Conditions: Urinary Bladder Neoplasms
Keywords: Carcinoma-in-situ High-grade Ta or T1 disease Papillary Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 15
Healthy volunteers: no

Brief summary:
Background:

Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy cancer cells.

Objective:

To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people with bladder cancer that has not spread to the muscle in the bladder.

Eligibility:

People ages 18 and older who have bladder cancer that has not spread to the muscle in the bladder and was treated unsuccessfully with Bacillus Calmette-Guerin

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small piece of tumor is removed.

Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing tumors.

Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that takes pictures of the body.

Electrocardiogram to test heart function

Participants will receive Durvalumab and Vicineum in 2 phases:

First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months

Second phase: Durvalumab every 4 weeks and Vicineum once every other week

Participants will have tumor samples taken every 3 months. They will have blood and urine tests throughout the study.

Participants will continue treatment for up to 2 years.

Participants will have a visit about 30 days after their last treatment. This includes blood and urine tests. It may include a cytoscopy or additional biopsies.

Detailed description:
In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390 deaths associated with bladder cancer. Bladder cancer is associated with the highest costs among all types of cancer, due to the need for lifelong routine monitoring and treatment. Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high-grade disease, these therapies can become ineffective over time in up to two-thirds of patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%. Progression to MIBC portends a poor outcome as only 50% of patients will survive five years despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic options for NMIBC that recurs or progresses.

Vicineum(TM) is a recombinant fusion protein, VB4-845, that contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on the surface of urothelial carcinoma cells and therefore represents a good target for Vicineum(TM) to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with high grade bladder cancer, 16% of patients treated with induction and maintenance therapy with Vicineum(TM) remained disease-free at 1 year. As a result, Vicineum(TM) is currently being evaluated as a single agent in a phase III trial.

Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum(TM), demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it was done in a non-small cell lung cancer (NSCLC) model, the results were impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 \[B7-H1\], cluster of differentiation \[CD\]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one standard platinum-based regimen in a phase I trial.

Therefore, this trial will take two agents with single agent activity against urothelial cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously Treated with BCG.

Objectives:

Primary Objectives:

To evaluate the safety and tolerability of durvalumab and Vicineum when administered in combination to subjects with BCG-refractory high-grade NMIBC

Eligibility:

Subjects must have a histologically confirmed high-grade non-muscle invasive urothelial carcinoma (transitional cell carcinoma) of the bladder as follows:

Carcinoma-in-situ (CIS) with or without papillary tumors

High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.

Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the Food and Drug Administration (FDA): Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). See exception below for persistent T1 disease below. There is no upper limit on the amount of prior BCG a subject may have received.

Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy

Design:

This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects with high-grade NMIBC previously treated with BCG.

All subjects will receive Vicineum intravesically and durvalumab systemically at the standard doses for both drugs as determined by Phase II trials for each drug, as no synergy or additive effect is expected for adverse events.

Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.

Vicineum will be given as monotherapy for 1 week followed by treatment with the combination of Vicineum and durvalumab starting week 2.

In the initial six patients, three subjects at a time will enroll at these doses and schedules. Dose-liming toxicity (DLT) for each subject will be determined during the initial 6-week period that the subject is on treatment (i.e., the DLT period). When all subjects in the initial cohort have been on treatment through the DLT period, all available safety data will be considered in decisions to enroll additional subjects at this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard "3 + 3" design. There will be no dose-escalations in this study. The dose of durvalumab will remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the initial doses in combination induce DLTs.

After the first six patients, an additional 18 subjects will be enrolled at the initial doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain additional safety data, biomarker data and preliminary anti-tumor activity.

Each subject's course will consist of the following periods:

Screening/Baseline Period: The subject is consented and undergoes screening assessments to determine eligibility for the study.

Treatment Period: The subject is treated and monitored for safety. Biomarker data will be obtained prior to treatment and at periodic intervals during treatment. Subjects who remain free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment for an additional 12 months until they develop recurrent high-grade disease, disease progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent withdrawal, pregnancy).

Post-Treatment. The subject will return to the study site monthly for up to 90 days after the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically significant related adverse events (AEs) or serious adverse events (SAEs) will have additional follow-up after the initial post-treatment visit.

Arms:
arm 1: Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 participants. arm 2: Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 participants. arm 3: Level 1, Durvalumab 1500mg intravenous (IV) Every 4 Weeks (Q4WK) + Vicineum 20 mg arm 4: Arm 2, Durvalumab + Vicineum at the Maximum Tolerated Dose (MTD)

Interventions: intervention 1: Durvalumab intervention 2: Vicineum intervention 3: Acetaminophen intervention 4: Antihistamine intervention 5: Bladder Biopsy intervention 6: TURBT intervention 7: Cystoscopy intervention 8: Urine cytology intervention 9: Electrocardiogram intervention 10: CT intervention 11: MRI
Intervention descriptions: intervention 1: Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost. intervention 2: Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline. intervention 3: Acetaminophen or equivalent medications per institutional standard may be administered at the discretion of the investigator. intervention 4: Antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at the discretion of the investigator. intervention 5: Bladder biopsy at screening and every 3 months before each cystoscopy per schema. intervention 6: Transurethral resection of a bladder tumor (TURBT) at screening and every 3 months before each cystoscopy per schema. intervention 7: Urine cytology at screening and every 3 months before each cystoscopy per schema. intervention 8: Urine cytology at baseline and every 3 months before each cystoscopy per schema. intervention 9: Electrocardiogram (ECG) at screening, pre-durvalumb infusion and as clinically indicated during the trial. intervention 10: Computed tomography (CT) at screening and every 12 months while on study. intervention 11: Magnetic resonance imaging (MRI) at screening and every 12 months while on study.

Protocol document:
ICF_001.pdf: 
IRB NUMBER: 17C0157
IRB APPROVAL DATE: 2/21/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/10/2023
Page 1 of 17
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Vladimir Valera Romero, M.D.
STUDY TITLE: 
A Phase I Single-Arm Study of the Combination of 
Durvalumab (MEDI4736) and Vicineum (oportuzumab 
monatox, VB4-845) in Subjects with High-Grade Non-
Muscle-Invasive Bladder Cancer Previously Treated with 
Bacillus Calmette-Guérin (BCG)
STUDY SITE: 
NIH Clinical Center
Cohort: 
Standard 
Consent Version:
01/10/2023
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Vladimir Valera Romero, M.D. 
Phone:  240-858-3947
Email: vladimir.valeraromero@nih.gov
 
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). 
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. Taking part in research at the NIH is your choice.
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.  


IRB NUMBER: 17C0157
IRB APPROVAL DATE: 2/21/2023
PATIENT IDENTIFICATION
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WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to obtain information on the safety and effectiveness of 
combination treatment with Durvalumab and Vicineum when given to participants with bladder 
cancer that has not spread to the muscle in the bladder.  
If you join this research study, you will receive an investigational drug Vicineum. Investigational 
means that it has not been approved by the U.S. Food and Drug Administration (FDA) for 
treatment of your cancer. 
Vicineum is a drug made of an antibody connected to a protein that can kill cells.  This protein is 
a modified “pseudomonas exotoxin A.”  Vicineum is designed to attach to cells that have a 
different protein called EpCAM on the outside of the cell.  After attaching to a cell, the modified 
pseudomonas exotoxin A can be released inside the cell causing the cell to die.  It is thought that 
almost all bladder cancer cells have EpCAM on the surface of their cells.
Durvalumab is a drug designed to boost the body’s immune system by targeting a protein on tumor 
cells called PDL-1. PDL-1 normally maintains the balance of the immune system. In cancer, PDL-
1 helps tumors evade detection and elimination by the immune system. Durvalumab may increase 
the immune system’s ability to identify and destroy cancer cells. Durvalumab, was recently 
approved by the FDA for metastatic urothelial/bladder cancer. Although it was FDA approved at 
a different dose than what is administered in this trial, there is safety data from several trials for 
the dosage used in this protocol.
There is some evidence in a mouse model that the combination of these two drugs can be more 
effective in shrinking your tumor.  Therefore, we are evaluating both the safety of the combination 
as well as how well the combination works.  
As of February 2021, Durvalumab is no longer approved in the US for metastatic urothelial/bladder 
cancer who have had their disease worsen on chemotherapy. This decision was made between the 
manufacturer of this drug and the FDA and was not based on any safety issues. Durvalumab is 
considered investigational and the FDA has given us permission to use it in this study. Early results 
from the current study provide data to support the continuation of this trial.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being invited to participate in a research study because you have been diagnosed with 
bladder cancer and your cancer has not spread to the muscle in the bladder.  Your cancer may be 
spreading on the lining of the bladder (this is called carcinoma in situ [CIS]) and/or may look like 
a polyp (papillary disease).  In the past, you were treated with BCG, and either your bladder cancer 
did not respond to BCG treatment or your bladder cancer returned after your BCG treatment was 
completed.
Currently, your bladder cancer is thought to be curable by having surgery to remove your bladder. 
By participating in this study, you agree to have treatments with Durvalumab in combination with 
Vicineum, an experimental therapy, rather than having surgery now to remove your bladder. You 
will be checked approximately every 3 months with a cystoscopy, by examining cells in the urine, 
and possibly bladder biopsies or bladder tumor resection while on treatment to see if your cancer 
seems to be getting better or worse.  However, there is risk that by not having surgery to remove 


IRB NUMBER: 17C0157
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PATIENT IDENTIFICATION
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your bladder now, your bladder cancer could progress to the point where it is no longer curable by 
removing your bladder or from any other types of treatment.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 40 people will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
You will need to have some exams, tests and procedures to find out if you can be in the study.  
These exams, tests and procedures are usually a part of regular cancer care and may be done even 
if you do not join the study.  However, there are some extra exams, tests and procedures that you 
will need to have if you take part in this study. Most of these tests will be done under a separate 
protocol for screening or records will be collected if you had these performed for another reason 
(such as standard of care or outside of the NIH). If you have had some of them recently, they may 
not need to be repeated.   
During the study
Once it has been determined that you are eligible and agree to participate in the study, you will 
have additional blood (about 2 tablespoons) and urine tests and you will be asked again about any 
medications you have been taking.  A sample of your tumor will be tested to measure the amount 
of protein called EpCAM on the surface of the cancer cells.  You may also need to have some of 
the tests that were done at screening repeated depending on how much time has passed.  Your 
study team will let you know if any of the above tests need to be repeated. 
All participants in this study will receive Durvalumab and Vicineum. Vicineum will be 
administered using a Foley catheter placed in the bladder. You will hold the Vicineum for two 
hours and will have to change position every 15 minutes while sitting or lying in bed. After the 
two hours, the nurse will drain the Vicineum from your bladder.    
Durvalumab is an infusion administered approximately over 1 hour by placing an IV or using a 
peripherally inserted central catheter (PICC) placed in your arm.
If you are not able to continue to take one of the study drugs for any reason (such as for side 
effects), the study treatment with both drugs will be stopped.
Treatments are given in two phases.  The first phase is called the Induction Phase.  In the Induction 
Phase, you will receive Durvalumab every 4 weeks and Vicineum once a week for 3 months. After 
the Induction Phase, if you have no evidence of cancer or if you have a less aggressive form of 
cancer, you will continue to the Maintenance Phase.  In the Maintenance Phase, you will receive 
Durvalumab every 4 weeks and Vicineum once every other week.  
During the treatment, you will see the doctor periodically to have many of the same tests done as 
were done in screening to see how you are doing – these include a physical exam and vital signs, 
blood samples (such as to check blood counts and organ function), and urine tests.  You will also 
have an electrocardiogram (ECG or EKG) repeated at week 2 to check your heart function. An 


IRB NUMBER: 17C0157
IRB APPROVAL DATE: 2/21/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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additional sample of your tumor will be obtained every 3 months and a CT every year to determine 
whether your tumor has returned.
The research nurse will go over with you a study calendar that shows how often these tests, drug 
administration, and/or procedures will be done. 
How long will I be in this study?
You will receive treatment for a total of 2 years as long as you are tolerating treatment and your 
cancer does not return.
While on treatment, if your bladder cancer hasn’t returned, you will continue to be evaluated every 
3 months.  If your bladder cancer returns, your doctor will discuss your treatment options.  
Research tests
In addition to the tests that we will conduct to determine 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. These studies include:

Urine: before you have received any study drug, first void after you have received your 
week 1 dose of Vicineum; first void the next morning after week 1 Vicineum; day 7 void 
prior to start of week 2 Vicineum; week 6, week 10, and week 13 before study therapy; 3 
months; and 6 months.

Blood: Research tests will be done on blood taken at various times (before you have 
received any study drug, at 2 weeks, 3 weeks, 5 weeks, 8 weeks, 3 months, 6 months) 
during your participation in this study.  The NIH has set a limit on the maximum amount 
of blood that can be taken for research. This limit is based on your age. For adults, no more 
than 37 tablespoons can be taken over an 8-week period.

Tumor biopsies: Any biopsies done on this study will be for clinical reasons to rule out 
tumor recurrence, however, extra biopsy material (if available) will be used for research 
purposes.  

Genetic testing: We will use your tissue sample to compare gene expression profiles in 
tumor cells before and after treatment with Vicineum and Durvalumab.  This will help us 
better understand how the study drugs work inside the human body.

