immunotoxin half-life in serum.  
Athymic nude mice were administered LMB-100 (2.5 mg/kg) or HB21-PE40 (2.5 mg/kg) immunotoxin. 
Serum taken at indicated time points post-treatment was assessed by assay to determine immunotoxin 
concentration. AUC = area under the curve. N = 4 mice/ group. D. Fitzgerald lab, in press (JCI Insight). 
1.2.11 Lymphocyte signaling suppression by tofacitinib does not enhance tumor growth in 
mouse model 
Tofacitinib suppresses lymphocyte signaling by inhibiting JAKs. Lymphocyte signaling 
contributes to the anti-tumor immune response and, in fact, higher rates of non-melanoma skin 
cancers have been observed in patients with autoimmune disease receiving tofacitinib. It is 
currently not clear how long-term treatment tofacitinib impacts the growth of existing solid tumors. 
Pre-clinical studies were performed in immune competent mice to assess the effect of tofacitinib 
on tumor growth. Administration of tofacitinib to Balb-C mice bearing orthotopic 4T-1 murine 
breast cancer tumors did not increase the rate of tumor growth (Figure 9). In addition, the response 
of these tumors to anti-PD1 immune checkpoint inhibitor therapy was not impacted (Fitzgerald 
lab, unpublished, data not shown). These experiments suggest that the immunosuppression caused 
by short-term administration of tofacitinib does not enhance tumor growth. 


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Figure 9: Tofacitinib did not increase 4T-1 xenograft growth.  
Balb-C mice bearing orthotopic 4T-1 murine breast tumors were treated with tofacitinib (5 mg/kg BID) at 
days indicated by arrows. Tumor dimensions were serially measured by digital calipers. N = 10 mice/ 
group. D. Fitzgerald lab, in press (JCI Insight). 
1.2.12 Tofacitinib may increase the risk of venous thromboembolism (VTE) and overall 
mortality 
Post-marketing studies examining long-term effects of chronic daily tofacitinib use in rheumatoid 
arthritis (RA) and ulcerative colitis patients have suggested that higher dose tofacitinib (10 mg, 
BID) may increase the risk of VTE. A study of 50,865 patients in the United States observed a 
trend towards increased incidence of VTE in RA patients taking tofacitinib compared to those 
taking TNFα inhibitors that was not statistically significant (33). A similar European study (still 
ongoing and not yet published) which included 7866 RA patients with at least one risk factor for 
cardiovascular disease found that 10 mg twice daily dose of tofacitinib increased the risk of VTE 
and overall mortality in patients over age 50 compared to therapy with TNFα inhibitors. Based on 
these data, the FDA issued a warning and changed package labeling on tofacitinib in July 2019 to 
advise against the use of tofacitinib in rheumatoid arthritis patients at increased risk for VTE, like 
cancer patients. 
Pancreatic cancer is a highly pro-thrombotic malignancy. Guidelines from ASCO (American 
Society of Clinical Oncology) and the International Initiative on Thrombosis and Cancer now 
recommend routine prophylaxis against VTE in all patients with pancreatic cancer receiving 
systemic therapy who have low risk of bleeding (34,35). Prophylactic anticoagulation may also be 
recommended to cancer patients with other histologies who are receiving systemic therapy if their 
Khorana score predicting risk for chemotherapy-associated VTE in the ambulatory setting is ≥ 2 
(See Table 7). 


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Table 7: Predictive Model for Chemotherapy-Associated VTE in the Ambulatory Setting (35)  
 
1.2.13 Rationale for the combination of LMB-100 with tofacitinib  
Efficacy of LMB-100 is limited by the formation of ADAs in approximately half of patients before 
the 2nd cycle of treatment can be administered and almost all patients before a 3rd cycle. Tofacitinib 
is an FDA approved drug for the treatment of several autoimmune disorders. Based on the 
preclinical data on the combination of LMB-100 and tofacitinib described in Section 1.2.10, we 
hypothesize that co-administration of tofacitinib with LMB-100 will prevent or delay the 
formation of high titer ADAs to LMB-100, such that more than 2 effective cycles of immunotoxin 
can be administered to patients. The goal of this clinical trial is to assess the combination for 1) 
safety and tolerability and 2) immunogenicity. 
1.2.14 Rationale for use of mesothelin testing (NSR device) 
To be eligible for treatment on study, participants with tumor types other than pancreatic 
adenocarcinoma, extrahepatic cholangiocarcinoma and epithelioid subtype of mesothelioma are 
required to have positive mesothelin expression in archival tumor tissue, defined as at least 20% 
of tumor cells expressing mesothelin. Mesothelin expression testing is not FDA approved for this 
purpose; however, it is being used as an in-vitro diagnostic device. According to 21 CFR 812.3(m), 
a significant risk device presents a potential for serious risk to the health, safety and welfare of a 
subject and meets the significant risk criteria listed in the table below along with the sponsor’s 
conclusions with regard to the applicability of these criteria to the current study. The device has 
been assessed by the sponsor as non-significant risk per the below. 
 
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically confirmed solid tumor malignancy for which no 
curative therapy exists.  
2.1.1.2 Pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma or epithelioid subtype of 
mesothelioma, as determined by NCI Laboratory of Pathology, OR for all other tumor 
types, at least 20% of tumor cells must express mesothelin. Determination can be made 
using archival tumor tissue or fresh biopsy if archival tumor tissue is not available.  
2.1.1.3 All patients must have evaluable disease (i.e. measurable per RECIST 1.1. or by 
following CA19-9 tumor marker). Patients in the expansion cohort must have measurable 
disease, per RECIST 1.1. See Section 6.3 for the evaluation of measurable disease.  
2.1.1.4 Patients must have received at least one prior standard systemic treatment regimen for 
advanced disease OR be ineligible to receive available standards due to co-morbidities, 
prior toxicity, lack of standard options for tumor type, or having received all standards 
Significant Risk Criteria 
Applicable to 
current study 
Justification 
Is an implant 
No 
The mesothelin test is not introduced into the 
subject 
Is 
used 
in 
supporting 
or 
sustaining human life 
No 
The device is diagnostic 
Is of substantial importance in 
diagnosing mitigating or treating 
disease or preventing impairment 
of human health 
No 
While the device is diagnostic, we do not believe 
in presents a potential for serious risk to the health 
and welfare of the subject. The assessment of 
mesothelin positivity is only used in tumors that 
may not have a high rate of mesothelin expression 
and is assessed to help to increase the possibility 
that all persons enrolling on the study might derive 
benefit from therapy.  Persons that are deemed 
ineligible to enroll on the basis of this test may be  
eligible for studies with LMB-100 that are not 
reliant on this test.   
Otherwise poses a risk 
No 
Testing will be performed on archival samples or 
on fresh tissue that is collected at screening for 
confirmation of diagnosis.  No additional 
collection of tissue will occur for purposes of 
mesothelin testing. 


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available for prior treatment of early stage disease OR have refused first-line standard 
systemic treatment but have received prior anti-cancer treatments. 
2.1.1.5 Patients with dMMR/MSI-H disease must have received at least one prior anti-PD1 
therapy, be ineligible to receive this treatment due to concurrent medical conditions, or 
have refused this therapy. 
2.1.1.6 ECOG performance status (PS) 0-2 (Appendix A- Performance Status Criteria). 
2.1.1.7 Age >18 years. Because no dosing or adverse event data are currently available on the 
use of LMB-100 alone or in combination with tofacitinib in persons with <18 years of 
age, children are excluded from this study. 
2.1.1.8 Patients must be more than 14 days removed from most recent minor surgical procedure 
(such as biliary stenting), 28 days from most recent major surgical procedure and 14 days 
from radiation therapy, systemic treatments (such as chemotherapy), or experimental 
drug treatment. All acute toxicities from prior treatment must have resolved to grade 1 or 
less except alopecia, anemia, peripheral neuropathy, or endocrinopathies corrected by 
replacement therapy. 
2.1.1.9 Adequate hematological function: neutrophil count of  1.5  103 cells/µL, platelet count 
of  85,000/L, hemoglobin ≥ 9 g/dL  
2.1.1.10 Serum albumin ≥ 2.5 mg/dL without intravenous supplementation 
2.1.1.11 Adequate liver function: Bilirubin <2.5 x ULN for all, AST and ALT < 3 x ULN except 
for patients with significant tumor burden in their liver where AST and ALT < 5x ULN 
is acceptable in the absence of other etiologies for transaminitis 
2.1.1.12 Adequate renal function: creatinine clearance [Estimating glomerular filtration rate 
(EGFR) method or measured]  50 mL/min. Measured clearance will be used if both 
numbers are available. 
2.1.1.13 Must have left ventricular ejection fraction ≥ 50% 
2.1.1.14 Must have an ambulatory oxygen saturation of > 88% on room air 
2.1.1.15 The expansion phase patients must meet all eligibility criteria above (from 2.1.1.1 to 
2.1.1.15) AND must have diagnosis of pancreatic adenocarcinoma or extrahepatic 
cholangiocarcinoma with pathology confirmed to be consistent with one of these 
diagnoses by NCI Laboratory of Pathology. 
2.1.1.16 The effects of LMB-100 alone or in combination with tofacitinib on the developing 
human fetus are unknown. For this reason, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry until 3 months the last dose of study therapy. Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
2.1.1.17 Ability of participant to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Known or clinically suspected CNS primary tumors or metastases including 
leptomeningeal metastases as CNS penetration of LMB-100 is expected to be poor. CNS 


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metastases are permitted if they have been previously treated, are asymptomatic, and have 
had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days. 
2.1.2.2 Evidence of significant, uncontrolled concomitant diseases which could affect 
compliance with the protocol or interpretation of results, including significant pulmonary 
disease other than that related to the primary cancer, uncontrolled diabetes mellitus, 
and/or significant cardiovascular disease (such as New York Heart Association Class III 
or IV cardiac disease, myocardial infarction within the last 6 months, unstable 
arrhythmias, unstable angina, or clinically significant pericardial effusion).  
2.1.2.3 Any known diagnoses, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition (other than 
mesothelin [+] cancer diagnosis) that would contraindicate the use of an investigational 
drug, interfere with tumor measurement or lead to a life expectancy of less than 6 months 
as judged by the investigator. 
2.1.2.4 Contraindication to receiving prophylactic doses of low-molecular weight heparin 
(LMWH) or direct oral anticoagulants (DOAC) such as current active bleeding (except 
for grade 1 hematuria or epistaxis), recent history of significant bleeding without 
subsequent effective medical or surgical intervention, known history of gastric varices, 
uncontrolled malignant hypertension, history of coagulopathy that confers increased risk 
of bleeding. Patients on concurrent treatment with anti-platelet agents such as aspirin or 
clopidogrel are eligible if deemed to have acceptable risk of bleeding in consultation with 
Hematologist. Patients already receiving prophylactic or therapeutic doses of 
anticoagulant (heparin-based or DOAC) for at least 4 weeks with no indication of 
significant bleeding while on therapy are considered NOT to have a contraindication to 
this therapy. 
2.1.2.5 Inability to administer or unwillingness to comply with recommended VTE prophylaxis 
for the duration of study treatment. 
2.1.2.6 Prior diagnosis of hematologic malignancy 
2.1.2.7 Active or uncontrolled infections (including tuberculosis, HIV, HBV, or HCV) or 
reasonable clinical suspicion of an active infection (such as cholangitis) as tofacitinib 
suppresses lymphocyte signaling and will impair host response to infection 
2.1.2.8 Latent TB infection as identified by interferon-ɤ release assay (IGRA).  If IGRA is 
indeterminate, tuberculin skin test (TST) may be used to determine status. 
2.1.2.9 Live attenuated vaccinations within 14 days prior to treatment. 
2.1.2.10 Use of a strong inhibitor or inducer of CYP3A4 within 14 days prior to enrollment (see 
Flockhart Table (https://drug-interactions.medicine.iu.edu/Clinical-Table.aspx) or 
similarly updated source for a list of such agents) 
2.1.2.11 Inability to take or digest oral medication. 
2.1.2.12 Dementia or altered mental status that would prohibit informed consent. 
2.1.2.13 Pregnant women are excluded from this study because the effects of LMB-100 and/or 
tofacitinib on the developing fetus are unknown and may have the potential to cause 
teratogenic or abortifacient effects. Because there is an unknown but potential risk for 
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and/or tofacitinib, breastfeeding should be discontinued if the mother is treated with either 
of these agents.   
2.1.2.14 Baseline QTcF interval of > 470 ms, participants with baseline resting bradycardia < 45 
beats per minute, or baseline resting tachycardia >100 beats per minute. 
2.1.2.15 Participants with contra-indication and/or history of severe hypersensitivity reactions to 
any components related to LMB-100 and tofacitinib.  
2.1.2.16 Patients who have previously received LMB-100 (and therefore have high-levels of pre-
existing ADA’s to drug) 
2.1.3 Recruitment Strategies 
Information about the study will be posted on sites such as clinicaltrials.gov and the CCR 
recruitment website. Information about the trial will also be distributed on NIH social media 
platforms.  Subjects will also be drawn from patients seen in OP12 Medical Oncology clinic at the 
NIH Clinical Center as well as from referrals from outside providers.  
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.  
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
o Archival tumor sample for NCI Laboratory of Pathology confirmation of diagnosis. 
A block of primary tissue (or 10 unstained sections on charged slides) from the time 
of diagnosis will be required from each participant. Tissue blocks from a known 
recurrence will be accepted if original tumor samples are unavailable. Referring 
institutions will send the tumor block or 10 unstained sections on charged slides to 
CCR/NCI for correlative studies and confirmation of diagnosis. A fresh biopsy may 
be collected if tumor tissue is not available. 
2.2.2 Screening activities performed after a consent for screening has been signed 
For patients  requiring testing for MSLN expression (see Section 2.3.1), screening will occur on 
this study. For all other subjects, screening will occur on study 01-C-0129.  
The following activities will be performed only after the subject has signed the appropriate consent 
for screening. They will be performed within 28 days before registration for study treatment unless 
specified: 


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• Assess tumor MSLN expression by immunohistochemistry analysis in archival tissue or 
fresh biopsy samples ONLY for patients who do not have a diagnosis of epithelioid 
mesothelioma, extrahepatic cholangiocarcinoma or pancreatic adenocarcinoma. 
• Medical History and physical exam  
• Vital signs including ambulatory oxygen saturation by pulse oximetry 
• ECOG performance status 
• Pregnancy test in women of childbearing potential (within 7-days prior to initiation of study 
therapy) 
• ECG 
• Echocardiogram 
• CT scan of chest, abdomen and/or pelvis and areas of known or suspected disease 
involvement; MRI and/ or PET scan may also be performed when appropriate per PI 
discretion. 
• CBC with differential, Acute Care Panel (sodium, potassium, chloride, bicarbonate, 
creatinine, glucose, BUN), Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, 
direct bilirubin), Mineral Panel (albumin, calcium, magnesium, phosphorus), creatine 
kinase, C-reactive protein, 1,25-dihydroxy vitamin D, Coagulation (PT, PTT), lactate 
dehydrogenase 
• CA 19-9 serum tumor marker for pancreatobiliary cancer patients, or other appropriate 
tumor marker in other tumor types  
• Testing for HIV, HCV, HBV: anti-HIV antibody, Anti-HCV Antibody, HBs Ag Screening  
• Screening for latent tuberculosis by interferon-ɤ release assay: QuantiFERON-TB Gold 
Plus or similar 
• Urinalysis 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
2.3.1 Subjects that require pre-screening for MSLN 
Participants that do not have pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma or 
epithelioid mesothelioma must undergo pre-screening for MSLN expression.  
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
 


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2.4 
TREATMENT ASSIGNMENT PROCEDURES 
Cohorts 
Number Name 
Description 
1 
Dose Escalation 
1-6 patients per level x2 dose levels 
2 
Dose Expansion 
Up to 15 additional eligible and evaluable patients will 
be treated to assess the safety of optimal dose for 
patients with pancreatic cancer or extrahepatic 
cholangiocarcinoma 
Arms 
Number Name 
Description 
1 
Dose Escalation 
LMB-100 (escalating doses) + tofacitinib for 3 cycles 
2 
Dose Expansion 
LMB-100 + tofacitinib (at dose determined in dose 
escalation portion of the study) for 3 cycles. At least 8 
subjects must have PDAC. 
Arm Assignment 
Patients in Cohort 1 will be directly assigned to Arm 1. Patients in Cohort 2 will be directly 
assigned to Arm 2. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
Schema 
• This is a Phase I study which will accrue up to 45 participants.  
• Participants will be admitted to the NIH Clinical Center for LMB-100 administration.   
• For the dose escalation phase, a 3+3 dose escalation will be used. Two dose levels are 
planned. A minus dose level could be utilized if de-escalation is necessary. 
• Following identification of an optimal dose and schedule, an expansion phase of 15 
participants will be initiated at the optimal dose for patients with pancreatic 
adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the 
expansion phase must have pancreatic adenocarcinoma. 
• Participants on the Dose Escalation and Dose Expansion Arms will be treated for a 
maximum of 3 cycles with the exception described in the next bullet  
• Participants on the Dose Escalation and Dose Expansion Arms who appear to be deriving 
clinical benefit may continue to receive treatment beyond 3 cycles as indicated in Section 
Error! Reference source not found.. 


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• Toxicities and adverse events will be monitored continuously during treatment and for 30 
days beyond the last treatment. 
3.1.1 Dose Limiting Toxicity 
For the study, a DLT will be defined as any of the following events occurring during the first cycle 
of treatment (21 days), the DLT evaluation period. Toxicities determined to be unequivocally 
related to disease progression or intercurrent illness will not be regarded as DLTs. The following 
will be considered DLTs: 
• Any death not clearly due to the underlying disease or extraneous causes 
• Transaminitis that meets criteria for Hy’s Law: grade ≥2 elevation of AST or ALT with 
simultaneous elevation of total bilirubin to ≥ 2x ULN while alkaline phosphatase remains 
< 2x ULN. 
Hematological toxicities: 
• 
Grade 4 neutropenia (i.e. absolute neutrophil count (ANC) <0.5 x 103 cells/µL for a 
minimum duration of 7 days) 
• 
Grade 3 and 4 febrile neutropenia (i.e. ANC < 1.0 x103 cells/µL with a single temperature 
of >38.3°C or a sustained temperature of ≥38°C for more than one hour; or life-
threatening consequences with urgent intervention indicated) 
• 
Grade 4 thrombocytopenia (≤25.0 x103 cells/µL) 
• 
Grade 3 thrombocytopenia associated with bleeding episodes 
• 
Grade 4 anemia 
Grade ≥ 3 non-hematological toxicity with the exception of: 
• 
Grade 3 nausea and vomiting lasting <48 hours occurring in the absence of appropriate 
anti-emetic treatment 
• 
Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration 
• 
Infusion-related reactions up to and including Grade 3. IRRs are not considered to be 
DLTs since, based on experience with monoclonal antibodies, they are idiosyncratic and 
not dose-related events. Precautions will be taken if IRRs Grade ≥2 occur (see Section 
3.3).  
• 
 
Asymptomatic grade 3 elevation of ALT, AST, GGT, bilirubin or alkaline 
phosphatase attributable to study drug that persists for less than 7 days if not violating 
Hy’s Law. (Please note that all grade 4 elevations in these parameters should be 
considered a DLT)  
• 
 
Asymptomatic laboratory values (other than ALT, AST, GGT, bilirubin, alkaline 
phosphatase or creatinine) of Grade 3 that are judged not clinically significant by the 
investigator.  
• 
 
Isolated Grade 3 fever (without signs and/or symptoms of an infection) 
occurring within 48 hours after LMB-100 infusion and resolving within 48 hours to ≤ 
Grade 2 and fully resolved within 1 week. 


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Other toxicities: 
• 
Any other drug related toxicity considered significant enough to be qualified as a DLT in 
the opinion of the principal investigator. 
• 
Inability to start cycle 2 within 2 weeks after completing cycle 1 due to drug-related 
adverse events. 
If a participant experiences a DLT of any grade, the investigator will have the option to either stop 
treatment or to resume the treatment at the next lowest dose level based on best clinical judgment. 
Patients will be assessed based on the original cohort. This can be done to allow participants who 
could potentially benefit from LMB-100 to remain on the study drug treatment, if considered the 
most beneficial therapeutic option for the participant while managing and monitoring the 
participant’s safety risks. 
3.1.2 Dose Schedule  
The dose schedule is outlined below in Table 8. Patients will be enrolled as per standard 3+3 
design, if 0 of 3 or <2 of 6 patients experience DLT then dose escalation may proceed. If 2 or more 
patients experience DLT at any dose level, then dose de-escalation is required. 
The rule by which clinical team will decide when to escalate or de-escalate have been explained 
in Table 9.  
 
Table 8 
Dose Level 
LMB-100 infusion (mcg/kg) 
Given days 4, 6, 8 
Level -1 
65 
Level 1 
100 
Level 2 
140 
Note: A weight-based dose cap will be applied. LMB-100 dose for patients weighing more than 
100 kg will be calculated as if they weigh 100kg. 
*All patients will receive tofacitinib 10 mg BID on days 1-10 of each cycle 
Dose escalation will follow the rules outlined in Table 9. 


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Table 9 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped. This dose level will 
be declared the maximally administered dose (highest 
dose administered). Up to five additional patients will 
be entered at the next lowest dose level to complete a 
max cohort of 6. 
1 out of 3 
Per PI discretion, follow instructions for ≥ 2 DLT OR 
Enter up to 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed 
to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  UP to five 
additional patients will be entered at the next 
lowest dose level to complete a max cohort of 6. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended 
phase 2 dose. At least 6 patients must be entered at the 
recommended phase 2 dose. 
3.1.3 Treatment Extension 
Participants who complete 3 cycles of therapy with LMB-100/tofacitinib and appear to be deriving 
clinical benefit as evidenced by lack of progression on CT scan and decreasing serum tumor 
marker (in patients with serum tumor marker that has historically followed their disease trend) 
may continue to receive additional cycles of treatment at the discretion of the PI until unacceptable 
toxicity or patient is no longer thought to be benefiting, or PI’s decision to discontinue treatment. 
If a participant is offered treatment extension but refuses, he/she will be removed from protocol 
therapy. Participants offered treatment extension may defer immediate treatment with study drugs 
to take a treatment holiday or to receive other intervening treatments (including investigational 
treatments). If a participant chooses to defer treatment extension beyond 6 weeks or to have a 
different intervening therapy, the PI may require to repeat some screening safety evaluations 
before reinitiating LMB-100/tofacitinib and will require washout periods and criteria consistent 
with those described in Sections 2.1.1.8, 2.1.1.9 and 2.1.1.10. Safety monitoring while receiving 
treatment extension will continue as described in the Study Calendar. Limited research labs will 
be taken as described in Sample Collection Schedule (Section 5.2). 


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3.2 
DRUG ADMINISTRATION 
Appendix B-Model chemotherapy note provides a sample chemotherapy note describing the 
regimen. 
3.2.1 Tofacitinib 
Tofacitinib will be administered orally twice daily on days 1 -10 of each cycle by the participant 
while at home and by nursing if the participant is admitted to the inpatient unit. A diary (see 
Appendix C- Patient Medication Diary) will be kept to document dose, date and time of day the 
drug was dosed. If a participant vomits after taking tofacitinib, then no action is required; the 
participant should simply take the next dose of tofacitinib as scheduled. If a participant omits/ 
skips a dose, the participant should take the dose as soon as possible and contact the study team 
for instruction on when to administer the next dose.  
3.2.1.1 VTE prophylaxis for patients receiving tofacitinib 
VTE prophylaxis will be provided to all patients on study who are not already on treatment with 
appropriate anticoagulant (note that Vitamin K inhibitors are NOT considered appropriate therapy 
in this patient population) as per criteria below: 
Patients with Khorana Score < 2 will receive enoxaparin 40 mg subcutaneous daily beginning Day 
1 and continuing until 24 hrs after the last dose of tofacitinib for each cycle (Day 11 unless 
tofacitinib is discontinued early). Patients with contraindication to enoxaparin (e.g. prior history 
of heparin-induced thrombocytopenia or inability to perform subcutaneous injection) may instead 
receive another regimen (see Table 10). 
Patients with Khorana Score ≥ 2 (including all pancreatic cancer and extrahepatic 
cholangiocarcinoma patients) will be initiated on prophylactic anticoagulation therapy throughout 
treatment (from Cycle 1 Day 1 until 14 days post the last dose of the study medications tofacitinib 
and LMB-100) as per ASCO guidelines (35). List of appropriate therapies for prophylaxis that are 
on CCR formulary are shown below in Table 10 . Choice of therapy should be based upon patient 
preference, concurrent medications, bleeding risk/ tumor type, renal function, and ability to take 
and digest oral medication. 
Table 10: Prophylaxis for VTE in Ambulatory Cancer Patients Receiving Outpatient or 
Inpatient Systemic Therapy (Khorana Score ≥ 2) 
enoxaparin 
40 mg subcutaneous injection once daily 
rivaroxaban 
10 mg by mouth once daily 
apixaban 
2.5 mg by mouth twice daily 
3.2.2 LMB-100 
The qualified health care professional responsible for dispensing the study drug will prepare the 
correct dose according to the cohort or group allocation of each participant.  
LMB-100 will be given as a ~30-minute infusion on days 4, 6 and 8 (QOD x3) each 21-day cycle. 


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LMB-100 must be administered in a hospital or clinic equipped for IV chemotherapy. Full 
emergency resuscitation facilities should be immediately available, and participants should be 
under close supervision of the investigator or delegate at all times. For this study, participants will 
be admitted to the NIH Clinical Center for LMB-100 administration. 
The compatibility and stability of the active ingredient was tested under simulated 
preparation/administration conditions. 
3.2.2.1 General Instructions 
1. LMB-100 drug product should be inspected visually for particulates prior to 
administration. 
2. Do not use the solution if there is particulate matter or if it is discolored. 
3. Do not shake or freeze the vial contents. 
4. Ensure the drug vial content is protected from light during preparation and administration 
(ambient light conditions are acceptable but avoid exposure to direct sunlight). 
5. LMB-100 drug product does not contain any preservatives. Vials are for single use only 
and partially used vials must not be reused.   
6. Any unused product should be kept for drug reconciliation. 
7. No dilution of LMB-100 drug product into 0.9% saline bags should be performed. 
8. Do not administer as IV push or bolus. 
9. Other drugs that require parenteral co-administration (if applicable) should be delivered 
via separate infusion lines and at separate infusion sites and should not be mixed with the 
study drug. 
3.2.2.2 Specific Instructions  
LMB-100 is diluted with 0.9% Sodium Chloride Injection, USP (0.9% NaCl) in-line immediately 
prior to administration (see Figure 10 below).  
The undiluted LMB-100 drug product (DP) is administered by intravenous infusion using a 
disposable syringe and syringe driver pump. So as not to compromise drug product physico-
chemical stability, dilution with 0.9% NaCl will be done in-line, immediately prior to 
administration of the neat DP. 
In order to allow in-line dilution (1:10) immediately prior to administration of neat drug product, 
a side flow with 0.9% NaCl must be applied (as illustrated in Figure 10).   
The pump used to administer 0.9% NaCl will be programmed at 9-times the hourly rate of LMB-
100 in order to deliver LMB-100 at a concentration of 0.1 mg/mL. An IV infusion pump and 
syringe driver should be used to control the infusion rates for 0.9% NaCl solution and LMB-100, 
respectively.   
LMB-100 is administered either peripherally or centrally through a patient’s vascular access 
device. If there is no pre-existing central vascular access device and peripheral access is 
inadequate, a central access device will be installed.  