Additional research testing:  Tumor and blood samples collected for research purposes on 
this study may be used to look for specific changes in the DNA in tumors that could be 
used to develop new ways of diagnosing and treating cancer. DNA (also called 
deoxyribonucleic acid) in the cells carries genetic information and passes it from one 
generation of cells to the next – like an instruction manual. While normal tissue contains 
the DNA (instructions) that you were born with, DNA in tumor cells has changed – or 
mutated – and we think that change in the DNA is what causes tumors to form and to grow. 
RNA (also called ribonucleic acid) carries the instructions from the DNA to the parts of 
your cells that make proteins. 


IRB NUMBER: 17C0157
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To look at your DNA and RNA, we may use do what is called “DNA or RNA sequencing.” 
This is where we will do special tests in the lab to look at the sequence, or order, of how 
your DNA or RNA are put together. This is what makes you unique. 
To determine which parts of the DNA or RNA have mutated, we will compare the DNA 
or RNA in your tumor cells to DNA or RNA from normal cells. We will then analyze the 
results from similar tumors to see if there are any changes in the DNA or RNA that are 
common to a particular type of tumor. To examine the tumor and normal tissue we may 
use several different techniques depending on the type of tissue we collect. These could 
include growing cell lines (cells which keep dividing and growing in the laboratory, 
sometimes for years allowing us to continually study those cells), xenograft studies 
(placing or growing cells in another animal, such as mice), and looking in detail at the parts 
of the genes that produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for 
research purposes only; they may not be as accurate as the tests that are performed in a 
laboratory that is certified to perform genetic testing or testing for routine clinical care. For 
these reasons, we will not give you the results of the research tests done on your research 
samples in most cases. There may be exceptions to what we share with you, and this is 
described later in this consent form in the section for “Return of research results”.
When you are finished taking the drugs (treatment)
You will return to the clinic for  monthly evaluations for up to 90 days after your last treatment, 
whenever that occurs.  You will have the following tests done: physical exam, vital signs, routine 
blood tests (about 2 tablespoons of blood each time) and urine tests.  If your bladder cancer hasn’t 
returned, you will have a cystoscopy, biopsies of any areas of the bladder suspicious for cancer, 
and a urine test for cancer cells.  If you have ongoing significant side effects, you will continue to 
be followed until the side effects end or they are not changing.  
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we do not know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice a highly effective form of birth control and a barrier method before starting 
study treatment, during study treatment, and for 120 days after you finish study treatment.  If you 
think that you or your partner is pregnant, you should tell your study doctor or nurse at once.  
Please use effective forms of birth control or make sure your partner uses method from the list 
below: 
Highly effective methods:
•
Abstinence 

Intrauterine device (IUD)
•
Hormonal [birth control pills, injections, or implants]
•
Tubal ligation
•
Vasectomy


IRB NUMBER: 17C0157
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Additional Effective methods:

Male condom

Diaphragm

Cervical Cap 
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study? 
Durvalumab 
The following are side effects observed in patients receiving Durvalumab alone:
Very Common

Diarrhea

Rash/itchy skin

Abdominal pain

Cough with or without mucus 

Fever 

Low thyroid function (hypothyroidism) which may cause fatigue, increased sensitivity to 
cold, constipation, dry skin, unexplained weight gain, puffy face, muscle weakness, slow 
heart rate, thinning hair, impaired memory.

Upper respiratory tract infections
Common

Increased liver enzymes 

High thyroid function (hyperthyroidism)which may cause anxiety or nervousness, weight 
loss, frequent and loose bowel movements, breathlessness, feeling hot and possibly having 
heart palpitations.

Pain or difficulty urinating  

Night sweats

Inflammation in the lungs (pneumonitis that can be fatal). In some cases, this could be 
caused by your immune system attacking your lungs.

Hoarse voice

Swelling of arms and legs

Muscle pain 

Decreased kidney function (you may have an increase of creatinine levels in a blood test)

During or after drug infusion having fever, chills, change in blood pressure or difficulty in 
breathing, which might be serious 

Pneumonia

Oral thrush


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
Dental and oral soft tissue infection

Influenza
Uncommon

Scarring of the lungs (interstitial lung disease)

Inflammation to the liver (hepatitis), that can be fatal. In some cases, this could be caused 
by your immune system attacking your liver.

Inflammation of the colon which can lead to abdominal pain and diarrhea with or without 
blood. If left untreated, this may lead to a tear in the wall of the intestine which can be 
serious and life threatening. In some cases, this could be caused by your immune system 
attacking your colon. 

Inflammation of the thyroid

Inflammation of the kidney

Dry itchy skin

Inflammation of the muscles or associated tissues, such as blood vessels that supply the 
muscles which may cause weakness and aches, tired feeling when standing or walking, 
muscle pain and soreness

Problems with your adrenal glands (adrenal insufficiency): may cause stomach pains, 
vomiting, muscle weakness and fatigue, depression, low blood pressure, weight loss, 
kidney problems, and changes in mood and personality. These complications may be 
permanent and may require hormone replacement

Inflammation of the pancreas which may cause increased pancreas enzymes (lipase and 
amylase) and symptoms of persistent upper abdominal pain (sometimes made worse by 
eating and drinking), nausea, vomiting and general weakness.

Inflammation or sores in the lining of the small rectum that may be painful, bloody bowel 
movements, rectal bleeding or mucoid discharge
Rare

Type 1 Diabetes mellitus (high blood sugar)

Allergic reactions, causing:
o
swelling of the face, lips and throat
o
breathing difficulties 
o
hives or nettle like rash

Pain, blistering, thickening, burning, and reddening at the site of injection.

Problems with the pituitary gland (hypopituitarism/hypophysitis): Hypopituitarism refers 
to decreased output of hormones from the pituitary gland in the brain and may be caused 
by inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular periods 
in women. These complications may be permanent and may require hormone replacement.

Thirstiness caused by an imbalance of fluids in the body (diabetes insipidus)


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
New allergies to previously exposed substances, other than Durvalumab. For example, it 
is possible that you could develop an allergy to shellfish or IV contrast while taking 
Durvalumab. These allergies may be severe and life threatening

Rash, blistering and ulcers on the legs, arms, and abdomen (pemphigoid) 

Inflammation of the blood vessels, heart and the tissue that surrounds the heart

Inflammation of the brain or the tissues that cover the brain

Inflammation of your heart causing fast or slow heart rate, chest pain and shortness of 
breath

Problems with decrease number of platelets causing a rash or bleeding of your mouth, nose, 
gut and bladder (in some cases caused by your immune system)

Inflammation of the bile duct system (cholangitis) that leads to scarring (sclerosis) and 
narrowing of the ducts. The bile duct system carries bile from your liver and gallbladder 
into the first part of your small intestine

Inflammation of the bladder (cystitis)

Low white blood cell count which may caused by your immune system attacking these 
type of cells.

Weakness in the arm and leg muscles, double vision, and difficulties with speech and 
chewing caused by a breakdown in communication between nerves and muscles 
(myasthenia gravis).

Inflammation of the middle layer of the eye and other events involving the eye

Growths of tiny collections of inflammatory cells in different parts of the body

Hardening and tightening of the skin and connective tissues and loss of skin color

Rheumatological events (inflammatory disorder causing muscle pain and stiffness and 
autoimmune arthritis)

Myasthenia Gravis which results in weakness and rapid fatigue of any of the muscles under 
your voluntary control.
In addition to the possible risks identified in patients treated with durvalumab, other immune- 
mediated side effects are possible that have not been observed and can result in inflammatory side 
effects in any organ or tissue.
Vicineum
Likely 

Pain or difficulty urinating  

Blood in the urine

Frequent urination 

Fatigue (tiredness) 

Urge to urinate quickly 

Bladder and urinary systems infection


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
Frequent urination at night

Uncontrolled leaking or passing of urine

Bladder pain, spasm or discomfort
Less Likely

Dizziness

Flu-like symptoms

Diarrhea

Bone or joint pain

Fever
Rare

Kidney failure or acute kidney injury (kidneys suddenly stop working properly)

Inflammation of the liver 

Allergic reaction
Tell your study doctor right away if you have any of these symptoms as they may need to be treated 
urgently. 
A new drug may show an increase in side effects or unexpected effects as more studies are 
conducted. For your safety, you will be followed closely by your study doctor and the study staff 
for any undesirable or unexpected side effects during your participation in this study and each time 
you receive Durvalumab and Vicineum.
There may be other side effects of Durvalumab and Vicineum that are unknown. You will be told 
about any new findings that develop during this study that may affect your decision to stay in the 
study.
Risks from Blood Collection 
The risks from drawing blood may include discomfort from insertion of the needle, bruising, pain, 
redness or swelling at site of blood drawing, fainting and rarely, infection at the site of blood 
drawing.
Risks from Bladder Procedures
Cystoscopy, TURBT, biopsies and catheterization may cause the following discomforts:  burning 
when passing urine, blood-tinged urine, bladder infection or the need to urinate frequently 
following the procedures.  The insertion of a catheter into the bladder through the urethra may be 
uncomfortable. You may be provided a local anesthetic (pain reliever put on your skin around 
where the catheter goes in) and sterile lubricant (jelly that makes the catheter easier to put in) at 
the time of the catheter placement.  There is also a small risk that these procedures, particularly 
cystoscopy, TURBT and biopsies, could damage the lining of the bladder or cause a small hole in 
your bladder.  This could lead to urine or drugs leaking out of the bladder causing severe side 
effects.  


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Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component. 
Radiation Risk
During your participation in this research study, you will be exposed to radiation from CT scans.  
The amount of radiation exposure you will receive from these procedures is equal to approximately 
1.4 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. 
The CTs that you get in this study will expose you to the roughly the same amount of radiation as 
4.7 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.
CT contrast risks
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath and 
swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT can 
cause kidney problems for certain participants, such as those with impaired kidney function.


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Electrocardiogram risks
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
You may or may not receive direct medical benefit from participating in this study.  Even if 
treatment with Durvalumab and Vicineum demonstrates some efficacy such that some participants 
in this study are able to delay or avoid having their bladder removed, such a benefit cannot be 
guaranteed for all participants in the study. The possible benefit to other people with this condition 
includes learning more information about treatment in participants with bladder cancer that has 
not spread to the muscle in the bladder.
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
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to provide a sample to verify the findings we have seen in our lab. If the results 
are verified, you will be re-contacted and offered a referral to a genetic healthcare provider to 
discuss the results.


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ALTERNATIVE APPROACHES OR TREATMENTS
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
You do not have to participate in this study to be treated for your cancer.  Your doctor will discuss 
your treatment options with you.  These may include:

Having your bladder removed

Receive additional treatment (with other approved or standard therapies) without being in 
a research study

Taking part in another study
STOPPING THERAPY 
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 comes back during treatment

if your health status changes during the study such that receiving therapy might be too 
dangerous

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if you are unable to follow the study requirements

if the study is ended
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.
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 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 are using drugs developed 
by AstraZeneca and Sesen Biotherapeutics through a joint study with your researchers and the 
company. The company also provides financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 


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to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
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.


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On this study, 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.

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.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor Center for Cancer Research or their agent(s) 

Qualified representatives from AstraZeneca, the pharmaceutical company who produces 
Durvalumab and qualified representatives from Sesen Biotherapeutics, the pharmaceutical 
company who produces Vicineum
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
 


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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 records 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 medical 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.


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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, Vladimir 
Valera Romero at vladimir.valeraromero@nih.gov or 240-858-3947. You may also call the NIH 
Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 
301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.


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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 should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.