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1. The syringes for administration must be prepared under appropriate aseptic conditions as 
LMB-100 drug product does not contain antimicrobial preservatives. All preparation 
should be conducted within a biological safety cabinet with appropriate personal protective 
garb to contain and minimize exposure to the drug product under conditions of inadvertent 
release.  
2. Transfer from LMB-100 product vials to a syringe a volume of LMB-100 appropriate for 
a patient’s dose PLUS 3 mL excess volume to prime the extension tubing and filter set that 
will be attached to the syringe (see step 3). 
3. Attach to the syringe (first) an extension tubing set (e.g., medex REF MX448HL60) and 
(second) a filter set with pore size within the range of 0.2- to 0.22-μm (e.g., medex REF 
MX448HF). The syringe with extension set and filter set attached is “the syringe 
assembly”. 
4. Prime the syringe assembly tubing with LMB-100 from the syringe and cap it with a 
closing cone/stopper (e.g., Spinning Spiros® connector or comparable closed system 
transfer device cap). 
5. The syringe assembly should be stored under refrigeration (2°– 8°C; 35.6° – 46.4°F) until it 
is used. 
6. Chemical and physical in-use stability for LMB-100 drug product in syringes has been 
demonstrated for 24 hours at 2°–8°C and 24 hours at ambient temperature (not >25°C; 77°F). 
The LMB-100 drug product does not contain antimicrobial preservatives; LMB-100 solution 
will be transferred to syringes under appropriate aseptic conditions and should be used 
immediately. If not used immediately, total in-use storage times of prepared syringes for 
infusion should not exceed 24 hours when stored under refrigeration. 
7. Attach (spike) the 0.9% NaCl container (bag) with an administration set. Attach the distal 
end of the administration set to the most distal port on a 4-way stopcock (or two 3-way 
stopcocks connected end-to-end), and prime the tubing and stopcock with 0.9% NaCl. 
8. Attach the stopcock to the patient’s vascular access device. 
9. Undiluted LMB-100 will be filtered during administration before it is diluted in-line with 
0.9% NaCl (see Figure 10). Place the syringe containing LMB-100 in the pre-programmed 
syringe driver, remove any caps or closures from the end of the syringe assembly and attach 
the syringe assembly tubing to the stopcock/manifold at the port closest to a patient’s 
vascular access device. 
10. Start the pump driver for 0.9% NaCl to establish line patency and unimpeded flow 
BEFORE starting to administer LMB-100 with the syringe pump. 
11. When 0.9% NaCl flow is established, start the syringe pump to administer LMB-100. 
12. The end of infusion is defined as the time point at which the syringe driver finishes 
administering the total volume of LMB-100 to be infused.  
13. In case of any adverse events related to the infusion, please refer to the specific 
recommendation described in Section 3.3.1.  


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14. The line for drawing blood for LMB-100 PK samples should be placed in the opposite 
extremity from the one with the infusion line in patients who do not have a mediport. 
3.2.2.3 Monitoring 
Vital signs (including, if possible, supine diastolic and systolic blood pressure, pulse rate, and 
temperature) must be monitored pre-infusion, every 15 minutes (± 5 minutes) until the end of the 
infusion, and at 30, 60 and 120 minutes (±15 minutes) from the end of the infusion (EOI). Vital 
signs pre-infusion, EOI, and 120 minutes post-EOI must be captured in the eCRF. Other vital signs 
measurements are not required to be captured in the eCRF unless abnormalities are observed. 
3.2.2.4 Standard Pre-medication for Participants Receiving LMB-100 
Due to the prevalence of infusion related reactions (IRRs) seen in previous studies of LMB-100, 
all patients will be pre-medicated prior to each LMB-100 administration with the following 
medications: 
o Diphenhydramine 25-50 mg PO or IV 
o Ranitidine 150 mg PO 
o Acetaminophen 650 mg PO 
Dexamethasone 8 mg IV PRN (when necessary) should be physically available in the infusion unit 
in case of severe IRR during LMB-100 administration.   
Note: An alternative histamine H2 antagonist may be substituted for PO ranitidine such as IV 
ranitidine or famotidine 20 mg PO or IV if the preferred pre-medication is unavailable.  
Pre-medication should be given 30-60 minutes prior to LMB-100 infusion. 
3.2.2.4.1 Additional Precautions for administration of LMB-100 in patients with IRR during 
LMB-100 
Participants receiving LMB-100 who have experienced an IRR of Grade 2 to 4 during a previous 
infusion despite standard pre-mediation should also receive: 
o Dexamethasone 8 mg IV, or equivalent dose of another corticosteroid as clinically 
indicated 
(See Section 3.3.1 for complete instructions on response to IRRs) 
Participants who experienced an IRR of Grade 3 or 4 where dexamethasone or another steroid was 
pre-administered should not receive further LMB-100 and will be discontinued from study therapy. 


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Table 11. Pre-medications for LMB-100 
Dose (mg) 
Route 
Acetaminophen 
650 
PO 
Diphenhydramine 
25-50 
PO or IV 
Ranitidine# 
150 
PO 
Dexamethasone* 
8 
IV 
*Given only in case of prior IRR 
# IV ranitidine or famotidine 20 mg PO or IV are allowed if the preferred pre-medication is 
unavailable. 
 


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3.2.3 Schematic view of the administration set-up 
Figure 10 
 
3.3 
DOSE MODIFICATIONS 
3.3.1 LMB-100 
LMB-100 infusion may be held for up to 48 hours due to drug-associated toxicity or adverse events 
from other intercurrent medical conditions (such as primary cancer diagnosis) that resolve with or 
without medical intervention to grade 1 or less within this time frame. Toxicities for which further 
LMB-100 treatment should NOT be given are stated below in Table 12, which also provides 
guideline on how to manage some toxicities anticipated with LMB-100.  
 
 


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Table 12. Guidelines for Managing LMB-100 Adverse Events 
Event 
Action to Be Taken 
IRR/hypersensitivity 
reaction 
during administration of LMB-100  
 
If an IRR/hypersensitivity develops, the infusion of LMB-100 
should be temporarily interrupted. The participant should be 
monitored until complete resolution of the symptoms and treated as 
clinically indicated. Treatment or concomitant medication may 
include IV saline, oxygen, bronchodilators, corticosteroids, and 
vasopressors depending on the symptoms. 
 
If the infusion is interrupted: 
• In the event of IRR CTCAE Grade1, upon resolution of 
symptoms, the infusion will resume at the rate being used at the 
time that the IRR occurred 
• In the event of IRR Grade 2 or 3, upon resolution of symptoms, 
the infusion will resume at one-half the previous rate.  
• In the event of IRR CTCAE Grade 3 or Grade 4 (which may 
include pulmonary or cardiac events) or an anaphylactic reaction, 
the infusion should not be restarted, and the participant should 
receive aggressive treatment 
• Participants experiencing IRR CTCAE Grade 4 or anaphylaxis 
must be permanently discontinued from study treatment 
 
For participants receiving LMB-100 who previously experienced 
IRR CTCAE ≥ Grade 2, the infusion rate for subsequent LMB-100 
infusion should be reduced to one-half of the previous rate and 
corticosteroids premedication should be given 30 minutes prior to 
infusion in addition to standard pre-medications: 
o Dexamethasone (20 mg PO 6 -12hrs before infusion or 8 
mg IV, 30 – 90 min before infusion) or equivalent dose of another 
corticosteroid as clinically indicated  
Capillary leak syndrome (CLS)  
 
For Grade 1-3 Capillary leak 
syndrome, the symptoms that 
make up this syndrome will be 
recorded separately, instead of 
classifying them as CLS.  
 
If the PI determines that the 
symptoms meet the definition of 
Grade 4 or 5 CLS, they will be 
recorded separately and CLS 
Grade 4 or 5 will also be recorded. 
In the event of Grade 4 CTCAE capillary leak syndrome (urgent 
intervention indicated): 
o 
Vasopressor support (e.g., phenylephrine) if indicated to 
stabilize blood pressure 
o 
Administer colloidal solutions (e.g., albumin) if there is a 
clinically significant, symptomatic and persistent systolic 
blood pressure drop, urine output significantly declines, or 
serum albumin falls to 2.5 mg/dL or lower 
o 
For pulmonary congestion provide diuretic and/or albumin 
treatment as appropriate 
o 
Progressive shortness of breath may require endotracheal 
intubation or drainage of a pleural effusion 
o 
For oliguria and /or rising serum creatinine level delay LMB-
100 if Grade 3 urine output decrease (<10 mL/hr) 


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Event 
Action to Be Taken 
o 
Use dopamine if participant is unresponsive to or unable to 
tolerate fluids  
o 
Manage pericardial effusion as outlined in section on 
“Inflammatory reactions to serosal membranes” below 
Inflammatory reactions to serosal 
membranes  
o 
Hydrocortisone (200 mg IV) or a glucocorticoid equivalent 
as clinically indicated 
o 
In the event of Grade ≥2 CTCAE pericardial effusion 
(asymptomatic effusion small to moderate size), consider 
delaying LMB-100 administration. In the event of Grade ≥3 
CTCAE pericardial effusion (effusion with physiologic 
consequences) permanently discontinue LMB-100 treatment. 
Consult 
cardiology 
service 
for 
management 
recommendations which may include pericardial drainage. 
o 
In the event of pleuritis resulting in mild to severe pleuritic 
pain, treat with analgesics or steroids as clinically indicated 
o 
For participants who have previously experienced pleuritis 
consider administration of dexamethasone 4 mg, PO bid 
beginning with first LMB-100 infusion and completing 24 
hours after the last LMB-100 infusion of the cycle. (If 
participant is already receiving corticosteroids at dose and 
schedule at or above this amount as part of the pre-medication 
regimen, do not give additional steroids for pleuritis) 
Dehydration 
Encourage participants to maintain oral hydration (~1.5 L/ day) 
Nausea 
Ondansetron or another anti-emetic should be available as needed 
Renal toxicity 
In the event of Grade 1 or greater renal toxicity consider increasing 
oral or intravenous hydration, and consider delaying LMB-100 
administration by up to 48hrs. 
In the event of Grade 2 or greater renal toxicity hold LMB-100 
administration until recovery to Grade 1 or better.  If this does not 
occur within 48hrs, no further LMB-100 should be given during the 
cycle.  
IRR = infusion related reaction; IV = intravenous; CTCAE = Common Terminology Criteria for Adverse 
Events 
3.3.2 Dose Adjustment of tofacitinib 
Tofacitinib dose should be reduced for infection, hepatic impairment, myelosuppression or other 
events as per package insert. Dose modifications will be based on the package insert 
recommendations for ulcerative colitis and should be followed for renal impairment, hepatic 
impairment, lymphopenia, neutropenia, anemia, and in patients taking strong or moderate 
CYP3A4 inhibitors (as can be found here: Flockhart Table or in another frequently updated 
source). 


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Abbreviated Title: LMB100 + tofacitinib in PDA 
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If VTE prophylaxis medication is missed or held for more than 3 days (e.g. in case of renal 
impairment or procedure like tumor biopsy), then tofacitinib should be held until anticoagulation 
can be restarted. 
3.3.3 Schedule Modifications When Study Drugs must be Held 
If a patient begins treatment with tofacitinib but is unable to receive any planned dose of LMB-
100 on schedule due to medical or other complications unrelated to tofacitinib treatment: 
• For delays in LMB-100 administration anticipated to be ≤ 48 hrs, tofacitinib should be 
continued. LMB-100 administration should resume within the 48-hour window. 
Tofacitinib treatment should be extended so that patients continue to receive tofacitinib 
treatment for two days beyond the last LMB-100 infusion 
• For delays lasting or anticipated to last >48hrs, tofacitinib treatment should be stopped. 
When tofacitinib is stopped mid-cycle due to medical or other complications related or unrelated 
to tofacitinib: 
• If any LMB-100 was administered, the remaining doses of LMB-100 may be given with 
or without restart of tofacitinib, per investigator’s discretion. If tofacitinib is restarted, it 
should be continued for two days beyond the last LMB-100 infusion 
If no LMB-100 was administered, the cycle is aborted. Patients have 4 weeks from the date of the 
last tofacitinib dose to restart (from Day 1) the planned schedule for the cycle. No more than 2 
cycles may be aborted and restarted. If Cycle 1 treatment is aborted and baseline imaging studies 
to assess tumor burden (CT CAP or other) were performed >28 days before cycle restart, then 
baseline imaging studies should be repeated prior to first LMB-100 dose of the restarted cycle. 
Baseline tumor biopsy should not be repeated. 


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3.4 
STUDY CALENDAR 
Unless otherwise specified, screening assessments must occur within 28 days prior to registration for study treatment.  Cycle 1, day 1 
assessments may occur up to 7 days prior to treatment initiation. If screening tests were performed within this window, then they 
do not need to be repeated on C1D1. Dosing cycles may be delayed for up to one week or started up to 2 days early to accommodate 
schedule conflicts, federal holidays and inclement weather, etc. They may be delayed for up to two weeks due to toxicity. There is no 
time limit on dosing cycle delays for patients receiving treatment extension. 
 
Procedure 
Screening 
All Cycles (21 days) 
 
 
 
Post Therapy 
Day 1 
Day 3* 
Day 4 
Day 6 
Day 8 
Day 9 
Day 15 
Day 21 
Safety 
Follow 
Up 
Visit7 
Long 
Term 
Follow 
Up11 
Tofacitinib 
 
administered BID days 1-10 of each cycle 
 
 
 
 
Prophylactic anti-
coagulation 
 
Khorana Score < 2: administer daily on days 1-11 of each cycle 
Khorana Score ≥ 2: administer throughout treatment until 14 days after 
last dose of tofacitinib/ LMB-100 
 
 
 
LMB-100 
 
 
 
X 
X 
X 
 
 
 
 
 
History and PE 
X 
C1 only 
X 
 
X 
X 
 
 
 
X 
 
Weight 
 
 
X 
 
X 
X 
C1 only 
 
 
X 
 
Height 
 
 
C1 only 
 
 
 
 
 
 
 
 
Vital signs1 
X 
C1 only 
X 
X 
X 
X 
C1 only 
 
 
X 
 
ECOG Performance 
Status 
X 
C1 only 
X 
 
 
 
 
 
 
X 
 
Labs2 
X 
C1 only 
X 
 
X 
X 
 
C1 
only14 
C1 
only14 
X 
 
D-dimer 
 
C1 only 
X 
 
 
X 
 
 
 
 
 
Cholesterol Panel 
 
C1 only 
 
 
 
 
 
 
 
X 
 
TBNK 
 
C1 only 
C1 and 
C3 only 
 
 
 
C1 only 
 
 
 
 
1,25-dihydroxy Vit D 
X 
 
 
 
 
 
 
 
 
X 
 


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Procedure 
Screening 
All Cycles (21 days) 
 
 
 
Post Therapy 
Day 1 
Day 3* 
Day 4 
Day 6 
Day 8 
Day 9 
Day 15 
Day 21 
Safety 
Follow 
Up 
Visit7 
Long 
Term 
Follow 
Up11 
Hepatitis and HIV 
screening panel 
X 
 
 
 
 
 
 
 
 
 
 
IGRA  
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
X 
X 
 
 
 
X 
 
Urine albumin and 
creatinine 
C1 only 
 
C1 only 
 
C1 
only 
C1 
only 
 
 
 
 
 
Pregnancy test3 
X 
 
X 
 
 
 
 
 
 
 
 
Confirmation of Dx4 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of tumor 
MSLN expression4, 5 
X 
 
 
 
 
 
 
 
 
 
 
CT CAP and/or MRI8 
X 
After 3 cycles of study treatment (from 7 days 
post-treatment completion) 
 
 
 
X 
X 
CA 19-9 or appropriate 
tumor-specific marker5 
 
 
X 
 
 
 
 
 
 
X 
 
Doppler U/S of 
bilateral lower 
extremities 
 
Optional15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
C1 only 
 
 
C1 
only 
 
 
 
X 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Ambulatory Oxygen 
Saturation 
X 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
 
 
X9 
 
 
 
 
 
 
 
 
NIH Advance 
Directives Form6 
 
C1 only6 
 
 
 
 
 
 
 
 
 
Biopsy  
X13 
C1 only12 
C2 
only12 
 
 
 
 
 
 
 
 


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Procedure 
Screening 
All Cycles (21 days) 
 
 
 
Post Therapy 
Day 1 
Day 3* 
Day 4 
Day 6 
Day 8 
Day 9 
Day 15 
Day 21 
Safety 
Follow 
Up 
Visit7 
Long 
Term 
Follow 
Up11 
PKs 
Please refer to Section 5.2 
 
 
 
 
 
Correlative Studies  
Please refer to Section 5.2 
 
 
 
 
 
Annual phone call to 
monitor survival and 
additional CA therapy 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events10 
  
 
 
Monitored continuously 
 
Concomitant meds 
  
 
 
Monitored continuously 
 
 
*If not performed on day 3, may be performed on day 4 prior to the start of LMB-100 infusion 
1 
Vital signs including temperature, blood pressure, pulse rate, and oxygen saturation should be recorded on the 
indicated days. In addition, systolic blood pressure, pulse rate, and oxygen saturation must be monitored pre-
infusion, every 15 minutes (± 5 minutes) during the infusion, at end of infusion (EOI), then 30, 60 and 120 
minutes (±15 minutes) following EOI.  
2 
CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, C-reactive protein (CRP), Creatine 
Kinase (CK), PT, PTT, LDH. PT and PTT will be done only at the time of screening, Day 1 of each cycle, and 
within 24hrs prior to biopsies (if biopsy will be performed). 
3 
Pregnancy test required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years 
after menopause (menopause is defined as amenorrhea for > 2 years) 
4 
Assessment may occur at any time prior to enrollment 
5 
Applicable only to patients on dose escalation with tumor types other than pancreatic adenocarcinoma, 
extrahepatic cholangiocarcinoma, or epithelioid subtype of mesothelioma  
6 
As indicated in Section 11.3, all subjects will be offered the opportunity to complete an NIH advanced 
directives form. This should be done preferably prior to beginning treatment but can be done at any time during 
the study as long as the capacity to do so is retained. The completion of the form is strongly recommended but 
is not required. 
7 
Safety follow up will occur 3 – 6 weeks after last dose of study therapy. If the patient is unable to return to the 
clinic for the follow up visit, an adverse event assessment will be performed by telephone. 


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8 
Scans, every ~9 weeks, will only be performed until disease progression. Note: for patients on long term follow 
up, scans may be performed outside of NIH. Gadolinium will be used for MRI in patients where MRI is 
required. 
9 
Chest x-ray on cycle 1 only for patients with existing mediport. Chest x-ray is required with each cycle to 
confirm placement of a central line if placement is required for drug administration. 
10 Adverse events will be monitored continuously for 30 days beyond the last treatment.  
11 Study visits after safety follow up visit will be encouraged but not required. Only patients who are removed 
from study therapy for reasons other than disease progression will be invited to return to clinic (approximately 
every 6 weeks) for the indicated scans and labs until disease progression.  All patients will be followed until 
death through phone contact for overall survival.   
12 Optional at cycle 1 day 1 and cycle 2 day 3.  
13 Only if archival tumor tissue is not available 
14 +/- 1 day 
15 Should not be performed in patients on daily systemic anticoagulation prior to study enrollment / start. May be 
performed up to 14 days before or 3 days after cycle 1 day 1. 
 


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3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit as 
indicated in the Study Calendar following the last dose of study therapy.  Criteria for removal 
from protocol therapy 
• Completion of study therapy 
• Progressive disease 
• Participant requests to be withdrawn from active therapy 
• Pregnancy 
• Unacceptable Toxicity as defined in Sections 3.1.1 and 3.3 
• Requirement for any of the prohibited medications listed in Section 4.1.2 
• Investigator discretion 
3.5.1 Off-Study Criteria 
• Completed study follow-up period 
• Decision to end the study 
• Participant requests to be withdrawn from study 
• Death 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1.1 Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter (OTC) 
drugs, approved dietary and herbal supplements, nutritional supplements) used by a participant 
from the screening period until the follow-up visit. If any treatment is given within 4 weeks prior 
to screening this should be reported to the investigator and recorded in the eCRF. 
All therapy and/or medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF. 
4.1.2 Prohibited Therapy 
Patients should be treated for all concomitant conditions and adverse events according to accepted 
standards of medical care at the discretion of the investigator. The following treatments are not 
permitted during the study: 
• Any other investigational therapy 
• Cytotoxic chemotherapy agents other than study agents 
• Radiotherapy. Note: palliative radiotherapy is allowed. 


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• Strong inhibitors or inducers of CYP3A4 (as can be found here: Flockhart Table or in 
another frequently updated source) 
• Any medications or treatments that may adversely affect the immune system such as 
allergy injections, immune globulin, interferon, immunomodulators, cytotoxic drugs, or 
systemic corticosteroids (oral or injectable) at doses higher than needed for adrenal 
replacement (except as specified as part of protocol treatment). 
• Other systemic anti-neoplastic agents and targeted therapies 
• Live vaccines 
If any anti-neoplastic or investigational therapies listed above are needed, the patient will be 
considered to have evidence of progressive neoplastic disease and have experienced treatment 
failure with study treatment and should be withdrawn from study treatment. 
All concomitant treatments must be documented in the eCRF. 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
5.1.1 LMB-100 Pharmacokinetic Assessments 
All blood samples for PK assessment will be collected from an IV line different to that receiving 
the infusion to measure free and total concentrations for LMB-100 for all patients. The pre-
treatment PK assessment may be drawn from the line that will be used to administer LMB-100. 
The date and time of each sample collection will be recorded. If multiple samples are drawn at a 
given time point, the PK sample should take precedence. 
Free and total plasma concentrations of LMB-100 will be measured using validated ligand-binding 
assays. 
5.1.1.1 Sample collection 
Blood will be collected in 2 mL K2EDTA tubes (purple top) at the times defined in Section 5.2. 
Samples should be inverted 8 to 10 times after collection. Store on wet ice or at 4°C. Processing 
within 60 minutes of blood collection is highly preferred, but not required as samples are stable at 
4°C for up to 24 hours.   
5.1.1.2 Sample processing 
Samples will be processed in the Clinical Pharmacology Program.  
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
Upon arrival in the CPP the following procedures should be followed: 


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Abbreviated Title: LMB100 + tofacitinib in PDA 
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1. Store on wet ice until centrifugation.  
2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection.  
3. Transfer plasma specimen to 2mL cryovials and store at -70°C.   
The analyses will be performed retrospectively in batched samples or at the end of the trial. 
5.1.1.3 Sample Shipping 
Samples will be shipped by the CPP on dry ice to Ms. Yanyu Wang in Frederick for analysis. 
Leidos Biomedical, Inc. 
Attention: Ms. Yanyu Wang, Dr. Jon Inglefield 
Building 469, Room 120 
Miller Drive 
Frederick, MD 21702 
Phone: 301-846-6905/301-846-6865 
5.1.1.4 Sample storage 
Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick.  
5.1.2 Assessment of LMB-100 anti-drug antibodies (ADAs)  
5.1.2.1 Sample Collection   
Samples will be collected before the first dose of LMB-100 during each cycle as per Section 5.2.  
Draw 2mL into K2EDTA tube (purple top). Samples should be inverted 8 to 10 times after 
collection. Store on wet ice or at 4°C. Processing within 60 minutes of blood collection is highly 
preferred. 
5.1.2.2 Sample Processing, Shipping and Storing  
Samples will be processed in the Clinical Pharmacology Program as described in Section 5.1.1.2 
and autoantibody levels will be retrospectively assessed. Samples will be shipped as described in 
Section 5.1.1.3 and stored as described in Section 5.1.1.4.      
5.1.3 Cytokines and circulating endothelial cells (CECs) for identification of a mechanism 
for PE-mediated capillary leak syndrome (CLS) 
PE-based RITs cause dose-limiting CLS. At low doses CLS manifests as mild and transient weight 
gain, hypoalbuminemia, and peripheral or facial edema. At higher doses it can cause life-
threatening cardiopulmonary compromise. Previous studies in rats have indicated that pathological 
changes indicative of CLS onset occur within just two hours of toxin administration and even when 
the PE fragment lacks a targeting domain (36). In vitro studies with cultured endothelial cells have 
demonstrated that super-physiologic doses of PE-based RITs cannot induce endothelial cell 
toxicity unless the cells express the RIT target (37). Together these data suggest the hypothesis 
that PE-based RITs cause CLS by triggering release of vasoactive cytokines by specific 
immune cells rather than through direct damage to endothelial cells. To test this hypothesis, 
we will collect additional blood from participants. Levels of a panel of cytokines known to affect 
the vasculature will be assessed. Change in cytokine levels from baseline will be compared.  


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In addition, circulating endothelial progenitor cells (CEP) and mature circulating endothelial cells 
(CEC) will be collected to assess endothelial cell dynamics (see Section 5.2 for specific time 
points). These cells will be assessed by multiparameter flow cytometry. Cells will be analyzed for 
forward and side scatter, and cells expressing hematopoietic markers will be excluded.  Endothelial 
cells will be identified using co-expression of markers, such as CD31 and CD146 for CEC, and 
CD31 and CD133 for CEP. The cell populations will also be analyzed for viability using scatter 
profiles and a vital stain, such as Hoechst 33258. Percentages of stained cells will be determined 
and compared with appropriate negative controls. Multiparameter flow cytometric analysis will be 
performed with a Miltenyi Quant equipped with FlowJo software, using a minimum of 100,000 
events per analysis. 
5.1.3.1 Specimen collection- cytokine analysis 
Plasma and serum will be collected from participants on the days and time points shown in 
Sections 5.2. 
Draw 2mL into K2EDTA tube (purple top). Samples should be inverted 8 to 10 times after 
collection. Store on wet ice or at 4°C. Samples must be processed within 120 minutes of blood 
collection due to instability of some analytes. 
Draw 2mL into SST tube (red top).  
5.1.3.2 Sample processing- cytokine analysis 
Samples will be processed in the Clinical Pharmacology Program as described in Section 5.1.1.2. 
Upon arrival in the CPP, each plasma sample (K2EDTA tube) should be processed in the following 
manner:  
1. Store on wet ice until centrifugation.   
2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection.  
3. Immediately transfer plasma specimen (maintaining samples at 4°C throughout handling 
process) to 2mL cryovials and store at -70°C.   
Upon arrival in the CPP, each serum sample (SST tube) should be processed in the following 
manner:  
1. Store at room temperature for 15-30 minutes to allow blood to clot 
2. Centrifuge at 1500xg for 10 minutes at 4°C to remove clot 
3. Immediately transfer serum specimen (maintaining samples at 4°C throughout handling 
process) to 2mL cryovials and store at -70°C.  
5.1.3.3 Sample Storage- cytokine analysis 
Samples will be stored in the CPP. Deidentified samples will be transferred to the Alewine 
laboratory for analysis within 12 months of freezing. 
5.1.3.4 Sample Collection- CECs 
Draw blood into one 8-cc CPT citrate (BD) tube as specified in Section 5.2 


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Abbreviated Title: LMB100 + tofacitinib in PDA 
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5.1.3.5 Sample Processing-CECs 
Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepel- 
trepelj@mail.nih.gov; 
Min-Jung- 
Lee-leemj@mail.nih.gov; 
and 
Sunmin 
Lee- 
leesun@mail.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn 
at 240 760 6330and a lab member will pick up the sample.   
5.1.4 To evaluate changes in the tumor microenvironment following treatment with LMB-
100 and tofacitinib 
We hypothesize that tofacitinib and LMB-100 will alter the tumor microenvironment. Pre-clinical 
studies have shown that tofacitinib treatment depletes levels of some immune cells within tumors. 
We will perform intrapatient comparison of tumor tissue before and after treatment. These samples 
will be assessed for change in 1) volume of stroma versus tumor cells, 2) volume, density and 
architecture of collagen and other matrix proteins, 3) density of tumor blood vessels, 4) tumor 
MSLN expression, 4) infiltration of immune cells, and 5) PD-L1 expression by the tumor.  
5.1.4.1 Specimen collection, preparation and storage 
Tumor biopsy specimens will be obtained when feasible with patient consent. Specimens will be 
processed and stored by NCI Laboratory of pathology and presence of tumor confirmed. 
5.1.5 Retrospective Analysis of Mesothelin Expression in tumor tissue 
IHC analysis will be performed by the Laboratory of Pathology at NCI to determine mesothelin 
expression within the tumor at any time after study enrollment. Leftover tissue from archival 
specimens or tumor biopsies obtained at screening will be used for analysis. Specimens will be 
used to correlate treatment with response with mesothelin expression in an exploratory analysis. 
5.1.6 Peripheral blood immune gene expression 
Peripheral blood mononuclear cells (PBMC) will be assessed by the Trepel Lab using 
multiparameter flow cytometry for immune subsets including but not necessarily limited to CD8+ 
T-cells, CD4+Foxp3- T-cells, Tregs, Th1, Th2 and Th17+ CD4+ T-cells, monocyte subsets, 
MDSC subsets. Assessment will include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, 
HLA-DR and/or CD40.  
Peripheral blood immune gene expression will be evaluated by the Trepel Lab using the 
NanoString nCounter® platform (NanoString Technologies, Seattle, WA). Collect peripheral 
whole blood in a PAXgene Blood RNA tube (PreAnalytix; 2.5 cc peripheral blood per tube) per 
the manufacturer’s instructions.  After the whole blood is drawn, the tube should be inverted 
several times and placed at room temperature.  RNA will be isolated using the PAXgene Blood 
RNA Kit according to the manufacturer’s instructions.  Peripheral immune gene expression will 
be evaluated using the PanCancer Immune Profiling codeset of 730 immune genes and 40 control 
genes at baseline and post-therapy by the Trepel Lab to look for correlates of clinical response 
with innate or adaptive immunity. 
5.1.6.1 Sample Collection 
Draw blood into one 8-cc CPT citrate (BD) tube at (1) baseline, just prior to beginning therapy, 
(2) cycle 1 following end of last infusion as specified in Section 5.2, and (3) cycle 2 day 1, prior 


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Abbreviated Title: LMB100 + tofacitinib in PDA 
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to therapy.  Draw blood into two one 2.5 ml PAXgene RNA tube at (1) baseline, just prior to 
beginning therapy, and (2) cycle 2 day 1, prior to therapy.   
5.1.6.2 Sample Processing 
Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepel- 
trepelj@mail.nih.gov; 
Min-Jung 
Lee- 
min-jung.lee@nih.gov; 
and 
Sunmin 
Lee- 
leesun@mail.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn 
at 240-760-6330. Please phone the lab as soon as it is drawn and a lab member will come to pick 
up the blood. 