Prot_SAP_002.pdf: 
Abbreviated Title: Durvalumab & Vicineum for NMIBC
Version Date: 05/22/2025
1
Abbreviated Title: Durvalumab & Vicineum for NMIBC
NIH Protocol #: 17-C-0157 
Version Date:  05/22/2025
NCT #: NCT03258593
Title: A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and 
Vicineum (oportuzumab monatox, VB4-845) in Subjects with High-Grade Non-Muscle-Invasive 
Bladder Cancer Previously Treated with Bacillus Calmette-Guérin (BCG)
NCI Principal Investigator:
Raju Chelluri, MD
Urologic Oncology Branch (UOB)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
10 Center Drive, 1-5940
Bethesda, MD 20892
Phone: 240-858-3700
E-mail: raju.chelluri@nih.gov  
  
Drug Name:
Durvalumab (MEDI4736)
Vicineum™ (oportuzumab monatox, 
VB4-845)
IND Number:
136199
136199
Sponsor:
Center for Cancer Research (CCR)
Center for Cancer Research (CCR)
Manufacturer:
AstraZeneca
Sesen Biotherapeutics
Supplier:
AstraZeneca
Sesen Biotherapeutics


Abbreviated Title: Durvalumab & Vicineum for NMIBC
Version Date: 05/22/2025
2
PRÉCIS 
Background:
In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390 deaths 
associated with bladder cancer.1 Bladder cancer is associated with the highest costs among all 
types of cancer, due to the need for lifelong routine monitoring and treatment.2 Approximately 
70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and are treated 
by transurethral resection of bladder tumor (TURBT) followed by intravesical treatment with 
BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high grade disease, 
these therapies can become ineffective over time in up to two-thirds of patients and disease 
progression to muscle invasive bladder cancer (MIBC) can occur.3  In patients who present with 
CIS (carcinoma in situ) rates of progression are greater than 50%.4  Progression to MIBC 
portends a poor outcome as only 50% of patients will survive five years despite undergoing 
radical cystectomy.5 Clearly, there is a large unmet need in therapeutic options for NMIBC that 
recurs or progresses.
Vicineum™ is a recombinant fusion protein, VB4-845, that contains a humanized single-chain 
antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked to 
ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed 
on the surface of urothelial carcinoma cells and therefore represents a good target for 
Vicineum™ to bind to.  In a previous phase II study in BCG refractory or BCG intolerant 
patients with high grade bladder cancer, 16% of patients treated with induction and maintenance 
therapy with Vicineum™ remained disease-free at 1 year.  As a result, Vicineum™ is currently 
being evaluated as a single agent in a phase III trial.  
Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum™, demonstrated 
an abscopal effect and synergy with the use of a checkpoint blockade inhibitor.  Although it was 
done in a NSCLC model, the results were impressive in causing tumor shrinkage. Durvalumab is 
a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1 
(PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 
(PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against 
advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one 
standard platinum-based regimen in a phase I trial. 
Therefore, this trial will take two agents with single agent activity against urothelial cancer and 
combine them in a Phase I trial for patients with high-grade NMIBC Previously Treated with 
BCG.
Objectives:
Primary Objectives:
•
To evaluate the safety and tolerability of durvalumab and Vicineum when administered in 
combination to subjects with BCG-refractory high-grade NMIBC


Abbreviated Title: Durvalumab & Vicineum for NMIBC
Version Date: 05/22/2025
3
Eligibility:
•
Subjects must have a histologically-confirmed high-grade non-muscle invasive urothelial 
carcinoma (transitional cell carcinoma) of the bladder as follows: 
o
Carcinoma-in-situ (CIS) with or without papillary tumors
o
High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of 
the initial dose of study treatment.  If multiple bladder biopsies/TURBTs are required to 
confirm eligibility, the timing of the last bladder biopsy to the initial dose of study 
treatment must be within 12 weeks.
•
Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and 
the FDA6,7:  Subjects must have received at least two courses of intravesical BCG (at least 5 
of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a 
maintenance regimen or at least 2 doses of a repeat induction course).  See exception below 
for persistent T1 disease below.  There is no upper limit on the amount of prior BCG a 
subject may have received.  
•
Patients with persistent T1 high grade disease on TURBT following a single induction course 
of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is 
surgically unfit for cystectomy as deemed by the investigator or the patient declines 
cystectomy
Design:
•
This is a Phase I, open-label study of the combination of durvalumab and Vicineum in 
subjects with high-grade NMIBC previously treated with BCG.
•
All subjects will receive Vicineum intravesically and durvalumab systemically at the 
standard doses for both drugs as determined by Phase II trials for each drug, as no synergy or 
additive effect is expected for adverse events. 
•
Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase 
for at least one year with an option for a total of up to 2 years of treatment. During the 
Induction Phase, Vicineum is administered once weekly for 12 weeks.  During the 
Maintenance Phase, Vicineum is administered every other week.  The dose of Vicineum is 30 
mg in 50 mL of saline.  
•
Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months 
with an option to continue therapy for an additional 12 months (total of 24 months) provided 
that patient is tolerating therapy and remains free of recurrent high grade NMIBC (see 
Treatment Period below).  The dose of durvalumab is 1500 mg.  If optional maintenance 
therapy continued in the second year, durvalumab 1500 mg will be administered 
intravenously once every 3 months to provide an immune boost.  
•
Vicineum will be given as monotherapy for 1 week followed by treatment with the 
combination of Vicineum and durvalumab starting week 2.  
•
In the initial six patients, three subjects at a time will enroll at these doses and schedules. 
Dose-liming toxicity (DLT) for each subject will be determined during the initial 6-week 


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4
period that the subject is on treatment (i.e., the DLT period).  When all subjects in the initial 
cohort have been on treatment through the DLT period, all available safety data will be 
considered in decisions to enroll additional subjects at this dose level, or to de-escalate the 
dose(s) of study drug(s), based on a standard “3 + 3” design.  There will be no dose-
escalations in this study.  The dose of durvalumab will remain at 1500 mg every 4 weeks, 
and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the initial 
doses in combination induce DLTs.  
•
After the first six patients, an additional 18 subjects will be enrolled at the initial doses or at 
the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain additional safety 
data, biomarker data and preliminary anti-tumor activity.
•
Each subject’s course will consist of the following periods:
o
Screening/Baseline Period:  The subject is consented and undergoes screening 
assessments to determine eligibility for the study.
o
Treatment Period:  The subject is treated and monitored for safety.  Biomarker data 
will be obtained prior to treatment and at periodic intervals during treatment. Subjects 
who remain free of high-grade NMIBC after 12 months of study treatment may 
continue to receive treatment for an additional 12 months until they develop recurrent 
high-grade disease, disease progression, or intolerable toxicity, or meet another 
withdrawal criterion (e.g., consent withdrawal, pregnancy). 
o
Post-Treatment.  The subject will return to the study site monthly for up to 90 days 
after the last dose of immunotherapy for end-of-treatment assessments.  Subjects with 
ongoing clinically-significant related AEs or SAEs will have additional follow-up after 
the initial post-treatment visit.


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SCHEMA 
Please note, at the end of each maintenance cycle there is a 2 week window in order to allow the 
patients sufficient time to recover from biopies prior to continuing treatment.
INDUCTION
Week 
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Evaluation
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Vicineum
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Evaluation
(Cysto, 
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 = each symbol indicates the number of treatments for that week
MAINTENANCE #2
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9
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Evaluation
(Cysto, 
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MAINTENANCE #3
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OPTIONAL MAINTENANCE #4
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b
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15
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Evaluation
(Cysto, 
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Biopsy)
 = each symbol indicates the number of treatments for that week
OPTIONAL MAINTENANCE #5
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Durvaluma
b
Vicineum
18
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Evaluation
(Cysto, 
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OPTIONAL MAINTENANCE #6
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b
Vicineum
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Evaluation
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Cytol, 
Biopsy)
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OPTIONAL MAINTENANCE #7
Week 
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Durvalumab
Vicineum
24
Month
Evaluation
(Cysto, 
Cytol, 
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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
SCHEMA.........................................................................................................................................5
TABLE OF CONTENTS ................................................................................................................8
STATEMENT OF COMPLIANCE ..............................................................................................14
1
INTRODUCTION .................................................................................................................15
1.1
Study Objectives .............................................................................................................15
1.1.1
Primary Objective....................................................................................................15
1.1.2
Secondary Objectives ..............................................................................................15
1.2
Background and Rationale..............................................................................................15
1.2.1
Durvalumab Background.........................................................................................18
1.2.2
Vicineum Background.............................................................................................22
1.2.3
US FDA withdrawal of metastatic Urothelial Carcinoma (mUC) indication for 
Imfinzi (durvalumab) granted under the accelerated approval pathway ...............................24
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................25
2.1
Eligibility Criteria ...........................................................................................................25
2.1.1
Inclusion Criteria .....................................................................................................25
2.1.2
Exclusion Criteria ....................................................................................................27
2.1.3
Recruitment Strategies.............................................................................................30
2.2
Screening Evaluation ......................................................................................................30
2.3
Participant Registration and Status Update Procedures..................................................31
2.3.1
Treatment Assignment Procedures..........................................................................32
2.4
Baseline Evaluation.........................................................................................................32
2.4.1
Baseline studies .......................................................................................................32
2.4.2
Urine studies (within 7 days prior to initiation of study therapy)............................32
2.4.3
Research Assessments at Baseline (within 7 days prior to initiation of study 
therapy) 33
2.4.4
Other Assessments...................................................................................................33
3
STUDY IMPLEMENTATION .............................................................................................33
3.1
Study Design...................................................................................................................33
3.1.1
Dose Limiting Toxicity (DLT) ................................................................................33
3.1.2
Dose De-Escalation / Cohort Expansion .................................................................34
3.2
Drug Administration .......................................................................................................35


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3.2.1
Durvalumab .............................................................................................................36
3.2.2
VicineumTM..............................................................................................................37
3.3
Dose Modifications.........................................................................................................38
3.3.1
Durvalumab .............................................................................................................38
3.3.2
Vicineum..................................................................................................................39
3.4
Study Calendar................................................................................................................41
3.5
Cost and Compensation ..................................................................................................53
3.5.1
Costs ........................................................................................................................53
3.5.2
Compensation ..........................................................................................................53
3.5.3
Reimbursement........................................................................................................53
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................53
3.6.1
Criteria for Removal from Protocol Therapy ..........................................................53
3.6.2
Off-Study Criteria....................................................................................................54
3.6.3
Lost to Follow-up ....................................................................................................55
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................55
4.1
Permitted Concomitant Medications...............................................................................55
4.2
Excluded Concomitant Medications ...............................................................................55
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................56
5.1
Biospecimen Collection ..................................................................................................56
5.1.1
Blood studies ...........................................................................................................56
5.1.2
Research urine studies .............................................................................................57
5.1.3
Tissue studies...........................................................................................................58
5.2
Sample Collection Schedule ...........................................................................................63
5.3
Sample Storage, Tracking and Disposition.....................................................................64
5.3.1
UOB Research Laboratory ......................................................................................65
5.3.2
Samples (serum samples for cytokines) Stored with Clinical Pharmacology 
Program (Figg Laboratory)....................................................................................................65
5.3.3
Clinical Services Program .......................................................................................66
5.3.4
Protocol Completion/Sample Destruction ...............................................................67
5.4
Samples for Genetic/Genomic Analysis .........................................................................67
5.4.1
Proposed Genetic Analysis......................................................................................67
5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized................................................................................................68


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5.4.3
Management of Results ...........................................................................................68
5.4.4
Genetic counseling...................................................................................................68
6
DATA COLLECTION AND EVALUATION .....................................................................69
6.1
Data Collection ...............................................................................................................69
6.2
Data Sharing Plans..........................................................................................................69
6.2.1
Human Data Sharing Plan .......................................................................................69
6.2.2
Genomic Data Sharing Plan.....................................................................................70
6.2.3
Response Criteria.....................................................................................................70
6.2.4
Evaluable for Objective Secondary Endpoints/Response........................................70
6.3
Toxicity Criteria..............................................................................................................71
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....71
7.1
Definitions.......................................................................................................................71
7.2
OHSRP Office of Compliance and Training/IRB Reporting..........................................71
7.2.1
Expedited Reporting ................................................................................................71
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................71
7.3
NCI Clinical Director Reporting.....................................................................................71
7.4
NIH Required Data and Safety Monitoring Plan............................................................72
7.4.1
Principal Investigator/Research Team.....................................................................72
8
SPONSOR SAFETY REPORTING......................................................................................72
8.1
Definitions.......................................................................................................................72
8.1.1
Adverse Event..........................................................................................................72
8.1.2
Serious Adverse Event (SAE) .................................................................................72
8.1.3
Life-threatening .......................................................................................................73
8.1.4
Severity....................................................................................................................73
8.1.5
Relationship to Study Product .................................................................................73
8.1.6
Adverse Events of Special Interest (AESI) .............................................................73
8.2
Assessment of Safety Events ..........................................................................................75
8.3
Reporting of Serious Adverse Events .............................................................................75
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................76
8.4.1
Safety Reporting Criteria to AstraZeneca................................................................76
8.4.2
Safety Reporting Criteria to Sesen Biotherapeutics ................................................77
8.5
Reporting Pregnancy.......................................................................................................77


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8.5.1
Maternal exposure ..................................................................................................77
8.5.2
Paternal exposure.....................................................................................................77
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................78
8.7
Sponsor Protocol Deviation Reporting ...........................................................................78
9
CLINICAL MONITORING PLAN ......................................................................................78
10
STATISTICAL CONSIDERATIONS ..................................................................................79
10.1
Statistical Hypotheses .....................................................................................................79
10.2
Sample Size Determination.............................................................................................80
10.3
Populations for Analysis .................................................................................................81
10.4
Statistical Analyses .........................................................................................................81
10.4.1
General Approach....................................................................................................81
10.4.2
Analysis of the Primary Endpoint............................................................................81
10.4.3
Analysis of the Secondary Endpoints......................................................................81
10.4.4
Safety Analyses .......................................................................................................82
10.4.5
Baseline Descriptive Statistics.................................................................................82
10.4.6
Planned Interim Analyses........................................................................................82
10.4.7
Subgroup Analyses ..................................................................................................82
10.4.8
Tabulation of Individual Participant Data ...............................................................82
11
COLLABORATIVE AGREEMENTS..................................................................................82
11.1
Cooperative Research and Development Agreement (CRADA)....................................82
12
HUMAN SUBJECTS PROTECTIONS................................................................................83
12.1
Rationale For Subject Selection......................................................................................83
12.2
Participation of Children.................................................................................................83
12.3
Participation of Subjects Unable to Give Consent..........................................................83
12.4
Evaluation of Benefits and Risks/Discomforts ...............................................................83
12.4.1
Study Agents Risks..................................................................................................83
12.4.2
Research Blood Sampling Risks..............................................................................84
12.4.3
Risks from Bladder Procedures ...............................................................................84
12.4.4
Non-Physical Risks of Genetic Research ................................................................84
12.4.5
Radiation Risks........................................................................................................84
12.4.6
CT Contrast Risks....................................................................................................84
12.4.7
Electrocardiogram Risks..........................................................................................84