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5.2 
SAMPLE COLLECTION SCHEDULE 
Cycle 
Day 
LMB-
100 PKs 
ADA 
Plasma & 
Serum 
Cytokines 
CECs 
Immune 
Subsets 
Immune 
gene 
expression 
Tumor 
Sample 
5.1.4, 
5.1.5 
5.1.1 
5.1.2 
5.1.3 
5.1.3 
5.1.6 
5.1.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 mL 
K2EDTA 
tube 
2 mL 
K2EDTA 
tube 
2 mL 
K2EDTA 
and SST 
tubes  
two 8-cc CPT citrate 
(BD) tubes 
2.5 mL PAX 
gene RNA 
tube 
N/A 
Screening 
 
 
 
 
 
 
 
       Xa 
 
1b 
 
Pre-
tofacitinib 
Pre-
tofacitinib 
 
Pre-
tofacitinib 
Pre-
tofacitinib 
X0 
 
1 
4 
Pre-, EOI, 
then 1, 2, 
4, 8-10, 
12-16 hrs 
post-
LMB-100 
Pre-dose 
LMB-
100c 
Pre-dose, 
EOI, 4hrs 
post-  
LMB-100 
Pre-dose 
LMB-100 
Pre-dose 
LMB-100 
 
 
 
8 
Pre-, EOI 
LMB-100 
 
 
 
 
 
 
 
9 
 
 
X 
X 
X 
X 
 
≥2 
3 
 
Xc 
 
 
 
 
 
4 
Pre-, EOI 
LMB-100 
C3 only: 
1, 2, 4, 8-
10, 12-16 
hrs post-
LMB-100 
 
pre-LMB-
100 
C2 only: 
pre- 
LMB-100 
C2 only: 
pre- 
LMB-100 
 
 
 
8 
Pre-, EOI 
LMB-100 
 
EOI  
LMB-100 
 
 
 
Xd 
Treatment
Extension 
4 
Pre-, EOI 
LMB-100 
pre-LMB-
100 
 
 
 
 
 
At time of 
Progression 
 
 
X 
X 
 
 
 
 
Withdrawal 
Visit 
 
 
X 
X 
 
 
 
 
Safety 
Follow-up 
Visit 
 
 
X 
X 
 
 
 
 


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ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; CEC=circulating endothelial cell 
a. 
Archival tissue collection permitted if tissue was collected within 1 month of completion of last treatment or 
biopsy if no tissue available.  
b. 
May be drawn up to 7 days prior 
c. 
May be drawn on day 3 or 4 before LMB-100 administration 
d. 
Cycle 2 only. May be obtained on any one of Days 4-8. 
C1D1 (within 7 days prior to treatment): optional biopsy.  
Note: Timed samples scheduled for EOI must be drawn within 5 minutes of this reference point. 
Those scheduled within 4hrs of EOI should be collected within +/- 20 minutes of indicated time. 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.  
5.3.1 Clinical Pharmacology Program 
Upon arrival in the Clinical Pharmacology Program (CPP), OCD, CCR, NCI, all samples are 
barcoded, with data entered and stored in Labmatrix, the system utilized by the CPP. This is a 
secure program, with access to the Labmatrix system limited to defined CPP personnel, who are 
issued individual user accounts. Labmatrix creates a unique barcode ID for every sample and 
sample box, which cannot be traced back to patients without Labmatrix access. The data recorded 
for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle, time 
point, dose, material type, as well as box and freezer location. There are patient demographics that 
can be obtained to correlate with the samples through Labmatrix. For each sample, there are notes 
associated with processing method (delay in sample processing, storage conditions on the ward, 
etc.) 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20°C or -80°C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Samples will be stored until requested 
by the researcher assigned to the protocol. All requests are monitored and tracked in Labmatrix. 
All researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per IRB approved protocol) and that any unused samples 
must be returned to the CPP. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
5.3.2 Leidos Biomedical, Inc. Lab 
Blood and tissue collected during the course of this study will follow storage, handling and labeling 
procedures to ensure that security, confidentiality and sample integrity are maintained. All samples 
(blood or tissue) are tracked by distinct identification labels that include a unique patient identifier 
and date of specimen collection. Thus, samples will be de-identified of personal data, with access 
to personal data restricted to the study investigators.   


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All cryopreserved samples are tracked for freezer location and storage criteria. All Samples are 
stored in a locked freezer at -70C according to stability requirements.  These freezers are located 
offsite at NCI-Frederick, at the Leidos Biomedical, Inc. Lab in Frederick, MD.  Samples will be 
stored until requested by a researcher named on the protocol.  All use and requests for use will be 
recorded by the Leidos Biomedical, Inc. Lab.  Any unused samples must be returned. 
Some samples as indicated below may be stored in monitored freezers/refrigerators in the 
investigator’s laboratory at specified temperatures with alarm systems in place.  
At the termination of this protocol, samples will remain in storage as detailed above.  If additional 
studies are to be performed on any samples retaining patient identifiers, obtained during the 
conduct of this trial, a Request to Conduct Research for Stored Human Samples Specimens, or 
Data Collected in a Terminated NCI-IRB Protocol will be submitted.  Otherwise, access to these 
samples will only be granted following IRB approval of an additional protocol, granting the rights 
to use the material. If specimens are to be discarded at any point, they will be disposed of in 
accordance with the environmental protection laws, regulations and guidelines of the Federal 
Government and the State of Maryland. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). The PI will report any loss 
or unanticipated destruction of samples per Section 7.2. 
5.3.3 Laboratory of Jane Trepel 
Samples will be processed immediately by the Trepel laboratory.  Biospecimens will be collected 
and processed using validated SOPs that will ensure both specimen quality and patient 
confidentiality. Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented, and the specific location of each 
specimen will be tracked. Each new specimen collected will be assigned a unique barcode 
identifier that can be linked to the original specimen collected and other relevant information 
within the inventory system.  Specimen labels will indicate protocol number, order in which the 
patient enrolled on the trial, type of sample, collection time, and total volume collected, as 
appropriate.  The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality. Access to the inventory system and associated documents will 
be restricted to appropriate individuals. Requests to use specimens stored in the repository must 
be approved. SOPs ensure that any changes in informed consent made by a patient and relayed to 
the PI will be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for 
high-quality performance. 
5.3.4 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed. Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 


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samples, provided they have an IRB-approved protocol and participant consent or an exemption 
from OHSRP.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of Section 7.2. 
5.3.5 NCI Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not placed in 
paraffin blocks is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, 
the slides and tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D and Labmatrix databases) and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts.  All data obtained during the conduct 
of the protocol will be kept in secure network drives or in approved alternative sites that comply 
with NIH security standards. Primary and final analyzed data will have identifiers so that research 
data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1, through the end of the treatment. 
After 30 days, only adverse events which are serious and related to the study intervention need to 
be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 


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• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
• Coded, linked data in an NIH-funded or approved public repository.   
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
• Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
How and where will the data be shared?  
Data will be shared through: 
• An NIH-funded or approved public repository: cliniclatrials.gov 
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 
When will the data be shared?  
• Before publication. 
• At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
No large scale genomic data will be generated on this study; therefore, the NIH GDS policy does 
not apply. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained no less than 4 weeks 
following initial documentation of objective response. 


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Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).(38) Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
For pleural mesothelioma, modified RECIST for MPM (malignant pleural mesothelioma)(39) 
should be used as described in Section 6.3.9.  
6.3.1 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
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 disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 


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and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 


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measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published.(40-42)  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.(43) 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 


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in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.3 Response Criteria 
6.3.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
6.3.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
6.3.4 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.3.5 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.3.6 Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients with partial response or 
complete response. 
6.3.7 Disease Control Rate 
Disease control rate (DCR) is defined as the percentage of patients with partial response, complete 
response, or stable disease. 


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6.3.8 Overall Survival 
Overall survival (OS) is defined as the length of time from start of treatment until death from any 
cause. 
6.3.9 Pleural Mesothelioma 
Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.(39) Therefore, 
modified criteria were defined in 2004 adjusting target lesion measurements to the specific needs 
of this disease. 
6.3.9.1 Modified RECIST Criteria for MPM 
Target lesion:  
Measurable at baseline and defined as tumor thickness measurements perpendicular to the chest 
wall or mediastinum in two positions at three separate levels on transverse cuts of CT scan. The 
sum of those 6 measurements define a pleural unidimensional measure. For reproducibility of 
lesion identification in follow up scans, cuts were taken at least 1 cm apart and close to anatomical 
landmarks in the thorax. Reassessments should be done at same position at the same level and by 
the same reader. Nodal, subcutaneous, and other measurable lesion were measured as per RECIST 
criteria. All unidimensional measurements were added to obtain total tumor measurement. 
Evaluation of target lesions  
• 
Complete Response (CR): Disappearance of all target lesions with no evidence of tumor 
elsewhere.  
• 
Partial Response (PR): At least a 30% decrease in the total tumor measurement  
• 
Confirmed response (PR and CR): require a repeat scan at least 4 weeks apart  
• 
Progressive Disease (PD): At least a 20% increase in the total tumor measurement, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). (Note: the appearance of one or more new lesions is also considered 
progression).  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study.  
6.3.9.2 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Response 
for 
this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN  
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here.  


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7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING  
7.2.1 Expedited Reporting   
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.4.2 Safety Monitoring Committee (SMC) 
This protocol will protocol will be periodically reviewed by an intramural Safety Monitoring 
Committee (SMC).  Initial review will occur as soon as possible after the annual NIH Intramural 
IRB continuing review date.  
Subsequently, each protocol will be reviewed every 6 months as the quarterly meeting schedule 
permits or more frequently as may be required by the SMC based on the risks presented in the 


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study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual 
within the review period.  
The SMC review will focus on unexpected protocol-specific safety issues that are identified during 
the conduct of the clinical trial.  
Written outcome letters will be generated in response to the monitoring activities and submitted to 
the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
7.4.3 Independent Monitoring Committee (IMC) 
The protocol will also have an Independent Monitoring Committee (IMC), consisting of the 
Principal Investigator and two independent, qualified investigators who are outside of the 
Laboratory of Molecular Biology (LMB) branch and are not involved in the study. The committee 
will meet after the first 5 subjects have been treated and completed the DLT evaluation window. 
The IMC will review adverse events and other associated safety data (this review may occur prior 
to the first annual continuing review date). The committee will be responsible for deciding whether 
treatment can proceed under the current protocol, whether protocol modifications are required for 
study continuation, or whether the protocol should be closed to further accrual due to toxicity of 
the study agents. The IMC may be convened for an ad hoc evaluation of protocol safety by the 
Principal Investigator or at the request of the IRB or SMC at other occasions during the study if 
concerns about study drug or research protocol safety or toxicity arise. 
The minutes of the IMC meetings will be submitted to the IRB at the time of continuing review, 
unless an issue arises that requires prompt reporting to the IRB and then results will be submitted 
more expeditiously. 
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2). 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see Section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 


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o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
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. 
8.1.3 Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32). 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 


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occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to Section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. 
All SAE reporting must include the elements described in Section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
REPORTING PREGNANCY 
8.4.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (see Section 8.1.2) should be reported as 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 


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8.4.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of study drugs. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 3 months after the last dose 
should, if possible, be followed up and documented. 
8.5 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expedited manner to the FDA in accordance 
to 21 CFR 31.2.32.  CCR will report an AE as a suspected adverse reaction only if there is evidence 
to suggest a causal relationship between the study product and the adverse event.  CCR will notify 
FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing 
drug under its INDs or under any investigator’s IND) in an IND safety report of potential serious 
risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 
312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.  