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12.5
Consent Process and Documentation..............................................................................84
12.5.1
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation...........................................................................................................................85
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................85
13.1
Study Discontinuation and Closure.................................................................................85
13.2
Quality Assurance and Quality Control..........................................................................86
13.3
Conflict of Interest Policy...............................................................................................86
13.4
Confidentiality and Privacy ............................................................................................87
14
PHARMACEUTICAL INFORMATION .............................................................................87
14.1
Durvalumab (IND #: 136199).........................................................................................87
14.1.1
Source ......................................................................................................................87
14.1.2
Toxicity....................................................................................................................88
14.1.3
Formulation, packaging and storage........................................................................92
14.1.4
Study Drug Preparation ...........................................................................................93
14.1.5
Study Drug Administration......................................................................................93
14.1.6
Incompatibilities ......................................................................................................93
14.1.7
Accountability and dispensation..............................................................................93
14.1.8
Disposition of unused investigational study drug....................................................93
14.2
Vicineum (IND #: 136199).............................................................................................93
14.2.1
Source ......................................................................................................................93
14.2.2
Toxicity....................................................................................................................93
14.2.3
Formulation, packaging and storage........................................................................95
14.2.4
Product preparation..................................................................................................96
14.2.5
Administration procedures.......................................................................................96
14.2.6
Incompatibilities ......................................................................................................96
14.2.7
Accountability and dispensation..............................................................................96
14.2.8
Disposition of unused investigational study drug....................................................96
15
REFERENCES ......................................................................................................................97
16
APPENDICES .....................................................................................................................100
16.1
Appendix A: Performance Status Criteria ....................................................................100
16.2
Appendix B: Durvalumab Dose Calculations...............................................................101
16.3
Appendix C: Durvalumab Dosing Modification and Toxicity Management Guidelines
102


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16.4
Appendix D: Complete List of Peripheral Immune Cell Subsets31 ..............................135
16.5
Appendix E: Urine Collection.......................................................................................136


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


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
To evaluate the safety and tolerability of durvalumab and Vicineum when administered in 
combination to subjects with BCG-refractory high-grade NMIBC
1.1.2
Secondary Objectives 
•
To assess potential predictive biomarkers and biomarkers of the immune response in bladder 
tissue, urine, and peripheral blood to durvalumab and Vicineum when administered in 
combination to subjects with BCG-refractory high-grade NMIBC
•
To assess the pharmacokinetics of Vicineum with urine samples
•
To assess if urinary EpCAM correlates with response to therapy
•
To assess the preliminary antitumor activity of durvalumab and Vicineum when administered 
in combination to subjects with BCG-refractory high-grade NMIBC
•
Assess PD-L1 expression and PD-1 expressing T cells in paired bladder biopsies pre and post 
treatment with durvalumab and Vicineum as a marker of response/benefit
1.2
BACKGROUND AND RATIONALE
Bladder cancer is the 6th most common cancer in the United States, affecting more men than 
women. It is the 3rd most common cancer in men and the 11th most common in women. 
(Bladder cancer treatment (PDQ® 2015) Approximately 75% of bladder cancers are of the non-
muscle invasive type.8  Non-muscle invasive bladder cancers (NMIBCs) can be categorized as 
Ta (non-invasive papillary carcinoma), T1 (tumor invades lamina propria or subepithelial 
connective tissue), and Tis (carcinoma in situ). Ta tumors are the most common, representing 
about 70% of NMIBCs, but only about 7% of these are categorized as high-grade.9 About 20% 
of NMIBCs are T1 tumors.10 T1 tumors are more aggressive than Ta tumors, and considered 
high-risk.8 Flat, high-grade tumors confined to the mucosa (non-invasive) are characterized as 
carcinoma in situ (CIS),8 and these represent approximately 10% of the NMIBCs.10 
The usual first treatment for NMIBC (Ta, T1, and CIS) is transurethral resection of the bladder 
tumors (TURBT), followed by intravesical immunotherapy, most commonly with bacillus 
Calmette-Guérin (BCG).8 In patients with T1 tumors, a second TURBT is recommended.8 
Induction therapy with BCG is usually dosed as 6 once-weekly instillations.8 In patients with 
high-grade Ta, T1, and CIS, maintenance therapy with BCG of at least 1 year is 
recommended,8,10 although the optimal dose, dosing schedule, and duration of treatment are 
unknown. Local and systemic side effects are common with intravesical BCG therapy, causing 
discontinuation of treatment in approximately 20% of patients.11 Approximately 75% of patients 
experience local side effects (including cystitis, irritative voiding symptoms, and hematuria), 
while 40% report systemic side effects, including general malaise and fever.11 Intravesical BCG 
failure occurs in up to 40% of patients.11 In ~20-35% of cases that failed an initial induction 
course of BCG, a second course of induction BCG may be beneficial, but patients who fail two 


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courses are often best served by radical cystectomy.3,12,13 Therefore, cystectomy is recommended 
for CIS and high-grade Ta and T1 patients who experience disease recurrence following 
intravesical therapy.8 However, Shabsigh et al. reported that 64% of patients who undergo 
cystectomy suffer at least one complication within the first 90 days after surgery14 and the 
operation has been reported to have at least a 2.5% perioperative mortality rate even at a high-
volume center.5  For patients unable or unwilling to undergo cystectomy, treatment options are 
limited.
High grade non-muscle invasive bladder cancer tends to respond well to BCG and when it does 
not, there is evidence to suggest an incomplete or inefficient immune response.  Immune 
responses directed against tumors are one of the body’s natural defenses against the growth and 
proliferation of cancer cells. However, over time and under pressure from immune attack, 
cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver inhibitory 
signals to cytotoxic T cells.
Programmed cell death ligand 1 (PD-L1) is one such protein, and is upregulated in a broad range 
of cancers with a high frequency, with up to 88% expression in some tumor types. In a number 
of these cancers, including lung,15 renal,16-18 pancreatic,19-21 ovarian cancer,22 and hematologic 
malignancies,23,24 tumor cell expression of PD-L1 is associated with reduced survival and an 
unfavorable prognosis.  Programmed cell death ligand 1 is part of a complex system of receptors 
and ligands that are involved in controlling T-cell activation. PD-L1 acts at multiple sites in the 
body to help regulate normal immune responses and is utilized by tumors to help evade detection 
and elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory 
signal to the T cell.25,26  This results in reduced T-cell activation and fewer activated T cells in 
circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and 
CD80 on activated T cells reaching the tumor. This delivers an inhibitory signal to those T cells, 
preventing them from killing target cancer cells and protecting the tumor from immune 
elimination.27  Therefore, targeting the PD-1/PD-L1 protein has emerged as an interesting 
strategy in bladder cancer especially given recent FDA approval of atezolizumab in the treatment 
of metastatic urothelial cancer.  Durvalumab, a novel PD-L1 inhibitor, has not been investigated 
in NMIBC but has demonstrated activity in metastatic urothelial cancer as well.  
 Limited agents have demonstrated response in the setting of BCG-refractory disease.  One such 
agent is Vicineum™.  Vicineum™ consists of a recombinant fusion protein, VB4-845, that 
contains a humanized single-chain antibody fragment specific for the epithelial cell adhesion 
molecule (EpCAM) antigen linked to ETA (252-608), a truncated form of Pseudomonas 
exotoxin A (ETA).  In 135 bladder cancer patients with CIS, TaG2-3, or T1G2-3 screened for 
trial enrollment for BCG-refractory disease, EpCAM staining was performed and revealed that 
132 (98%) patients had some EpCAM staining.  In fact, two of the 3 patients with negative 
staining, did not actually have tumor on the specimen analyzed.  Ninety-four percent of all 
tumors had 2+ or 3+ staining.  Therefore, EpCAM appears to be a good target in BCG-refractory 
bladder cancer.  In a previous phase II study in patients with high grade bladder cancer 
previously treated with BCG, the 3-month complete response rate was 40% and 16% of patients 
treated with induction and maintenance therapy with Vicineum™ remained disease-free at 1 
year.


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Given activity of Vicineum™ in such patients and activity of durvalumab in metastatic urothelial 
cancer, the combination of both drugs may be more effective than either drug alone.  PD-1/PD-
L1 checkpoint inhibitors do not directly induce anti-tumor immune responses.  Instead they 
function by taking the breaks off of existing T cell clones with a specificity for antigens 
expressed on the surface of tumor T cells.  Therefore, in order for checkpoint inhibitor therapy to 
be effective, the checkpoint inhibitors should be used in conjunction with agents that are capable 
of inducing a cellular anti-tumor immune response. It is generally accepted that a type of cell 
death known as immunogenic cell death (ICD) is associated with effective stimulation of these 
cellular host immune responses.  ICD can be identified by the presence of damage associated 
molecular patterns or DAMPS – these are characterized by distinct signals such as the release of 
ATP and HMGB1 (High Mobility Group Box 1) and cell surface translocation of calreticulin, an 
endoplasmic reticulum chaperone protein.  Preclinical work demonstrates that Vicineum (VB4-
845) mediated killing of tumor cells results in the presence of these DAMPS, thereby suggesting 
that it could promote the desired anti-tumor cellular immune responses.  Additionally, as bladder 
cancer is one of the cancers associated with higher levels of somatic mutations, it follows that 
targeted killing of EpCAM positive cancer cells should present these antigens to the immune 
system, thereby providing targets for the cellular immune response.  Therefore, use of both 
agents may lead to synergistic killing of tumors. 
Based on the thoughts of synergy, an in vivo study was performed with a drug called Proxinium, 
an earlier version of Vicineum™, demonstrating an abscopal effect and synergy with the use of a 
checkpoint blockade inhibitor.  Although it was done in a NSCLC model, the results were 
impressive in causing tumor shrinkage.  In this experiment, a humanized mouse model was used 
with an engrafted immune system (myeloablated and engrafted with human bone marrow stem 
cells) and a human EpCAM-expressing NSCLC PDX tumor placed in the flanks bilaterally.  The 
mice had circulating human T cells and B cells.  Four treatment groups were used.  In group 1, 
vehicle alone was given to serve as a control group.  Group 2 was treated with direct injection of 
VB4-845 (Proxinium/Vicineum) unilaterally into only one of the flank-bearing tumors.  Group 3 
was treated with PD-1 checkpoint inhibitor alone (nivolumab) and finally group 4 was treated 
with the combination of VB4-845 and the PD-1 checkpoint inhibitor.  The left graph shows the 
tumor size of the injected tumor in the four groups while the right graph shows the tumor size of 
the uninjected tumor in the four groups.  As can be seen in the left graph, intratumoral treatment 
of the EpCAM positive subcutaneous PDX tumor with VB4-845 led to cessation of tumor 


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growth. PD-1 inhibitor by itself or in combination with VB4-845 was not that effective in 
reducing the size of the injected tumor.  However, intratumoral treatment of the EpCAM positive 
subcutaneous PDX tumor with VB4-845 increased the ability of a PD-1 checkpoint inhibitor to 
decrease the growth rate of an uninjected contralateral PDX tumor as compared to treatment with 
the checkpoint inhibitor alone as shown on the right graph.  The small number of animals per 
cohort and the use of a rapidly growing PDX model decreased the impact of the combination but 
interestingly the flattening of the growth rate of the uninjected tumors in the combination group 
was not observed until a sufficient period of time passed to allow for the induction of a cellular 
immune response.  The preclinical study was performed with Vicineum in combination with a 
PD-1 inhibitor targeting the receptor, rather than durvalumab which is a PD-L1 inhibitor that 
targets the ligand of the PD-1/PD-L1 interaction.  However, there is no reason to believe that 
durvalumab would act differently.  It would be difficult to truly predict the safety of the 
combination of the two drugs in a preclinical model as neither antibody cross reacts with mouse 
homologues.  Therefore, this trial is evaluating the safety and tolerability of the combination of 
Vicineum and durvalumab in BCG-refractory NMIBC.  A secondary endpoint would be 12-
month recurrence-free survival (RFS) with the combination.  Historical data suggests that the 12-
month recurrence-free survival (RFS) rate is approximately 20-35% for patients who failed one 
previous induction course of BCG and are treated again with BCG alone.  
1.2.1
Durvalumab Background
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 
1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and 
CD80 (B7-1). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, 
with an overall molecular weight of approximately 149 kDa. Durvalumab contains a triple 
mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding 
to complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved in 
triggering effector function.    
1.2.1.1
Summary of non-clinical experience
The non-clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure.   
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release of 
interferon gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent 
cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. In vivo studies show that durvalumab inhibits tumor growth in a xenograft 
model using pancreatic and melanoma human cancer cell lines via a T lymphocyte (T-cell) 
dependent mechanism. Moreover, an anti-mouse PD-L1 antibody demonstrated improved 
survival in a syngeneic tumor model when given as monotherapy and resulted in complete tumor 
regression in > 50% of treated mice when given in combination with chemotherapy. 
Combination therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 
[CTLA-4]) resulted in tumor regression in a mouse model of colorectal cancer. 


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1.2.1.2
Summary of clinical experience
Clinical experience with durvalumab is fully described in the current version of the durvalumab 
Investigator’s Brochure.
As of the DCO date (12 July 2016), across the entire clinical development program, an estimated 
5225 patients have been exposed to 1 or more doses of durvalumab in AstraZeneca- or 
MedImmune-sponsored studies, either as monotherapy or in combination, including 2878 
patients in open label trials, and 2347 patients as an estimate based on the random scheme in 
studies where the treatment arm is blinded. Additionally, more than 1700 patients have been 
exposed to 1 or more doses of durvalumab in ESR/IITs.  Of the 2878 patients exposed to 
durvalumab in ongoing AstraZeneca- or MedImmune-sponsored open label studies, 1744 
patients received durvalumab monotherapy, 808 patients received durvalumab in combination 
with tremelimumab, 140 patients received durvalumab in combination with other investigational 
products and 186 patients received durvalumab in combination with approved products. No 
studies have been completed and no study has terminated prematurely due to toxicity. For a 
summary of the different studies including study design, dosing regimen, study populations and 
exposure, please see IB.
Pharmacokinetics and Product Metabolism 
Study CD-ON-durvalumab-1108: 
As of 24 July 2016, PK data were available for 977 patients who have been treated with 
durvalumab 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W (dose escalation), 10 mg/kg Q2W (dose 
expansion), and 20 mg/kg Q4W (dose-exploration) durvalumab administered as an iv infusion 
over 60 minutes. Following the first iv dose, durvalumab exhibited nonlinear PK at doses <3 
mg/kg Q2W likely due to saturable target-mediated CL and exhibited linear PK at doses ≥3 
mg/kg Q2W. The AUC0-14 increased dose-proportionally at doses of 3 to 20 mg/kg and more 
than dose proportionally at doses of <3 mg/kg, likely due to saturable target-mediated CL. Cmax 
increased in a dose proportional manner within the dose range examined. The steady state was 
achieved at approximately Week 16. Accumulation of durvalumab was observed following 
repeated dosing.
As of 24 July 2016, a total of 790 patients provided samples for ADA analysis. Only 25 of 790 
patients (1 patient each in 0.1 and 3 mg/kg cohorts, 17 patients from 10 mg/kg cohort) were 
ADA positive. Based on population PK covariate analysis, ADA positive status was not 
associated with a clinically relevant reduction of exposure to durvalumab. At the 10 mg/kg Q2W 
dose, sPD-L1 suppression in ADA positive patients was similar to that observed in ADA 
negative patients. The relevance of ADA on safety and efficacy is unknown given the small 
number of ADA positive patients.
Safety 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important 


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potential risk particularly with durvalumab and tremelimumab combination therapy. These 
events are manageable by available/established treatment guidelines as described in the study 
protocols.
Safety data have been pooled for 4 durvalumab monotherapy studies (CD-ON-MEDI4736-1108, 
D4190C00002, ATLANTIC and D4193C00001 [HAWK]) for patients who received a 
durvalumab dose of 10 mg/kg Q2W; a total of 1645 patients are included in this pooled data set.
•
Overall, AEs reported in ≥10% of patients were fatigue (31.1%), decreased appetite 
(22.5%), nausea (20.5%), dyspnoea (17.9%), constipation (17.8%), cough (17.4%), 
diarrhoea (16.0%), anaemia (15.3%), pyrexia (15.0%), vomiting (13.4%), back pain 
(12.5%), pruritus (11.0%), arthralgia (10.6%) and abdominal pain (10.2%).
•
AEs that were considered by the investigator as related to durvalumab in ≥5% of patients 
were fatigue (14.5%); nausea (7.3%); diarrhoea (6.9%); hypothyroidism (6.6%); pruritus 
(6.4%); decreased appetite (6.0%) and rash (5.2%).
•
A total of 820 patients (49.8%) reported AEs of Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or higher: of these, 487 patients (29.6%) had events of 
Grade 3, 63 patients (3.8%) had events of Grade 4 and 270 patients (16.4%) had Grade 5 
(fatal) events. AEs of Grade 3 or higher considered related to durvalumab were reported 
in 164 patients (10.0%): of these, 144 patients (8.8%) had events of Grade 3, 12 patients 
(0.7%) had events of Grade 4 and 8 patients (0.5%) had Grade 5 (fatal) events.
•
Grade 3 events occurring in ≥1% of patients were: anaemia (5.5%); dyspnoea (4.4%); 
hyponatraemia (4.1%); fatigue (2.9%); gamma-glutamyltransferase (GGT) increased 
(2.7%); abdominal pain (2.0%); decreased appetite and back pain (1.9% each); 
pneumonia (1.8%); aspartate aminotransferase (AST) increased and dehydration (1.6% 
each); hypertension (1.3%); blood alkaline phosphatase (ALP) increased, hypokalaemia, 
urinary tract infection and vomiting (1.2% each); alanine aminotransferase (ALT) 
increased and pleural effusion (1.1% each); bilirubin increased, asthenia, nausea and 
pulmonary embolism (1.0% each). Grade 3 events considered related to durvalumab 
occurring in ≥0.5% patients were fatigue (1.2%), GGT increased (0.8%) and AST 
increased (0.6%).
•
The most commonly reported Grade 4 event was sepsis (15 patients [0.9%]). Other 
commonly reported Grade 4 events were: GGT increased (9 patients [0.5%]); dyspnoea, 
hypercalcaemia and respiratory failure (7 patients each [0.4%]) and pneumonia (5 
patients [0.3%]). All other Grade 4 events were reported in less than 5 patients each. 
Grade 4 events considered related to durvalumab occurring in ≥2 patients were GGT 
increased and pneumonitis (0.1% each).
•
Grade 5 events occurred in the system organ class (SOC) of ‘neoplasms benign, 
malignant and unspecified (including cysts and polyps)’ for 172 of the 270 patients with 
Grade 5 events (63.7%), with the highest number of events occurring for NSCLC (40 
patients). Amongst the other SOCs, the most common Grade 5 events were general 
physical health deterioration (12 patients), respiratory failure (8 patients); Grade 5 events 
of pneumonia and sepsis occurred in 5 patients each with the remainder of the Grade 5 


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events occurring in ≤4 patients for each event. The only Grade 5 event considered related 
to durvalumab occurring in ≥2 patients was pneumonitis (0.1%).
•
A total of 134 patients (8.1%) discontinued from study treatment due to an AE. The most 
common events leading to treatment discontinuation were: general physical health 
deterioration (10 patients); pneumonitis (7 patients); pneumonia (6 patients); dyspnoea 
and NSCLC (5 patients each); all other discontinuation events occurred in ≤4 patients.
•
A total of 89 patients (5.4%) had serious treatment-emergent AEs (TEAEs) that were 
considered by the investigator as related to durvalumab. The most common were:  
pneumonitis (12 patients [0.7%]); fatigue (5 patients [0.3%]); colitis, infusion related 
reaction and ILD (4 patients each [0.2%]); dehydration, diarrhoea, nausea and nervous 
system disorder (3 patients each [0.2%]); abdominal pain, acute kidney injury, adrenal 
insufficiency, AST increased, bilirubin increased, dyspnoea, hepatic function abnormal, 
nephritis, transaminases increased, tumor haemorrhage and vomiting (2 patients each 
[0.1%]).
•
A total of 854 patients (51.9%) experienced an AESI during the study. The most common 
grouped term AESI was diarrhoea (263 patients [16.0%]; of whom 12 patients [0.7%] 
had events of Grade ≥3). Other common AESIs (grouped term) were: selected hepatic 
events (248 patients [15.1%]; of whom 113 patients [6.9%] had events of Grade ≥3); 
dermatitis (237 patients [14.4%]; of whom 3 patients [0.2%] had events of Grade ≥3); 
rash (199 patients [12.1%]; of whom 7 patients [0.4%] had events of Grade ≥3); 
hypothyroidism (170 patients [10.3%]; of whom 2 patients [0.1%] had events of Grade 
≥3); hyperthyroidism (93 patients [5.7%]; of whom 1 patient [<0.1%] had events of 
Grade ≥3); and select renal events (87 patients [5.3%]; of whom 16 patients [1.0%] had 
events of Grade ≥3). There were 6 patients who had AESIs of CTCAE Grade 5 (fatal 
events): three patients had hepatic events (autoimmune hepatitis; hepatic failure and 
hyperbilirubinemia); two patients had pneumonitis and 1 patient had immune 
thrombocytopenic purpura.
Efficacy 
Study CD-ON-durvalumab-1108: 
Urothelial carcinoma 
A phase 1/2 multicenter, open-label study conducted in patients with inoperable or metastatic 
solid tumors, reported the results a urothelial carcinoma expansion cohort.28  Durvalumab (10 
mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end-
point was safety, and objective response rate (ORR, confirmed) was a key secondary end point.  
A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or 
more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 
months). The most common treatment-related adverse events (AEs) of any grade were fatigue 
(13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs 
occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One 
treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 
31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in 
the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. 


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Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet 
reached (range, 4.1+ to 49.3+ weeks). 
1.2.2
Vicineum Background 
Vicineum™ (Vicineum) contains the active pharmaceutical ingredient VB4-845, which is a 
recombinant fusion protein produced in Escherichia coli (E. coli) that expresses a humanized 
single-chain antibody fragment (scFv) specific for the epithelial cell adhesion molecule 
(EpCAM) antigen linked to ETA(252-608). ETA(252-608), which is a truncated form of 
Pseudomonas exotoxin A (ETA) that lacks the cell binding domain, is a single polypeptide 
fusion protein produced by continuous translation of a single construct.  
The mechanism of action is dependent upon the 2 components of Vicineum. Once bound to the 
EpCAM antigen on the surface of carcinoma cells, Vicineum is internalized through an 
endocytic pathway. Furin contained within the endosomal compartment cleaves a proteolytic site 
on the surface of ETA(252-608), releasing ETA(252-608). The ETA(252-608) induces cell death 
by irreversibly blocking protein synthesis through adenosine diphosphate (ADP)-ribosylation of 
a post-translationally modified histidine residue of elongation factor-2 (EF-2), called 
diphthamide. (Oppenheimer 1981) The truncated version of ETA, ETA(252-608), has been 
engineered to retain the active domains necessary to induce cell death, but the cell binding 
domain has been eliminated thereby preventing the ETA(252-608) moiety from entering the cell 
in the absence of some alternate vehicle, such as via antibody-mediated internalization. Binding 
to EpCAM must occur to result in ETA(252-608)-mediated effects.
The ETA(252-608) component of the Vicineum fusion protein can cause an immunogenic 
response when administered systemically to humans. Therefore, Vicineum is being developed as 
a locally targeted therapeutic in order to limit its systemic exposure and to maximize the 
concentration of the drug in its target cells. By administering Vicineum via intravesical 
instillation, the probability of systemic exposure and subsequent generation of neutralizing 
antibodies is decreased. Furthermore, the high local concentrations of Vicineum maximize the 
likelihood of achieving a therapeutic benefit.
Clinical experience with Vicineum is fully described in the current version of the Vicineum 
Investigator’s Brochure (Version 8.0).  
1.2.2.1
Preclinical Studies
Preclinical study data have shown that Vicineum exhibits potent activity [inhibitory 
concentration 50% (IC50) = 0.001 - 10 pM] against numerous EpCAM-positive cell lines, with 
selectivity for EpCAM-expressing tumors. In vivo pharmacology demonstrated that Vicineum 
effectively inhibits tumor growth in several human xenograft animal models. Studies in rats 
found that the toxicological effects of Vicineum occur at doses 1,000-fold greater than the IC50 
for activity on tumor cells, with a safety margin of at least 5- to 100-fold. 
1.2.2.2
Clinical Studies
VB4-845-02-I
A Phase 1 trial (VB4-845-02-I) of Vicineum evaluated doses up to 30.16 mg administered 
intravesically to 64 subjects with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma (TCC) 
or CIS, either refractory to or intolerant of BCG therapy.29 No dose-limiting toxicities (DLTs) 