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10 STATISTICAL CONSIDERATIONS   
10.1 STATISTICAL HYPOTHESIS 
10.1.1 Primary Endpoints  
The primary endpoint of the dose escalation phase is to identify the MTD and the desirable dose 
of LMB-100 with tofacitinib.  
The primary endpoint of the expansion phase is to determine the number of participants that meet 
a threshold serum drug concentration during cycle 2 of treatment. The threshold drug level has 
been set at >600 ng/mL as measured at EOI for any LMB-100 administration during the cycle of 
interest. 
10.1.2 Secondary Endpoints 
The secondary endpoints for both the dose expansion and dose escalation cohorts are the LMB-
100 peak serum level, half-life and AUC during cycle 1, and the percentage of participants with 
EOI LMB-100 serum drug concentration that meets threshold during cycle 3. For the dose 
escalation cohort, the percentage of participants with EOI LMB-100 serum drug concentration that 
meets threshold during cycle 2 of treatment will also be measured. For the dose expansion cohort, 
the number and description of adverse events by grade will also be reported. 
10.2 SAMPLE SIZE DETERMINATION 
The primary endpoints of this trial are to 1) identify the MTD and the desirable dose of the 
tofacitinib + LMB-100 combination format and 2) to determine whether the combination results 
in 80% of patients achieving threshold drug levels during cycle 2 of LMB-100.  The MTD is 
defined as the maximum dose at which less than 33% of patients experience a DLT. The desirable 
dose will be selected from among the dose levels at or below the MTD. A lower dose than the 
MTD might be assessed in the expansion phase if chronic toxicity of LMB-100 is judged to be 
intolerable by the investigator at the MTD. 
As per standard 3+3 design, if 0 of 3 or <2 of 6 patients experience DLT then dose escalation may 
proceed. If 2 or more patients experience DLT at any dose level, then dose de-escalation is 
required. 
Dose escalation will proceed from dose level 1 to 2. If 0 of 3 or 0-1 of the first 6 patients in dose 
level 1 have a DLT, then dose escalation will proceed to dose level 2. Alternatively, if 2 or more 
patients in level 1 experience DLT, then dose will be de-escalated to dose level -1.  
Based on two dose levels, the theoretical maximum number of subjects that can enroll on the dose 
escalation would be 12 (6 patients per level x2 dose levels).  
Following completion of the dose escalation, enrollment of an additional 15 patients with 
pancreatic cancer or extrahepatic cholangiocarcinoma will be undertaken to better assess the a) 
safety of the optimal dose in the target population, and b) ability of tofacitinib to delay 
development of ADAs against LMB-100 and result in serum LMB-100 drug levels reaching 
threshold in cycle 2 and beyond. Participants on the dose escalation arm who are treated at MTD 
and meet eligibility requirements for the dose expansion phase can be counted towards the 15 
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who start treatment will develop progressive disease by restaging after 2 cycles and would 
therefore be uninformative for assessing the longer-term immunogenicity endpoint. Thus, 
additional patients may be needed to complete the evaluation of toxicity and possible efficacy at 
the escalating dose levels. 
This evaluation in 15 patients of either histology (but at least 8 patients in this expansion phase 
must have pancreatic adenocarcinoma) will be undertaken using the following guidelines: The 
objective will be to determine if the fraction of patients who are able to achieve threshold levels 
of LMB-100 in cycle 2 is consistent with 80% and greater than 50%. If 15 evaluable patients are 
enrolled, and if 11 or more patients meet threshold drug levels in cycle 2, then the probability of 
this occurring is 5.9% if the true probability of achieving threshold drug levels in cycle 2 were 
50% and the probability of this occurring is 83.6% if the true probability of achieving threshold 
drug levels in cycle 2 were 80%. Thus, the expansion phase would be considered to have a positive 
outcome if 11 or more of 15 patients in the expansion phase achieve threshold drug levels. In 
practice, after the trial has ended accrual, the fraction of evaluable patients assessed during the 
expansion phase that achieve threshold drug levels in cycle 2 will be determined and reported 
along with two-sided 80% and 95% confidence intervals to aid in interpretation of the results.  The 
fraction of patients who achieve threshold drug levels in cycle 3 will also be reported along with a 
95% confidence interval, but this may be a small fraction and will be interpreted as being an 
exploratory evaluation. 
As an early stopping rule, if after the first 5 evaluable patients in the expansion cohort have been 
treated, 0 of the 5 achieve threshold drug levels in cycle 2, then no further patients will be accrued 
as soon as that can be determined, with no pause in accrual, since this would be inconsistent with 
the goal of having 11 or more of 15 patients achieving threshold drug levels in cycle 2.  
With up to 12 patients in the dose escalation phase and 15 in the expansion cohort, a maximum of 
27 evaluable patients are required to complete accrual to this study. The accrual ceiling will be set 
at 45 patients to account for screen failures or patients who are treated but unable to complete the 
DLT period. It is anticipated that up to two patients per month may enroll onto this trial. Thus, 
accrual is expected be completed in approximately 2 years. 
10.3 POPULATIONS FOR ANALYSES 
10.3.1 Evaluable for toxicity  
All patients who receive treatment during dose escalation will be reported. Any patient who 
receives any study drug treatment and experiences a DLT related to study drug within 21 days of 
initial treatment is evaluable. Otherwise, patients evaluable for DLT must: 1) receive all doses of 
study drugs, 2) be followed for study drug toxicity for at least 21 days after the administration of 
the first dose of LMB-100.  
In the expansion phase, up to 15 evaluable patients who can have their drug levels assessed in 
cycle 2 will be included in analyses. Up to 5 patients will be replaced if they have PD before C2, 
but if more than 5 patients progress before C2, then no further patients will be accrued as soon as 
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10.3.2 Evaluable for objective response:  
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response.  
These patients will have their response classified according to the definitions stated below.  (Note: 
Patients who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) Responses or progressions noted in patients receiving treatment extension 
will be recorded in the study database but will not be reported in the aggregate objective response 
rate, which only corresponds to assessments taken prior to the start of a 4th cycle.  
10.3.3 Evaluable Non-Target Disease Response:   
Patients who have lesions or tumor marker present at baseline that are evaluable but do not meet 
the definitions of measurable disease, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions or increase 
in tumor marker.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
The DLTs among patients enrolled during the dose escalation phase will be determined and 
reported at each dose level. In the expansion phase, the fraction of evaluable patients who have 
achieved threshold drug levels in cycle 2 will be reported. 
10.4.2 Analysis of the Primary Endpoints 
The DLTs among patients enrolled during the dose escalation phase will be determined and 
reported at each dose level.  
In the expansion phase, the fraction of evaluable patients who meet the endpoint drug level 
threshold in cycle 2 will be reported along with two-sided 80% and 95% confidence intervals to 
aid in interpretation of the results. 
10.4.3 Analysis of the Secondary Endpoint(s) 
The secondary endpoints are the number and description of adverse events by grade in the 
expansion cohort. For both dose escalation and expansion cohorts secondary endpoints include: 
the LMB-100 peak serum level and half-life and AUC during cycle 1. Each of these will be 
reported using descriptive measures such as percentages and counts as appropriate.  For both dose 
escalation and dose expansion cohorts, we will report the percentage of patients who have 
formation of neutralizing anti-LMB-100 ADAs affecting drug concentration during cycle 2 and 
cycle 3. 
10.4.4 Safety Analyses 
Safety will be evaluated during the dose escalation phase and will include reporting toxicities by 
grade and type at each dose level in addition to DLTs.  


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During the 15-patient expansion cohort, the following rule will be used: Within the initial 6 
patients, no more than 1 patient in 6 is permitted to experience a DLT attributable to study agents. 
After the initial 6 patients, safety will be monitored continuously per the following rule: if the 
cumulative fraction of patients enrolled who experience a DLT attributable to study agents is 1/6 
or less, patients will be allowed to continue to enroll onto this protocol.  
10.4.5 Baseline Descriptive Statistics 
Demographic and clinical characteristics of all patients will be reported. 
10.4.6 Planned Interim Analyses 
As an early stopping rule, if after the first 5 evaluable patients have been treated, 0 of the 5 meet 
threshold drug levels in cycle 2, then no further patients will be accrued since this is inconsistent 
with the goal of having 11 or more of 15 meeting threshold drug levels. Accrual will not be halted 
while awaiting the determination of drug levels in cycle 2 based on 5 patients; thus, additional 
patients may begin treatment while this determination is being made. 
10.4.7 Sub-Group Analyses 
In the expansion cohort, the fraction of patients meeting threshold drug levels in cycle 2 will be 
analyzed as an exploratory endpoint according to pancreatic adenocarcinoma vs. extra-hepatic 
cholangiocarcinoma history. 
10.4.8 Tabulation of individual Participant Data 
None will be provided 
10.4.9 Exploratory Analyses 
The following are the intended exploratory analyses focusing on the patients in the expansion 
cohort: 
Disease control rate (DCR) at 9 weeks will be estimated along with a 95% confidence interval. 
PFS and OS will be estimated by the Kaplan-Meier method, along with 95% confidence intervals. 
Changes in appropriate tumor markers with treatment (if applicable to patient’s tumor type) will 
be determined and tested for change from baseline using a Wilcoxon signed rank test. Titer of free 
anti-LMB-100 antibodies at the start of each cycle and following completion of treatment will be 
obtained and results reported descriptively; the relationship of these values with peak serum drug 
levels of LMB-100 will be explored. Association of response with tumor MSLN expression will 
be done by comparing levels between responders and non-responders using an appropriate non-
parametric test such as a Cochran-Armitage test or Fisher’s exact test. Changes in circulating 
endothelial cells following immunotoxin treatment, changes in serum cytokines following 
immunotoxin treatment, and changes in tumor microenvironment following immunotoxin 
treatment will be reported descriptively, with statistical testing of changes as appropriate. Any 
statistical tests performed on the exploratory endpoints will have results presented without formal 
adjustment but interpreted in the context of the number of tests performed. In patients receiving 
treatment extension, the anti-drug antibodies and peak plasma LMB-100 drug levels will be 
obtained at each cycle after cycle 3 and reported with descriptive statistics. The levels of these 


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measures after cycle 3 may be compared descriptively to those in earlier cycles for purposes of 
evaluating the effect of the agent in this small subset of patients. 
11 HUMAN SUBJECTS PROTECTIONS  
11.1 RATIONALE FOR SUBJECT SELECTION 
LMB-100 targets the cell surface antigen MSLN and is ineffective against tumor or normal cells 
that lack MSLN. Many different solid tumor types express MSLN such as mesothelioma, 
pancreatic, colorectal and lung adenocarcinomas, epithelial ovarian cancers, cholangiocarcinomas, 
gastric and triple negative breast cancers, as well as some tumors of squamous cell origin. At 
advanced stages, these tumors are incurable although standard therapies can improve duration of 
survival and symptoms. There is an unmet need to identify improved and less toxic therapies in 
these patient populations. Given the overall poor prognosis of these patients, particularly after 
progression of tumor on or after initial treatment regimen(s), the potential to directly benefit from 
treatment outweighs the risks of participating in the study. 
All patients meeting the criteria listed in Section 2.1 are eligible for enrollment. 
11.2 PARTICIPATION OF CHILDREN 
There are no dosing or adverse event data currently available on the use of LMB-100 with 
tofacitinib in patients <18 years of age; therefore, children are excluded from this study. 
11.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes 
for research and care, and assign a substitute decision maker on the “NIH Advance Directive for 
Health Care and Medical Research Participation” form so that another person can make decisions 
about their medical care in the event that they become incapacitated or cognitively impaired during 
the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment 
Team (ACAT) for evaluation as needed for the following: an independent assessment of whether 
an individual has the capacity to provide consent; assistance in identifying and assessing an 
appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. 
For those subjects that become incapacitated and do not have pre-determined substitute decision 
maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker 
for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or 
durable power of attorney, will be followed. 
11.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
11.4.1.1 Risks from Study Drugs 
Patient safety will be managed by careful proactive patient selection prior to study to exclude 
patients at risk from study treatment due to their pre-existing conditions. During the study, safety 
of patients will be proactively managed by protocol-mandated physical examinations, vital signs 


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assessments, chest X-rays, ECGs, clinical laboratory assessments, and collection of adverse events 
and their assessment.  
The risks of the study include those associated with study agent as discussed in Section 12.  
11.4.1.2 Blood Collection 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.  
11.4.1.3 Image Guided Biopsy Collection 
The risks of the research biopsies collected at screening, at cycle 1 day 1, and on day 3 of cycle 2 
include pain, bleeding and infection at the biopsy site.  
11.4.1.4 Risks of exposure to ionizing radiation 
This research involves up to 6 CT C/A/P scans, up to 3 chest X-ray, and up to 3 CT-guide biopsies 
per year. Subjects will be exposed to up to approximately 9.18 rem. This level of exposure is 
associated with an increased risk of cancer.  
11.4.1.5 MR Imaging 
MRI is a standard of care test for some patients with pancreatic and cholangiocarcinoma. The risks 
of MR imaging are relatively small.  
The US Food and Drug Administration has issued warnings that administration of gadolinium 
(updated September 9, 2010), the MRI contrast imaging agent used in this protocol, has been 
associated with development of a disease called nephrogenic systemic fibrosis (NSF). The 
syndrome is rare (approximately 600 cases reported worldwide as of September 2010, out of 
several million administrations of gadolinium), but disabling and in some cases, fatal. All cases to 
date have occurred in patients with severe renal disease, including patients on dialysis. NSF has 
been nearly eradicated secondary to careful screening of renal function and avoiding use of 
gadolinium in patients with eGFR <30 ml/min/1.73 BSA. Even in patients with end stage renal 
disease, there have been only rare occurrences of NSF because of precautions taken to use more 
stable contrast agents at lower doses. This protocol excludes patients with renal insufficiency 
(eGFR <50 ml/min). The FDA has issued warnings in 2017 and 2018 that some gadolinium may 
be retained in the brain, bone and skin although health risks of accumulation have not been reported 
to date. In accordance with the FDA Drug Safety Communication of 05/16/2018, the Medication 
Guide for gadobutrol (or other macrocyclic gadolinium contrast agent if applicable) will be made 
available to all subjects with scans that will involve gadolinium-based contrast agent 
administration. 
11.4.1.6 Central Line Insertion 
Patients without a mediport in whom peripheral access cannot be obtained can have a central line 
placed for treatment administration. The risks of this procedure include catheter contamination, 
pneumothorax, arrhythmia and air embolus. All care will be taken to minimize complications of 
central insertion during the procedure. 
11.4.2 Benefits 
Patients with many different solid tumor types expressing MSLN are in continuous need of 
improved therapy options, particularly patients with pancreatic and biliary adenocarcinomas, the 


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focus population of this clinical trial. Preclinical data has demonstrated promising anti-tumor 
efficacy of LMB-100 in xenograft models in monotherapy and combination therapy. Laboratory 
studies have demonstrated that tofacitinib inhibits the development of antibodies against LMB-
100. Therefore, LMB-100 + tofacitinib may improve clinical outcome of patients with mesothelin-
expressing tumors. Several clinically appropriate strategies to minimize risk to patients have been 
built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and 
management guidelines.  
11.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) for review 
prior to consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed. 
12 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION   
12.1 LMB-100 (IND # 123332) 
12.1.1 Source  
LMB-100 was transferred to the NIH CC Pharmacy by Selecta Biosciences, the drug manufacturer.  
For this trial, the drug will be supplied by the NIH CC Pharmacy.  
12.1.1.1 Mechanism of action 
LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) 
developed for the treatment of patients with solid tumors that express the mesothelin protein. 
Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in 
normal/non-malignant tissue and its high expression in several tumor entities including 
mesothelioma, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, and lung cancer. 
To target mesothelin, a humanized Fab fragment of the anti-mesothelin antibody SS1 is linked to 
a truncated and de-immunized recombinant 24 kD fragment of Pseudomonas exotoxin (PE24). 
After binding to mesothelin, the complex is internalized by endocytosis and kills cells by inhibition 
of eukaryotic elongation factor 2 (eEF2), leading to arrest of protein synthesis and secondarily 
triggering cell death by apoptosis or necrosis. 