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were observed. Vicineum was well tolerated, and the majority of adverse events (AEs) were 
mild. The most frequently reported treatment-related AEs were renal and urinary disorders, with 
dysuria (14.1%) and hematuria (10.9%) most commonly reported. Of the systemic AEs, fatigue 
was reported by 7.8% of subjects, while fever/chills and loss of appetite were each reported by 
6.2% of subjects. The frequency of treatment-related AEs did not increase with increasing doses 
of Vicineum. There was 1 serious adverse event reported (death due to cardiac failure), which 
occurred 3 weeks after stopping study drug; the Investigator assessed the event to be unrelated to 
Vicineum treatment, attributing it to the subject’s long-standing history of cardiovascular 
disease. Exploratory efficacy assessment at 3 months showed that of 61 evaluable subjects, a 
complete response (defined as non-positive urinary cytology and either normal cystoscopy or 
abnormal cystoscopy with negative biopsy) was achieved by 24 subjects (39%). Of the 17 
subjects with Tis, 29% achieved a complete response, while complete responses were observed 
in 44% and 43% of the subjects with T1 and Ta, respectively. 
Blood samples for assessing humoral immune reactivity to Vicineum were taken prior to dosing 
on days 1, 8, 15, 22, 29, 36, and at the final study visit. Antibody titers to the scFv and ETA252–
608 portions of the fusion protein (human antihuman antibodies (HAHA) and human anti-
Pseudomonas antibodies (HAPA)) were measured using an enzyme-linked immunosorbent 
assay. HAPA response was more vigorous, as patients developed a measurable titer earlier; the 
majority of patients exhibited HAPA by day 29, with 77% (47/61) having a measurable titer at 
final visit. In contrast, only 16% (10/61) of patients had HAHA by the end of the study. HAPA 
titers were also generally higher, with a mean maximum titer of 20,512 versus 3373 for HAHA 
responses. A comparison of mean titers of the HAPA and HAHA responses measured in samples 
taken on the final visit showed no significant difference between responders and nonresponders.
VB4-845-02-IIA
A Phase 2 study (VB4-845-02-IIA) evaluated once-weekly instillations of Vicineum 30 mg in 
two different induction schedules:  weekly x 6 weeks or weekly x 12 weeks, followed by up to 3 
maintenance cycles (3 once-weekly instillations followed by a 9-week drug-free period) in 46 
subjects with histologically-confirmed TCC of the bladder and residual CIS with or without 
concurrent Ta or T1 who were refractory or intolerant to BCG.30 Some subjects in the 6-weekly 
induction arm received a second induction cycle.  Forty-six subjects were considered evaluable 
for response.  A complete response (defined as no histological evidence of disease and negative 
urine cytology at the 3-monthly evaluations) was achieved by 44% (20/45) of subjects, and 16% 
(7/45) of subjects remained disease-free at the 1-year end-of-study (EOS) assessment. A post-
study assessment found that these subjects were still disease-free at 18-25 months. The median 
time to recurrence was 134 days longer in subjects who received 12 weeks of induction therapy 
compared to 6 weeks (408 vs 274 days, respectively; log rank test p=0.1708). The most 
frequently reported treatment-related AEs were renal and urinary disorders, including 50% with 
dysuria (61% of these were of mild intensity) and 13% with hematuria. Overall, most AEs were 
of mild severity. There were 3 severe events, all of which resolved without sequelae. No subject 
discontinued from the study due to AEs and there were no deaths or other serious AEs. 
Based on the preliminary positive therapeutic results and favorable tolerability profile, the 
present Phase 3 trial will evaluate the efficacy of Vicineum induction therapy administered for 
12 weeks, and the long-term effectiveness of Vicineum maintenance therapy (up to 24 months 
treatment in total) in preventing disease recurrence.


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VB4-845-02-IIIA
An open-label, single–arm Phase 3 trial of Vicineum (VB4-845-02-IIIA) is evaluating Vicineum 
in subjects who have received a least 2 courses of BCG and whose disease is considered BCG-
unresponsive.  One hundred thirty-three subjects will enroll of whom 77 will have CIS with 
relapsed/refractory disease within 6 months of their last dose of BCG.
Based on data in the database as of 03 October 2016, the most frequent adverse events regardless 
of causality were UTIs, dysuria, hematuria, fatigue, micturition, urgency, pollakiuria, diarrhea, 
and arthralgia.
Two subjects were reported to have suspected unexpected serious adverse reactions (SUSARs).  
A 90 year-old patient with an elevated lipase developed acute renal failure and LFT elevations.  
The patient required dialysis.  Cholestatic hepatitis progressed. The investigator judged these 
events as possibly related to study treatment.  After a few weeks of dialysis, the patient elected to 
stop further dialysis and go to hospice care.  After stopping dialysis, the patient passed away.
A 74-year-old patient also developed acute kidney injury with LFT elevations.  The LFT 
elevations resolved quickly upon stopping Vicineum treatment.  The kidney function improved 
with hospitalization and intravenous fluids.
Trial update – Investigator Brochure version date: 06/10/2020
Efficacy
Vicineum demonstrated efficacy in CR rate at 3 months with sustained CR and duration of 
response, as well as CR rate at 6, 9, and 12 months, cystectomy free days, event-free survival, 
progression-free survival, overall survival, recurrence-free rates in papillary disease subjects, and 
time to disease recurrence in papillary disease subjects, for the treatment of BCG-unresponsive 
subjects who are resistant to currently available therapy. Subjects that responded to Vicineum 
(CIS subjects with CR and papillary subjects who were recurrence-free at 3 months) were 5 
times more likely to remain cystectomy-free at 2 years than those who did not respond.
The CR rate at 3 months was 39% and 40% for the primary efficacy population (mITT) and all 
evaluable CIS subjects, respectively. Of those mITT subjects with a CR at post-induction phase 
(3 months), 69%, 53%, and 42% continued to have a complete response at 6, 9, and 12 months, 
respectively. All CIS subjects with fewer BCG cycles had a higher CR rate than those CIS 
subjects treated with more courses of BCG.
1.2.3
US FDA withdrawal of metastatic Urothelial Carcinoma (mUC) indication for 
Imfinzi (durvalumab) granted under the accelerated approval pathway
On 5/1/17, the FDA had granted accelerated approval to durvalumab for the treatment of locally 
advanced or metastatic urothelial carcinoma with disease progression after failing platinum-
based chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum-based chemotherapy.
As of February 2021, AstraZeneca has voluntarily withdrawn the indication for Imfinzi 
(durvalumab) in the US for the treatment of adult patients with locally advanced or metastatic 
urothelial carcinoma who:
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– Have disease progression within 12 months of neoadjuvant or adjuvant treatment with 
platinum-containing chemotherapy.
This decision was made in consultation with the US Food and Drug Administration (FDA) based 
on their broad evaluation of accelerated approvals. The voluntary withdrawal was for lack of 
efficacy and not for safety concerns.
The urothelial carcinoma indication was granted Accelerated Approval from the US FDA, based 
on tumor response rate and duration of response from Study 1108 and the significant unmet 
needs of patients.2 Accelerated approval is a specific regulatory path whereby confirmatory data 
is required to convert an accelerated approval to full approval. In this case, continued approval 
for this indication in the US was contingent upon positive results from the Phase III DANUBE 
trial of Imfinzi or Imfinzi plus tremelimumab versus chemotherapy as first-line therapy for 
patients with unresectable, locally advanced or metastatic urothelial carcinoma. The DANUBE 
trial did not meet either of its co-primary endpoints of improving overall survival versus standard 
of care chemotherapy for Imfinzi monotherapy in patients whose tumor cells and/or tumor-
infiltrating immune cells express high levels (≥25%) of programmed cell death ligand-1 (PD-L1) 
or for Imfinzi plus tremelimumab in patients regardless of their PD-L1 expression.
We would like to continue the drug-combination trial since our preliminary interim data analysis 
shows a 40% 12 week response rate (5/12 patients) with half of them showing a >12 month 
sustained response. We hypothesize that the prolonged response might be related to the systemic 
therapy (Durvalumab) administration. Also, most of the treatment related AEs are irritative 
voiding symptoms and most of them are grade 3 or lower, suggesting that the treatment is 
tolerated well thus far.Combination Therapy Dose Justification
In the single-agent phase I Vicineum study, there were no dose-limiting toxicities (DLTs) and no 
MTD was determined.  Only 2 subjects of 64 had detectable plasma Vicineum levels and these 
were very near the lower level of quantitation.  Durvalumab has been extensively studied in 
Phase I and Phase II and the recommended dose and safety profile has been established.  For 
these reasons, the initial dose level for the combination will be the standard doses for both drugs.  
The FDA approved dose for durvalumab is currently 10mg/kg every 2 weeks and this amounts to 
750 mg every 2 weeks for an average 75 kg individual.  Based on pre-clinical data, there is no 
difference in exposure between weight based Q2W dosing and fixed dose Q4W dosing.  
Therefore, we are administering 1500 mg every 4 weeks instead of 750 mg every 2 weeks for 
ease and dosing convenience.  
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically or cytologically confirmed by NCI Laboratory of 
Pathology as high grade non-muscle invasive urothelial (transitional cell carcinoma) of 
the bladder as follows: 
•
Carcinoma-in-situ (CIS) with or without papillary tumors


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•
High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks 
of the initial dose of study treatment.  If multiple bladder biopsies/TURBTs are 
required to confirm eligibility, the timing of the last bladder biopsy to the initial dose 
of study treatment must be within 12 weeks.
•
Patients with persistent T1 high grade disease on TURBT following a single 
induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial 
provided that the patient is surgically unfit for cystectomy as deemed by the 
investigator or the patient declines cystectomy.
2.1.1.2
Subjects with BCG unresponsive disease as defined by the Society of Urologic 
Oncology and the FDA6,7:  Subjects must have received at least two courses of 
intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 
maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat 
induction course).  Please note exception above for persistent T1 disease.  There is no 
upper limit on the amount of prior BCG a subject may have received. 
2.1.1.3
Patients who have met eligibility criterion 2.1.1.2 must have received last BCG dose 
within a year of enrollment.  
2.1.1.4
The investigator must document that he/she believes the subject would not benefit from 
additional BCG treatment at the time of study entry. 
2.1.1.5
Age ≥ 18 years at time of signing the informed consent form (ICF).  Because no dosing 
or adverse event data are currently available on the use of Vicineum in combination 
with durvalumab in patients <18 years of age, children are excluded from this study, but 
will be eligible for future pediatric trials.  Furthermore, NMIBC does not occur in 
children.  
2.1.1.6
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 ( Appendix 
A)
2.1.1.7
Adequate organ and marrow function as defined below: 
o
Hemoglobin ≥ 9.0 g/dL
o
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
o
Platelet count ≥ 75 x 109/L (>75,000 per mm3)
o
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  
o
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN
o
Creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 
1976) or by 24-hour urine collection for determination of creatinine clearance:


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Males:
Creatinine CL 
(mL/min)
=
Weight (kg) x (140 – Age)    
72 x serum creatinine (mg/dL)
Females:
Creatinine CL 
(mL/min)
=
Weight (kg) x (140 – Age)    x 0.85
72 x serum creatinine (mg/dL)
2.1.1.8 Female subjects must either be of non-reproductive potential (i.e., post-menopausal as 
described below) OR history of surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon 
study entry.  

Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution 

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, or had chemotherapy-induced menopause with last menses >1 year ago
2.1.1.9
The effects of Vicineum and durvalumab on the developing human fetus are unknown.  
Females of childbearing potential and and men who are sexually active must use a 
highly effective method of contraception (including abstinence, intrauterine system or 
intrauterine device contraceptive implant, hormonal, female or partner sterilization or 
menopause as defined in 2.1.1.8) and a second form of barrier contraception during 
study treatment and for 120 days after the last dose of study drug. Note: partner’s use of 
the same methods of contraception (barrier, hormonal, intrauterine device [IUD], 
surgical sterilization) is also acceptable. 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.
2.1.1.10 Written informed consent obtained from the subject prior to performing any protocol-
related procedures
2.1.1.11 Subject is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow 
up.
2.1.1.12 Body weight > 30 kg
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents.
2.1.2.2
QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms. [Any 
clinically significant abnormalities detected require triplicate ECG results and a mean 


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QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms 
calculated from 3 ECGs.]  
2.1.2.3
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Vicineum or durvalumab or other agents used in the study.
2.1.2.4
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  Urinary tract infections (UTIs) are excluded from being an 
exclusion criterion for treatment unless they are grade 3 or higher.  
2.1.2.5
Pregnant women are excluded from this study because it is unknown whether Vicineum 
and/or durvalumab have any teratogenic effects.  In nursing mothers, breastfeeding 
should be discontinued as these medications may have the potential risk for adverse 
events in nursing infants secondary to treatment of the mother.
2.1.2.6
Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab 
2.1.2.7
Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology, or 
radiological imaging within the past 2 years of treatment (e.g. upper tract transitional 
cell carcinoma, urethral urothelial carcinoma).  
2.1.2.8
Subjects with hydronephrosis, except for those subjects where hydronephrosis has been 
longstanding (i.e., predates the diagnosis of the CIS, Ta, or T1 by more than 2 years) 
and diagnostic evaluation at screening shows no evidence of tumor causing the 
hydronephrosis. 
2.1.2.9
Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy, 
targeted therapy, endocrine therapy, radiation therapy, intravesical therapy, 
investigational agent) within 28 days of the first dose of study therapy (and within 6 
weeks for nitrosourea or mitomycin C) other than a single dose of intravesical 
chemotherapy which is permitted between 28 days and 14 days prior to the first dose of 
study treatment.
2.1.2.10 The subject has a diagnosis of another malignancy within 2 years before the first dose 
of study treatment, except for superficial skin cancer, localized prostate cancer on active 
surveillance, or localized solid tumors deemed cured by surgery and not treated with 
systemic anticancer therapy and not expected to require anticancer therapy in the next 2 
years i.e., while the subject may be taking study treatment. 
2.1.2.11 Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid.
2.1.2.12 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g. colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]).  The following are exceptions to this criterion:


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•
Subjects with vitiligo or alopecia
•
Subjects with hypothyroidism (e.g. following Hashimoto syndrome) stable on 
hormonal replacement
•
Any chronic skin condition that does not require systemic therapy
•
Subjects without active disease in the last 5 years may be included but only 
after consultation with the Principal Investigator
•
Subjects with celiac disease controlled by diet alone
2.1.2.13 History of primary immunodeficiency.
2.1.2.14 History of allogeneic organ transplant.  
2.1.2.15 History of hypersensitivity to durvalumab or any excipient
2.1.2.16 History of hypersensitivity to Vicineum or its components
2.1.2.17 Active infection with tuberculosis (clinical evaluation that includes clinical history, 
physical examination, and radiographic findings, and PPD testing if indicated), hepatitis 
B (known positive HBV surface antigen (HBsAg) result, hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with HIV are excluded 
from participating on this clinical trial because their immunodeficiency would confound 
the evaluation of adverse events which would hinder meeting the primary objective. 
Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible.  Subjects positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA.  
2.1.2.18 History of leptomeningeal carcinomatosis
2.1.2.19 Receipt of live attenuated vaccination within 30 days prior to the first dose of Vicineum 
or durvalumab 
2.1.2.20 Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results
2.1.2.21 Subjects with uncontrolled seizures
2.1.2.22 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria 
•
Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Principal Investigator.
Subjects with irreversible toxicity not reasonably expected to be exacerbated 
by treatment with durvalumab may be included only after consultation with the 
Principal Investigator.


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2.1.3
Recruitment Strategies
This study will be posted on NIH websites and on NIH social media forums. Additionally, this 
study will be listed on available websites (www.clinicaltrials.gov and others) and participants 
will be recruited from the current patient population at NIH.
2.2
SCREENING EVALUATION 
Note: Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols). Assessments performed at outside facilities or on another 
NIH protocol within the timeframes below may also be used to determine eligibility once a 
participant has signed the consent.
Evaluations to be performed within 12 weeks prior to starting treatment: 
•
History and physical examination (including medications, medical history, surgical 
history, previous treatments for bladder cancer with dates, allergies, and demography)
•
ECOG performance status 
•
Formal review of available previous bladder tumor specimens by the Laboratory of 
Pathology, NCI, to confirm the bladder cancer diagnosis prior to enrollment into the 
study. 
o
If outside bladder tumor specimens are inadequate to accurately stage the 
patient’s disease, then additional biopsies will be performed at the NCI as part of 
standard of care therapy.  Tissues obtained at the NCI will be used to confirm 
diagnosis and for study of immune-related markers.  With preoperative patient 
permission, extra tissue not sent to Laboratory of Pathology, NCI, will be frozen 
for future analysis of immune-related markers and tumor infiltrates.  This 
additional harvested tissue will be used for research purposes only and is not 
required for a candidate to participate in this protocol. 
o
If outside bladder tumor specimens are adequate to accurately stage the patient’s 
disease, cystoscopy with or without biopsy and/or TURBT to confirm diagnosis 
and resect and remove any residual papillary disease and fulgurate any CIS may 
be performed as part of standard of care therapy.  With preoperative patient 
permission, extra tissue not sent to the Laboratory of Pathology, NCI, will be 
frozen for the future analysis of immune-related markers and tumor infiltrates.  
This additional harvested tissue will be used for research purposes only and is not 
required for a candidate to participate in this protocol.Blue light cystoscopy can 
be performed at urologist’s discretion.
•
Laboratory studies
o
Hematology (Complete blood count plus differential and platelet count)
o
Serum chemistries and liver function tests (Na+, K+, Cl-, CO2, glucose, BUN, 
creatinine, albumin, calcium, magnesium, phosphorus, alkaline phosphatase, 
ALT, AST, total bilirubin, LDH, pre-albumin, amylase, lipase
o
Coagulation parameters (PT, PTT)


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o
Viral Studies (Hepatitis B and C; HIV)
o
Thyroid function tests 
•
Urinalysis
•
24 hour urine (only if CrCL will not be calculated)
•
PPD if indicated
•
Computerized Tomography (CT) urogram or Magnetic Resonance Imaging (MRI) 
urogram.  If urogram protocol not available or contrast allergy/poor renal function 
preclude such imaging, then CT or MRI of the abdomen/pelvis without contrast will 
suffice and investigator may perform retrograde pyelogram at their discretion. 
•
Electrocardiogram (ECG) for QT interval – Mean QT interval corrected for heart rate 
using Fridericia’s formula (QTcF) will be calculated from a single ECG.  If QTcF ≥ 
470ms, then the patient must be excluded from trial.
o
Resting 12-lead ECGs will be recorded according to the assessment schedule. 
ECGs should be obtained after the patient has been in a supine position for 5 
minutes and should be recorded while the patient remains in that position.
o
ECG will be recorded at Screening, in Week 2 (pre-durvalumab treatment) and as 
clinically indicated.
o
In case of clinically significant ECG abnormalities, including a QTcF value >470 
ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 
minutes and at least 5 minutes apart) to confirm prolongation
•
Serum or urine beta-HCG for women of child-bearing age 
See section 3.4, Study Calendar for more details.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
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 at: https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit. 


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2.3.1
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Run in Cohort
Subjects with high grade non-muscle invasive urothelial (transitional 
cell carcinoma) of the bladder. Up to 12 subjects
2
Expansion 
Cohort
Subjects with high grade non-muscle invasive urothelial (transitional 
cell carcinoma) of the bladder. Up to 24 subjects enrolled after the 
run in cohort is filled. 
Arms
Number
Name
Description
1
Run In
Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will 
be evaluated in the first 6 – 12 subjects
2
Expansion
Durvalumab + Vicineum, at the MTD. Up to 24 subjects
Subjects in cohort 1 will be directly assigned to arm 1.  Subjects in cohort 2 will be directly 
assigned to arm 2.
2.4
BASELINE EVALUATION  
See section 3.4, Study Calendar.
2.4.1
Baseline studies 
Performed within 7 days before starting treatment.  If Clinical evaluation laboratory work was 
also performed within 7 days before starting treatment, then those values can be used for baseline 
evaluation.
•
Hematology (Complete blood count plus differential and platelet count)
•
Acute care panel (Na+, K+, Cl-, CO2, glucose, BUN, creatinine)
•
LDH
•
Pre-albumin
•
Pancreatic enzymes (amylase, lipase)
•
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin)
•
Mineral panel (albumin, calcium, magnesium, phosphorus)
•
Thyroid function tests 
2.4.2
Urine studies (within 7 days prior to initiation of study therapy)
•
Urine cytology 
•
Urinalysis 


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•
Urine culture and sensitivity
2.4.3
Research Assessments at Baseline (within 7 days prior to initiation of study therapy)
Please refer to section 5.2.
2.4.4
Other Assessments
•
Weight
•
Physical Exam, ECOG status, and medications
3
STUDY IMPLEMENTATION
This is a single arm study.  A run in cohort of up to 12 evaluable subjects and an expansion 
cohort of up to 24 evaluable will be evaluated. No randomization of stratification will be 
performed.
3.1
STUDY DESIGN
See SCHEMA.
3.1.1
Dose Limiting Toxicity (DLT)
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the initial 6-week 
period the subject is on treatment (i.e., the DLT evaluation period). Toxicity that is clearly and 
directly related to the primary disease or to another etiology is excluded from this definition.  
Since this trial also involves immunotherapy, immune-related AEs (irAEs) are defined as AEs of 
an immune nature (i.e. inflammatory) in the absence of a clear alternative etiology.  In the 
absence of a clinically significant abnormality, repeat laboratory testing will be conducted to 
confirm significant laboratory findings prior to designation as a DLT.  The following will be 
DLTs:
•
Inability to reduce prednisone dose below 10 mg within 6 weeks (rather than 12 weeks) 
due to ongoing immune-related adverse reaction of Grade >1
•
Any Grade 4 irAE not attributed to local tumor response (e.g., inflammatory reaction 
attributed to local tumor response or inflammatory reaction at sites of metastatic disease 
or lymph nodes)
•
Any ≥ Grade 3 colitis
•
Any Grade encephalopathy
•
Any ≥ Grade 3 neurotoxicity
•
Any ≥ Grade 3 peripheral neuromotor syndromes
•
Any Grade 2 or higher noninfectious pneumonitis irrespective of duration
•
Any Grade 3 irAE, excluding colitis that does not downgrade to Grade 2 within 3 days 
after onset of the event despite optimal medical management including systemic 
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•
Total bilirubin >1.5 - 3.0 x ULN (Grade 2 Hyperbilirubinemia)
•
ALT or AST >8x ULN
•
ALT or AST >5x ULN for more than 2 weeks
•
ALT or AST >3x ULN and 
•
ALT or AST >3x ULN and INR >1.5
•
ALT or AST >3x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
•
Any Grade ≥3 non-irAE toxicity that does not downgrade to Grade ≤1 or baseline status 
(for patients who entered the study with an existing laboratory abnormality) within 14 
days 
•
Inability to receive ≥ 75% or more of scheduled study treatment (both Vicineum and 
durvalumab) during the first six weeks of the trial
•
Persistent Grade 2 events possibly related to study drugs such as persistent nausea, 
vomiting, diarrhea, or fatigue that are refractory to maximal intervention or are severely 
limiting to the patient’s ability to carry out activities of daily living.
The definition excludes the following conditions: 
•
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic
•
Concurrent vitiligo or alopecia of any AE grade
•
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management
•
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days.
•
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.)
3.1.2
Dose De-Escalation / Cohort Expansion
•
This trial will begin with a fixed dose of Vicineum 30 mg intravesical (Dose Level 1) 
administered once weekly for the first 12 weeks. Durvalumab administration will begin after 1  
week of Vicineum monotherapy, at 1500mg IV once every 4 weeks. 
•
In the initial six patients, three subjects at a time will enroll at these doses and schedules (Dose 
Level 1). Dose-limiting toxicity (DLT) for each subject will be determined during the initial 6-
week period that the subject is on treatment (i.e., the DLT period).  When all subjects in the 
initial cohort have been on treatment through the DLT period, all available safety data will be 
considered in the decision to enroll additional subjects at this dose level, or to de-escalate the 
doses of the study drugs to Dose Level -1, based on a standard “3 + 3” design (see table below).  
There will be no dose-escalations in this study.  


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•
After the first six to twelve patients, an additional 18 subjects will be enrolled at the highest dose 
level at which fewer than 2 of 6 subjects experienced DLT in order to obtain additional safety 
data and preliminary anti-tumor activity. Treatment at this level will continue as long as the 
cumulative fraction of patients experiencing DLT is < 1/3.
Dose De-Escalation Schedule
Dose Level
Dose of IND Agent
Level 1
•
Durvalumab 1500mg IV every 4 weeks
•
Vicineum 30 mg intravesically per dose*
Level -1
•
Durvalumab 1500mg IV every 4 weeks
•
Vicineum 20 mg intravesically per dose*
* Vicineum administered weekly during the first 12 weeks of the study, then 
every 2 weeks thereafter.
Dose de-escalation will follow the rules outlined in the Table below.
If 2 or more DLTs occur at dose level -1, then accrual to the trial will end pending an amendment 
to consider other dosing options to explore for safety before proceeding to explore efficacy.
Number of Patients with 
DLT
at a Given Dose Level
De-Escalation Decision Rule
0 out of 3
Enter an additional 3 patients at same dose level
1 of 3
Enter an additional 3 patients at Dose Level 1
•
If 0 of these 3 patients experience DLT, enter 
additional patients at Dose Level 1
•
If 1 or more of this group suffer DLT then enter 
up to 3 patients at the next lowest dose level.  
Reduce by 1 
≥2 
•
Enter up to 3 patients at the next lowest dose 
level.  
3.2
DRUG ADMINISTRATION
In this trial, patients will receive both drugs in certain weeks as specified in the schema.  The 
order of administration will be determined by drug delivery by pharmacy to the day hospital on 


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the day of administration.  Therefore, patients can receive either both drugs concurrently or 
sequentially without a particular order.
3.2.1
Durvalumab
3.2.1.1
Durvalumab doses and treatment regimens
The initial dose of durvalumab (Cohort 1) is 1500 mg IV every 4 weeks for up to 52 weeks. 
Please note, at the end of each maintenance cycle there is a 2 week window in order to allow the 
patients sufficient time to recover from biopsies prior to continuing treatment. Refer to the 
schema for a detailed description of Durvalumab administration weeks. 
Study treatment should be discontinued prior to 12 months if there is confirmed PD, initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or if other reasons to 
discontinue study treatment occur.  
Subjects who have a dose interruption due to toxicity at any point in the first 12 months of 
treatment may resume treatment and complete the 12-month treatment period.  For patients 
without recurrent high grade disease and who are tolerating therapy well, optional maintenance 
therapy may be continued in the second year.  The maintenance dose will be durvalumab 1500 
mg administered intravenously once every 3 months to provide an immune boost.  During that 
second year, as per standard of care for high grade disease, cystoscopy and urine cytology will be 
performed every 3 months. This is depicted graphically in the schema in the optional 
maintenance section. 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 1500mg durvalumab (for patients >30 kg in weight) will be administered 
using an IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
(MEDI4736) concentration ranging from 1 to 20 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm in-line filter. 
Add 30.0 mL of durvalumab (MEDI4736) (ie. 1500 mg of durvalumab (MEDI4736)) to the IV 
bag.  The IV bag size should be selected such that the final concentration is within 1 to 20 
mg/mL.  Mix the bag by gently inverting to ensure homogeneity of the dose in the bag.
For patients who lose weight (<30 kg) during the course of the trial and maintain their enrollment 
ECOG status, further treatment with durvalumab will be weight based.   The dose volume of 
durvalumab and number of vials needed for the subject to achieve the accurate dose will be 
calculated according to Appendix B.
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 
durvalumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation.
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.