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12.1.1.2 Molecular Weight: approximately 73 kDa 
12.1.1.3 Chemical Structure 
 
H1L1 polypeptide structure consisting of one variable heavy chain containing the Pseudomonas 
Exotoxin A moiety and one variable light change held together by a disulfide bond. 
12.1.2 Toxicity  
Information in this section is based on preclinical studies with LMB-100, and clinical studies of the 
cytolytic fusion protein SS1-P. Participants should receive a full dose of LMB-100 unless a DLT 
and/or a treatment limiting toxicity is observed. In case of DLT and/or treatment limiting toxicities, 
treatment with LMB-100 will be stopped until resolution of toxicity to NCI CTCAE Grade  2 
hematological toxicities or Grade  1 non-hematological toxicities. A delay of LMB-100 
administration for up to two weeks of the planned schedule will be acceptable to allow for 
resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-
hematological toxicities. If toxicity does not resolve to NCI CTCAE Grade  2 hematological 
toxicities or Grade  1 non-hematological toxicities and the participant is unable to resume 
treatment with LMB-100 after this time, no additional doses will be administered, and the 
participant will be withdrawn from study treatment. 
12.1.2.1 Infusion-Related Reactions and Hypersensitivity Including Anaphylaxis 
LMB-100 administration may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Such reactions 
typically occur during or shortly after an infusion. Participants may also develop IgE-mediated 
hypersensitivity reactions to LMB-100. IRRs may be indistinguishable from an anaphylactic 
reaction. Participants should receive full supportive care to treat IRRs or anaphylaxis according to 
institutional practice. If infusion-associated signs or symptoms occur, participants should be 
monitored until complete resolution. 


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In vitro data and previous clinical experience with LMB-100 suggest that the risk for the release of 
pro-inflammatory cytokines upon first administration of LMB-100 to humans is low (Please refer 
to Sections 1.2.8 and 3.3.1 for details). Past experience with monoclonal antibodies that 
demonstrated a risk in the whole blood assay has shown that this risk could be effectively managed 
in the clinic with appropriate risk-minimization measures. The release of pro-inflammatory 
cytokines is believed to be partially responsible for the occurrence of IRRs. 
12.1.2.2 Risk of Immunogenicity and Potential Safety Impact 
LMB-100 may cause the formation of ADAs. These may trigger hypersensitivity reactions or 
immune complex-mediated responses. The development of ADAs to LMB-100, an improved 
cytolytic fusion protein with a humanized targeting moiety directed against mesothelin and a de-
humanized, truncated Pseudomonas exotoxin A is expected to be less likely than SS1P. Clinical 
trials with SS1P have led to the development of neutralizing ADAs in 75% and 88% of participants 
after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.(20)  
Participants will be monitored at regular intervals for the development of ADAs and cytokines. In 
particular, any clinical signs and symptoms suggestive of a hypersensitivity reaction and/or an 
immune complex-mediated reaction possibly due to ADA formation will be carefully investigated. 
12.1.2.3 Risk of Inflammatory Reactions to Serosal Membranes  
LMB-100 administration may cause inflammatory reactions to serosal membranes including 
pleuritis, characterized by pleuritic chest pain, dyspnea, and hypoxia and pericarditis, characterized 
by precordial chest pain, congestive heart failure, hypotension, and uremia. Clinical trials with 
SS1P monotherapy have led to reversible pleuritis and pericarditis. Participants who develop 
symptoms of serosal inflammation should be closely monitored and receive standard treatments 
which may include corticosteroids. 
12.1.2.4 Risk of Capillary Leak Syndrome 
LMB-100 administration may cause VLS characterized by hypotension, hypoalbuminemia, edema, 
weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to the 
development of reversible VLS. Participants will be monitored with frequent assessments of chest 
x-rays, weight, edema, blood pressure, and serum albumin levels prior to and during treatment. 
Participants who develop symptoms of VLS should be closely monitored and receive standard 
symptomatic treatments. 
12.1.2.5 Risk of Renal Toxicity 
LMB-100 administration may cause renal toxicity characterized by increased creatinine, BUN, and 
proteinuria. In preclinical cynomolgus monkey studies, LMB-100 has shown increases in 
creatinine and histological changes including regenerative and degenerative changes to the tubular 
epithelium. Hemolytic uremic syndrome has been reported for other cytolytic fusion antibodies in 
development. 
Participants should be monitored with renal laboratory assessments including creatinine, BUN, and 
urinalysis. 


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12.1.2.6 Risk of Cardiac Toxicity 
There may be a risk for cardiac immune-related adverse events, specifically myocarditis, as a rare 
but serious complication after treatment with LMB-100. During clinical trial 19C0128, a patient 
with history of intrahepatic cholangiocarcinoma arising out of primary sclerosing cholangitis, 
initiated C1 tofacitinib + apixaban treatment on Day 1 and LMB-100 on Day 4. The patient began 
experiencing fatigue and pleuritic pain symptoms on Day 5. A cardiac MRI was performed that 
suggested a component of inflammatory myocarditis in addition to capillary leak syndrome 
12.1.2.7 Injection Site Reactions 
LMB-100 administration may cause adverse reactions at the infusion site characterized by pain, 
swelling, induration, and nodules. In preclinical NHP studies for both SS1P and LMB-100 
reddening and swelling of the infusion site were noted. Participants who develop symptoms of 
infusion site reactions can be administered pain relieving medication (analgesic) as required, and 
rotation of infusion sites is recommended. 
12.1.2.8 Pregnancy 
No studies assessing the reproductive and developmental toxicity of LMB-100 have been 
conducted to date. It is not known whether LMB-100 can cross the placenta or cause harm to the 
fetus when administered to pregnant women or whether it affects reproductive capacity. LMB-100 
should not be administered to pregnant women. 
12.1.3 Formulation and preparation  
LMB-100 drug product (20 mg/20 mL) is provided for syringe infusion as a sterile, colorless to 
brownish, preservative-free liquid in single-use, 20 mL vials. The nominal fill volume is 20 mL 
and the approximate concentration of LMB-100 recombinant fusion protein in the vials is 1 mg/mL. 
12.1.4 Stability and Storage  
Chemical and physical in-use stability for undiluted LMB-100 drug product in syringes has been 
demonstrated for 24 hours at 2-8 °C and 24 hours at ambient temperature. 
12.1.5 Administration procedures 
Please refer to Section 3.2.2. 
12.1.6 Incompatibilities   
Pharmacodynamic drug interaction studies have not been conducted. LMB-100 is contraindicated 
in subjects with a history of severe allergic anaphylactic reactions to humanized, chimeric or mouse 
peptides/antibodies or to any components of the product. 
12.2 TOFACITINIB 
Please refer to the FDA-approved package insert for product information, and a comprehensive 
list of adverse events. 


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12.2.1 Source  
Tofacitinib is commercially available in 5 and 10 mg tablets. Immediate release formulation will 
be used for this protocol.  
12.2.2 Administration 
Oral 


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mutations and a poor prognosis. Oncotarget 6, 11694-11703 
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Chen, S. H., Hung, W. C., Wang, P., Paul, C., and Konstantopoulos, K. (2013) Mesothelin 
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constructed from Pseudomonas exotoxin A for the treatment of cancer. The FEBS journal 
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Hassan, R., Bullock, S., Premkumar, A., Kreitman, R. J., Kindler, H., Willingham, M. C., 
and Pastan, I. (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin 
given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, 
ovarian, and pancreatic cancers. Clinical cancer research : an official journal of the 
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J., Miettinen, M. M., Steinberg, S. M., Fowler, D. H., and Pastan, I. (2013) Major cancer 
regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and 
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Hollevoet, K., Mason-Osann, E., Liu, X. F., Imhof-Jung, S., Niederfellner, G., and Pastan, 
I. (2014) In Vitro and In Vivo Activity of the Low-Immunogenic Antimesothelin 
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Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triple-
negative breast and gastric cancers. Molecular cancer therapeutics 13, 2653-2661 
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Bauss, F., Lechmann, M., Krippendorff, B. F., Staack, R., Herting, F., Festag, M., Imhof-
Jung, S., Hesse, F., Pompiati, M., Kollmorgen, G., da Silva Mateus Seidl, R., Bossenmaier, 
B., Lau, W., Schantz, C., Stracke, J. O., Brinkmann, U., Onda, M., Pastan, I., Bosslet, K., 
and Niederfellner, G. (2016) Characterization of a re-engineered, mesothelin-targeted 
Pseudomonas exotoxin fusion protein for lung cancer therapy. Mol Oncol  
25. 
Zhang, J., Khanna, S., Jiang, Q., Alewine, C., Miettinen, M., Pastan, I., and Hassan, R. 
(2016) Efficacy of Anti-Mesothelin Immunotoxin RG7787 plus nab-Paclitaxel against 
Mesothelioma Patient Derived Xenografts and Mesothelin as a Biomarker of Tumor 
Response. Clinical cancer research : an official journal of the American Association for 
Cancer Research  
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Weldon, J. E., Xiang, L., Zhang, J., Beers, R., Walker, D. A., Onda, M., Hassan, R., and 
Pastan, I. (2013) A Recombinant Immunotoxin against the Tumor-Associated Antigen 
Mesothelin Reengineered for High Activity, Low Off-Target Toxicity, and Reduced 
Antigenicity. Molecular cancer therapeutics 12, 48-57 
27. 
Liu, W., Onda, M., Lee, B., Kreitman, R. J., Hassan, R., Xiang, L., and Pastan, I. (2012) 
Recombinant immunotoxin engineered for low immunogenicity and antigenicity by 
identifying and silencing human B-cell epitopes. Proceedings of the National Academy of 
Sciences of the United States of America 109, 11782-11787 
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(2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. The New 
England journal of medicine 367, 495-507 
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Woodworth, D., Mukherjee, A., Zhang, H., Healey, P., Panes, J., Octave Induction, O. I., 
and Investigators, O. S. (2017) Tofacitinib as Induction and Maintenance Therapy for 
Ulcerative Colitis. The New England journal of medicine 376, 1723-1736 
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Jak/STAT signaling in immunity and disease. Journal of immunology 194, 21-27 


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Venous Thromboembolism in Rheumatoid Arthritis Patients Receiving Tofacitinib Versus 
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14 APPENDICES 
14.1 APPENDIX A- PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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14.2 APPENDIX B-MODEL CHEMOTHERAPY NOTE   
Bolded text should be replaced with patient-specific information. 
(1) 
Tofacitinib, 10 mg PO bid, Days 1-10 
 
(2) 
LMB-100: <dose per schema> mcg/kg, IV on Days 4, 6, 8 given over 30 minutes 
• Run with 1:10 in-line dilution of normal saline = <mg LMB-100> * 18 = # ml/hr  
LMB-100 dose for patients weighing more than 100 kg will be calculated as if they weigh 100kg. 
Pre-medications to be given 30-60 minutes prior to LMB-100 
o Diphenhydramine 25-50 mg PO or IV 
o Ranitidine 150 mg PO (see Table 11 for alternative formulations) 
o Acetaminophen 650 mg PO 
Additional medications: 
-Dexamethasone 8 mg IV, PRN severe infusion related reaction (should be available on unit) 
-Ondansetron 8 mg PO q8h, PRN nausea 
 
Please encourage oral hydration of ~1.5 L daily while receiving LMB-100.


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14.3 APPENDIX C- PATIENT MEDICATION DIARY 
 
 
Cycle #_______ 
Patient Name________________________________ Patient Study ID _____________________________ 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each Cycle. 
2. You will take 1 pill of 10 mg tofacitinib in the morning and also 1 pill of 10 mg tofacitinib in the evening each day.  Do 
not crush or chew. 
3. Record the date and what time you took them.   
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottles and this form to your physician when you go for your next appointment. 
6. If a dose is missed, log this in Comments column and call the Study Team for instructions on what to do.  Do not take 
additional doses to make up missed dose unless instructed to do so by the study team. 
 
Date 
 
Day 
Tofacitinib 
(taken twice a day) 
Time (AM) 
Time (PM) 
Comments (side effects or missed doses) 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 


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5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
Patient’s Signature: ___________________________________  Date: ____________________ 
Staff Signature: _______________________________________Date: ____________________ 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/25/2020
Page 1 of 13
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:   Christine Alewine, MD 
STUDY TITLE:  
A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in 
Combination with tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma, 
Cholangiocarcinoma and other Mesothelin Expressing Solid Tumors
STUDY SITE:  NIH Clinical Center
Cohort:                                                Screening
Consent Version:   
6/25/20
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Christine Alewine, M.D., Ph.D.
 
Phone: 240-760-6146
Email: Christine.alewine@nih.gov
 
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes the research study and is designed to help you decide if you 
would like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you to in 
making your decision about participating in this study. Additional information that may help 
you make a decision can be found in other sections of the document. Taking part in research at 
the NIH is your choice.
You are being asked to consider joining this study because you have a solid tumor that has 
either worsened after previous treatment or you are unable for some reason to receive standard 
treatment. 
This consent form requests your permission for us to test if you are eligible for our study. 
Patients on the study will receive LMB-100 and tofacitinib. LMB-100 is an investigational 
drug, which means that it has not been approved by the U.S. Food and Drug Administration 
(FDA) to treat your cancer. LMB-100 has been given in other clinical trials, but its effect has 
not lasted for as long as we hoped.  Tofacitinib is approved by the FDA for treating specific 
kinds of arthritis and bowel inflammation.
You may only participate in this study if your cancer is positive for mesothelin. With your 
consent, we will first obtain your tumor tissue to test for mesothelin.  If your cancer is positive 
for mesothelin, before beginning the study, you will need to have tests and/or procedures to 
help your doctor verify whether you can participate. This is called screening. The exams, tests, 
and procedures you will have are part of the usual approach for your cancer. Most must be 
performed within 28 days before enrollment. These basic tests include blood tests, x-rays, and 
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 06/25/2020
Page 2 of 13
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
physical exams, etc. Other tests are described further on in this consent form. It is important 
that you read these. These tests will not be performed if your tumor tissue tests negative for 
mesothelin.
You will not benefit from this screening evaluation.
You may choose not to be tested for eligibility or to have any other studies done.
You are free to stop participating in the trial at any time.  If you decide to stop, the study 
doctor may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe this research study in more detail. This information 
should be considered before you make your choice. Members of the study team will talk with 
you about the information described in this document. Some people have personal, religious, or 
ethical beliefs that may limit the kinds of medical or research treatments they would want to 
receive (such as blood transfusions). Take the time needed to ask any questions and discuss this 
study with NIH staff, and with your family, friends, and personal health care providers.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to receive care 
at the NIH, you must be taking part in a study or are being considered for a study. If you do 
choose to leave the study, please inform your study team to ensure a safe withdrawal from the 
research.  
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this research study is to determine a safe dose of LMB-
100 plus tofacitinib in patients with solid tumors that make a protein called mesothelin. 
Mesothelin is found on many different tumors, but on very few non-cancer cells.
We are asking you to screen for this research study because you have a solid tumor that might 
make mesothelin. You have either received or are unable to receive standard therapy.  If you 
have received standard therapy, your disease has gotten worse after that treatment. 
If your cancer cells do not make mesothelin, you will not be eligible for this study. Your blood, 
biopsy or other tissue may also be tested for other factors for research purposes.  However, this 
consent does not permit any additional studies that would test for genes (i.e. tendency for 
diseases) that might be inherited from you by your children. 
WHAT WILL HAPPEN DURING THE STUDY?
The following research test will be performed to determine whether you are eligible for this trial:

Mesothelin testing.  You must provide a sample tumor tissue for formal evaluation by the 
NCI Laboratory of Pathology. The tissue may be from a previous surgery or biopsy.  If 
none is available, we will ask you to have a biopsy to provide a fresh sample. Your tumor 
tissue will be used to determine whether your tumor cells have mesothelin. If no tumor 
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Consent to Participate in a Clinical Research Study
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tissue is available for this evaluation and new biopsy is not possible then you will not be 
eligible for the trial.
In addition, this sample of tumor tissue will be used for confirmation of diagnosis by the NCI 
Laboratory of Pathology.  
If this research test shows that your tumor does not make mesothelin, then further screening tests 
will not be performed.  Otherwise, screening will continue as described below with standard 
clinical tests that are normally used to assess your disease.
You will need to supply a complete list of your current medications to the study doctor. This 
includes over-the-counter medications and herbal supplements. Some medications may interact 
adversely with the study drugs and it is important that your study doctor and prescribing 
physician be aware of any potential risks so that they can prescribe alternative medications as 
necessary. If you do not already do so, please carry a list of your medications at all times.
Laboratory results performed outside of the NIH may be accepted if they have been performed 
recently. Otherwise, you will need to come to NIH Clinical Center to have the following 
standard, clinical tests performed at the NIH to determine whether you are eligible for this trial, 
which include:

Medical history and physical examination

Routine blood and urine tests including pregnancy test in women who can have children.  
Pregnant women will not be allowed on study.

Scans and x-rays

Electrocardiogram (ECG)

Echocardiogram

Blood for tumor markers

Test for tuberculosis infection

Tests for viruses (hepatitis B and C)

HIV testing: As part of this study, we will test you for infection with the human 
immunodeficiency virus (HIV), the virus that causes AIDS.  If you are infected with HIV 
you will not be able to participate in this study. We will tell you what the results mean, 
how to find care, how to avoid infecting others, how we report HIV infection, and the 
importance of informing your partners at possible risk because of your HIV infection.
HOW LONG WILL THE STUDY TAKE?
If you agree to take part in this screening and your cancer makes mesothelin, your involvement 
will last for as long as it takes us to know if you are eligible to participate on the treatment phase 
of the study. The length of time may range anywhere from 1-4 weeks. You will be required to 
come to NIH at least 1 time during screening. This visit may last anywhere from 1 to 3 days.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
As not all persons screened will be eligible for study therapy, up to 45 patients will be screened 
in this study in order to treat up to 32 subjects on the study.
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IRB APPROVAL DATE: 08/20/2020


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Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (2)
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WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The following study procedures may have risks and cause discomfort while you participate on 
this study:
Blood draws 
The risk for taking blood samples involves the withdrawal of between a few teaspoons and a 
half-cup of blood and the potential for bruising or infection that occurs with any blood draw.  
Each time a blood sample is needed, a needle will be put into a vein in your arm (or into your 
central venous catheter, if you have one).  You may feel pain when the needle goes through the 
skin.  Other side effects associated with drawing your blood for blood tests may include 
infection, bruising, redness, discomfort or bleeding at the site of the needle stick, and possible 
lightheadedness and fainting.
Electrocardiogram (ECG)
An electrocardiogram or ECG is a test that records the electrical activity of the heart.  It is used 
to measure the rate and regularity of heartbeats as well as the size and position of the heart 
chambers, and the presence of any damage to the heart.  For this test, you will be asked to lie 
down, and small patches that have an adhesive edge with a gel in the middle, called electrodes, 
will be placed on your arms, legs, and chest. The areas where the electrodes are placed will be 
cleaned and, if needed, some hair may be shaved or clipped to allow for better attachment of the 
electrodes.  The adhesive from the patches may irritate your skin.
Tumor Biopsies and Effusions
Tumor biopsies and tumor effusions: local anesthesia of the skin will be given prior to any tumor 
biopsy or effusion collection, in order to prevent painful sensations.  However, you may still 
experience pain or discomfort at the biopsy site.  Irritation, redness, swelling and/or bleeding 
may also occur.  There is a risk of abnormal healing, fever, infection or of an allergic reaction to 
the anesthetic agent used to anesthetize the skin at the biopsy site.  Once the sample has been 
obtained, a stitch may be used to close the wound and assist in healing.
Radiographic Tests
MRI, CT, X-ray, Nuclear Medicine and PET Scans are common standard imaging tests used in 
the diagnosis and monitoring of many diseases.  Although these tests have been in use for many 
years, their potential long-term effects on the body are still being learned.  The most common 
discomfort is the length of time a patient must lay still or flat while an X-ray or scan is being 
performed.  Occasionally, a patient may become uncomfortable within the closed space of the 
scanners (claustrophobia), particularly during an MRI.  If this occurs, cool air can be blown over 
you by a fan if desired or your doctor can order a medicine for you to help you relax during this 
scan.  Keeping the room well lit can also reduce this claustrophobic feeling.  If a contrast agent 
(the special dye) is given with the scan there is a small risk of having a reaction to the contrast.  
In the small group of patients who have a reaction, the most common symptoms are nausea, pain 
in the vein where the contrast was given, headache, a metallic or bitter taste in the mouth, and a 
warm or flushing feeling that lasts from 1-3 minutes.  Rarely, these symptoms may require 
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treatment.  In very rare cases, people have had more severe allergic reactions that result in skin 
rashes, shortness of breath, wheezing, or lowering of the blood pressure.  If you have had a 
reaction in the past, be sure to tell your doctor or nurse about it.  The radiation dose you receive, 
if your scan includes the use of X-rays or radioactive chemicals, is within the safe limits defined 
by the NIH Radiation Safety Guidelines, and is considered essential for your medical care. In 
some cases, you may require medicines to make you sleep so you can be still during the 
procedure.  The risks from this sedation or anesthesia are dependent on the types of medication 
used.  These risks will be fully explained to you prior to the procedure and a separate informed 
consent will be obtained for anesthesia.
An IV line may need to be inserted for administration of the contrast agent or anesthetic.  This 
can cause pain at the site where the IV is placed and carries a small risk of bruising or infection.
Patients with a cardiac pacemaker, neural pacemaker, some types of surgical clips, cochlear 
implants, foreign metal objects, permanent retainers, or any iron-containing material within the 
body should not undergo MRI, because of the effect of the strong magnet on these objects.
What are the risks related to pregnancy? 
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study. You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 3 months after you finish study treatment (the restricted period). 
If you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that 
we did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period. If you think or know you have become pregnant during the 
restricted period, please contact the study team member as soon as possible.
If you are a sexually active person with a partner able to become pregnant, it is important that 
your partner not become pregnant during the restricted period. There may be unknown risks to a 
fetus or risks we did not anticipate. You and your partner must agree to use birth control if you 
want to take part in this study. If you think your partner has become pregnant during the 
restricted period, please contact the study team member as soon as possible. If you and your 
partner plan for your partner to become pregnant after the restricted period, please discuss this 
with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you will be exposed to radiation from one CT-
guided biopsy, and one CT scan. The amount of radiation exposure you will receive from these 
procedures is equal to approximately 1.9 rem. A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


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Consent to Participate in a Clinical Research Study
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The CT-guided biopsy, CT scan and PET scan that you get in this study will expose you to the 
roughly the same amount of radiation as 6.3 years’ worth of background radiation.  Most of the 
time, this amount of extra radiation is not harmful to you.  However, scientists believe that being 
exposed to too much radiation can cause harmful side effects.  This could include getting a new 
cancer.  We estimate that this could happen in about 1 out of every 1000 people who get a very 
large amount of extra radiation. 
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You will not benefit from being in this study.
However, if eligible for the study protocol the potential benefit to you might be that your lesions 
could go away or get smaller if the treatment is effective. The treatment could also decrease 
some of your symptoms, including pain, that are caused by your lesions. 
Are there any potential benefits to others that might result from the study?
We do not know if you will receive personal medical benefit from allowing us to perform these 
tests.  However, this testing may make you eligible for our trial.
If you become eligible for our treatment study and you choose to participate, you would need to 
give additional informed consent regarding the risks of the treatment.
WHAT OTHER OPTIONS ARE THERE FOR YOU?
You may choose not to be tested for eligibility or to have any other studies done.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
The results from the evaluations for this screening will be reported to you. You will be informed 
at that time if you are eligible for the main study at that time. 
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your participation for the following reasons:

if he/she believes that it is in your best interest

if you are ineligible for the study

if you become pregnant
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


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Consent to Participate in a Clinical Research Study
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
if new information shows that another treatment would be better for you

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.  
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to our collaborators or 
designated representatives. 
Will your specimens or Data be saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. 
We plan to use these data for studies going on right now, as well as studies in the future. 
We may share your specimens and data with other researchers. They may be doing research in 
areas similar to this research or in other unrelated areas. These researchers may be at NIH, 
other research centers and institutions, or industry sponsors of research. We may also put your 
research data in a large database for broad sharing with the research community. These 
databases are commonly called data repositories. These data repositories might or might not be 
located at the NIH. If your individual research data is placed in one of these repositories, it will 
not contain information that can easily identify you and only qualified researchers will be able 
to look at your data. These researchers must receive prior approval from individuals or 
committees that monitor the use of the research information.
If you change your mind and do not want us to store and use your specimens and data for 
future research, you should contact the research team member identified at the top of this 
document. We will do our best to comply with your request but cannot guarantee that we will 
always be able to destroy your specimens and data. For example, if some research with your 
specimens and data has already been completed, the information from that research may still be 
used. Also, if the specimens and data has been shared already with other researchers, it might 
not be possible to withdraw.
Please place your initials in the blank next to Yes or No for each of the questions below:
My specimens and data may be stored and used for future research as described above.
_____ Yes
_____ No
Initials
Initials
My specimens and data may be shared with other researchers and used by these researchers for 
future research as described above.
_____ Yes 
_____ No
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IRB APPROVAL DATE: 08/20/2020


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Consent to Participate in a Clinical Research Study
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Initials
Initials
How Long Will Your Data be Stored by the NIH?
If you are eligible for the study, your data will be stored at NIH indefinitely. 
Risks of Storage and Sharing of Specimens and Data
When we store your tissue specimens and data, we take precautions to protect your information 
from others that should not have access to it. When we share your specimens and data, we will 
do everything we can to protect your identity by removing information that can identify you. 
Even with the safeguards we put in place, we cannot guarantee that your identity will never 
become known or someone may gain unauthorized access to your information. New methods 
may be created in the future that could make it possible to re-identify your data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The 
amount of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this screening. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
The NCI generally does not cover expenses during screening. If you are scheduled for and begin 
treatment, the NCI will cover the cost for some of your expenses. Someone will work with you 
to provide more information.  
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or clinical care 
that you receive at the NIH Clinical Center.

If some tests and procedures are performed outside the NIH Clinical Center, you may 
have to pay for these costs if they are not covered by your insurance company.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide. You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020


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CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to 
health boards if they find a disease like tuberculosis. However, the researchers will do their best 
to make sure that any information that is released will not identify you.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA) 
and the Office for Human Research Protections, which are involved in keeping research 
safe for people.

National Institutes of Health Intramural Institutional Review Board
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release 
any information about your research involvement without your written permission. However, if 
you sign a release of information form, for example, for an insurance company, the NIH will 
give the insurance company information from your medical record. This information might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens and data. You should be aware that there is a 
slight possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act.
Certificate of Confidentiality 
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
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IRB APPROVAL DATE: 08/20/2020


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NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent 
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act. In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality. For example, sometimes the 
Privacy Act allows release of information from your record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit. However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Christine 
Alewine, Christine.alewine@nih.gov, at 240-760-6146. You may also call the NIH Clinical 
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Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been 
given the opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print 
Name 
of 
Research 
Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the 
explanation about this study and have been given the opportunity to discuss it and to ask 
questions. I am legally authorized to make research decisions on behalf of the adult participant 
unable to consent and have the authority to provide consent to this study. As applicable, the 
information in the above consent was described to the adult participant unable to consent who 
agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only:
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE 
OF AN INTERPRETER:
____An interpreter, or other individual, who speaks English and the participant’s  
preferred language facilitated the administration of informed consent and served as a 
witness. The investigator obtaining consent may not also serve as the witness                     
    
An interpreter, or other individual, who speaks English and the participant’s preferred language 
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facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 19C0128
IRB APPROVAL DATE: 08/20/2020