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Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 4 hours at room temperature.  The table below summarizes time 
allowances and temperatures.
Durvalumab hold and infusion times
Maximum time from needle puncture to 
start of administration
4 hours at room temperature, 24 hours at 2°C to 
8°C
Maximum time for IV bag infusion, 
including interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in the 
table above, a new dose must be prepared from new vials.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded.
3.2.1.2
Monitoring of dose administration
Subjects will be monitored before, during and after the infusion with assessment of vital signs at 
the times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood 
pressure) every 30 minutes during the infusion period (including times where infusion rate is 
slowed or temporarily stopped).
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion.  For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial 
rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications 
per institutional standard may be administered at the discretion of the investigator.  If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The 
standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 4 hours at room 
temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise 
requires new infusion preparation).  
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis.  The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary.
3.2.2
VicineumTM 
3.2.2.1
Doses And Treatment Regimens
The initial dose of vicineum is 30 mg in 50 mL of saline (Dose level 1).  Vicineum will be 
instilled through a catheter into the bladder. Subjects will be instructed to hold study drug in the 
bladder for 2 hours, and asked to refrain from fluid intake to reduce urine flow during this 
period. After complete administration of the Vicineum dose, the catheter may be clamped and 
remain in for the 2-hour dwell time, or may be removed, per the discretion of the investigator.  


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Subjects will be encouraged, when physically possible, to be upright (sitting or standing), prone, 
supine, and in the left and right lateral decubitus positions, for at least 15 minutes each, in any 
order. If physically unable, this should be recorded in the CRF. At the end of 2-hour period, the 
catheter will be unclamped and the bladder will be drained (if the catheter remained in place) or 
the subject will void to empty the bladder.
Study Phase 
Treatment Regimen
Induction Phase (Weeks 1-12)
One intravesical dose of Vicineum in 50 mL of saline instilled 
once weekly for a total of 12 weeks. 
Maintenance Phase (up to 
Week 104)
One intravesical dose of Vicineum 50 mL saline instilled once 
every other week for 12 months from the start of the Induction 
phase.  Please note, at the end of each maintenance cycle there 
is a 2 week window in order to allow the patients sufficient 
time to recover from biopsies prior to continuing treatment. 
Refer to the schema for a detailed description of Vicineum 
administration weeks. If remain disease-free, therapy can be 
continued for up to 24 months (Week 104) from the start of 
the Induction Phase.  
3.3
DOSE MODIFICATIONS
3.3.1
Durvalumab
Following any biopsy or TURBT, study drug must be interrupted for a maximum of 2 weeks 
before restarting Durvalumab treatment.  
For adverse events (AEs) that are considered at least partly due to administration of durvalumab 
outside of the DLT evaluation period, the following dose adjustment guidance may be applied:
•
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required).
•
If the symptoms promptly resolve with supportive care, consideration should be given to 
resuming the same dose of durvalumab along with appropriate continuing supportive 
care.
•
If medically appropriate, dose modifications are permitted for durvalumab. All dose 
modifications should be documented with clear reasoning and documentation of the 
approach taken (see Appendix C).
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Appendix C). In circumstances where subjects cannot tolerate durvalumab or 
do not meet retreatment criteria to receive either drug, subjects will be taken off protocol 
therapy.
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (see Appendix C).  


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Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the conduct 
of this study.  Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (e.g., infection or PD) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-related.  
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Appendix C.  
3.3.2
Vicineum
Following any biopsy or TURBT, study drug must be interrupted for a minimum of 1 week and 
maximum of 2 weeks before restarting Vicineum treatment.  Patients who develop low grade 
papillary disease will be allowed to stay on trial. In November 2016, the FDA published a draft 
guidance for trials involving patients with BCG-unresponsive disease in which only high-risk 
disease counts as a recurrence or an event.  In this clinical setting, low-risk disease would lead to 
transurethral resection while high-risk disease would lead to cystectomy, which is a much 
different clinical outcome. Therefore, in this trial, low grade recurrences will be documented but 
will not count as a trial-ending recurrence or event.  Furthermore, low grade recurrences are 
considered to be downstaging of disease since the inclusion criteria requires patients with high 
grade disease.  
Study drug administration must be postponed if a subject develops any Grade 3 or greater 
adverse event. Study treatment may resume when the AE returns to ≤ Grade 1 or baseline or 
sooner if there is agreement between the investigator and the sponsor. Study treatment may be 
postponed at the discretion of the investigator for unrelated AEs, if this is considered in the best 
interest of the subject.  If the causal relationship between Vicineum and an AE is initially 
uncertain, study drug should be interrupted until that determination is made.  Also study 
treatment may be postponed for lower grade AEs at the investigator discretion if considered in 
the best interest of the subject.  
The following specific criteria will be used for holding Vicineum dosing based on serum 
creatinine and calculation of creatinine clearance: 
Criteria for  Holding Vicineum Treatment*
Baseline Creatinine
Serum Creatinine
Creatinine Clearance
<1.0 mg/dl or <88 µmol/L
>1.5 mg/dl or >133 µmol/L
<40 ml/min or a decrease of 
25% from baseline
≥1.0 mg/dl or ≥88 µmol/L
Increase to >2 x Baseline Value
<40 ml/min or a decrease of 
25% from baseline
*Vicineum dosing should be held if either the serum creatinine or the creatinine clearance criteria, as defined in this 
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If changes in renal function are noted, the investigator should evaluate the subject for the 
etiology of these changes.  Vicineum treatment may be resumed upon improvement or 
stabilization at creatinine of  ≤ 2 x baseline or ≤ 2 x ULN.
•
Vicineum dosing must be held for any subject whose AST or ALT doubles from their 
baseline value and is ≥2xULN; OR for a bilirubin ≥2mg/dl (≥34 µmol/L). However, if Grade 
2 hyperbilirubinemia occurs during the DLT evaluation period, then a DLT is present and 
treatment will be permanently discontinued and patient will be removed from study. The 
investigator should evaluate subjects for the etiology of any changes in these values.  
Vicineum treatment may be resumed upon improvement or stabilization of AST and ALT of  
≤ 2 x baseline or ≤ 2 x ULN; OR for a bilirubin ≤ 2mg/dl (≤34 µmol/L) provided that Grade 
2 hyperbilirubinemia did not occur.
•
The investigator should consider holding Vicineum treatment for patients with a clinically 
significant UTI requiring antibiotic therapy until improvement.  Investigators should also 
consider holding Vicineum treatment for patients with grade II hematuria.  
Missed doses should not be made up.  In the Maintenance Phase, dosing should be restarted as 
soon as there is AE resolution i.e., treatment should not be postponed longer in order to align 
with the initial every-other-week schedule. 
If study treatment is postponed longer than 3 weeks, the investigator should consider whether the 
subject should remain on treatment.
In circumstances where subjects cannot tolerate Vicineum or do not meet retreatment criteria to 
receive either drug, subjects will be taken off protocol therapy.
The reasons and details relevant to the subject postponement and/or discontinuation of study 
treatment must be recorded on the CRF. The Investigator must notify Sesen Biotherapeutics if 
study treatment is discontinued. 


3.4
STUDY CALENDAR
SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Written informed 
consent/assignment 
of subject 
identification 
number
X
Inclusion/Exclusion 
criteria
X
Demography
X
Medical and 
surgical history
X


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Previous treatments 
for bladder cancer 
including 
dates/doses of prior 
BCG
X
Confirmation of 
diagnosis by NCI 
LP
X
Cystoscopy
X
X (every 3 
months as per 
SCHEMA)
Bladder biopsies / 
TURBTs 
X
X (every 3 
months as 
indicated as per 
SCHEMA)


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Urine cytology
X
X (every 3 
months 
preceding each 
cystoscopy as 
per SCHEMA)
EpCAM 
determination
X
Last biopsy on 
trial
Tissue PD-L1 assay
X
Last biopsy on 
trial
Hepatitis B and C; 
HIV
X
Urine hCG or 
serum βhCG2
X3
Week 4
Week 8
X
Prior to each 
durvalumab 
dose


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Durvalumab 
administration3 
Starting 
Week 2
Week 6
Week 10
Every 4 weeks 
resuming in 
week 15 and as 
per SCHEMA.  
Every 3 months 
if optional 
maintenance 
performed after 
first 12 months.
Vicineum 
administration4
X
X
X
X
X
Every 2 weeks 
resuming in 
week 15 and as 
per SCHEMA.


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Physical 
examination 
including weight5
X
X
Week 2
Weeks 6, 10
X
Targeted 
physical 
examination as 
needed.
Vital signs (pre- 
during and post-
durvalumab 
infusion; pre- and 
post-Vicineum 
drainage)6
X
X
All treatment visits
Electrocardiogram7
X
Week 2
If clinically 
indicated
If clinically 
indicated


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Adverse 
event/serious 
adverse event 
assessment
All visits
Concomitant 
medications
X
All visits
ECOG 
performance status
X
X
X
Acute care panel7
X
X
X
X
X
X
X
Every 2 weeks
LDH
X
X
X
X
X
X
X
Every 2 weeks
Pre-albumin
X
Pancreatic enzymes 
(amylase, lipase)
X
X
X
X
X
X
X
Every 2 weeks


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Hepatic panel
X
X
X
X
X
X
X
Every 2 weeks
Mineral panel
X
X
X
X
X
X
X
Every 2 weeks
Thyroid function 
tests (TSH and fT3 
and fT4)8
X
X
Week 2
Week 6
Week 10
Prior to each 
durvalumab 
dose
Hematology7
X
X
Week 2
Week 4
X
Week 8
X
Prior to each 
durvalumab 
dose
Urinalysis
X
X
X
X (weekly)
X
X (weekly)
X
X (prior to each 
Vicineum 
treatment)
Urine culture and 
sensitivity 
X


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
24 hour urine (only 
if CrCl to be 
measured rather 
than calculated)
X
PPD testing (if 
indicated)
X
Coagulation 
parameters
X
As clinically indicted
Urine cytokines
X
X
6 months
Serum circulating 
cytokine profile 
X
Weeks 2, 3, 
and 5


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
sPD-L1 
concentration (to 
assess target 
engagement)
X
Weeks 2, 3, 
and 5
Gene expression 
analysis
X
Tissue immune 
correlates (IHC and 
possibly RNAseq)
X
Last biopsy on 
trial


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Flow cytometry of 
PBMCs for 
immune subsets 
and antigen-
specific responses 
(T-cell clonal 
expansion if 
feasible)
X
X
6 months
Immunogenicity 
assessment
X
Week 8:  
ADA
Week 12:  
AVA
Tumor CT/CT 
urogram or 
MRI/MRI urogram 
of abdomen and 
pelvis9
X
Every 12 
months while 
on study


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SCHEDULE OF STUDY ASSESSMENTS:  Screening (Weeks -12 to -1), Induction Phase (Weeks 1 – 12), and Post-
Induction Evaluation (All assessments can be performed within +/-7 days of scheduled assessment to accommodate holidays 
and scheduling difficulties)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject15.
Screening
Baseline
Week 1
Weeks 2 - 5
Week 6
Weeks 7 - 11
Week 12
Post-Induction 
and 
Maintenance
Day
-84  to -1
-7 to 0
Week
-12 to -1
-1
Urinary PK for 
Vicineum
X
X10,11, 
X12
Urinary EpCAM 
levels
X
X10,11
X12
X (before 
Vicineu
m)
Week 10 
(before 
Vicineum)
X (before 
Vicineum)
Follow-up Safety 
Visits for patients 
who come off 
treatment or 
complete study13, 14
Every month up 
to 90 days post 
the last dose of 
immunotherapy14
1.
May be performed up to 12 weeks prior to enrollment.
2.
Pre-menopausal female subjects of childbearing potential only.
3.
Dose can be administered within +/- 7 days of scheduled administration to accommodate schedule and holidays.
4.
Once weekly intravesical administration for weeks 1-12; Dose can be administered within +/- 7 days of scheduled administration to 
accommodate schedule and holidays.
5.
Full physical examination at screening and/or baseline; targeted physical examination at other timepoints and when clinically indicated.


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6.
Vital signs will be obtained at a single timepoint at screening and baseline.  Subjects will have their blood pressure and pulse measured 
before, during and after the infusion at the following times (based on a 60-minute infusion):
•
At the beginning of the infusion (at 0 minutes)
•
At 30 minutes during the infusion (±5 minutes)
•
At the end of the infusion (at 60 minutes ±5 minutes)
•
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the 
infusion) (±5 minutes) – for the first infusion only and then for subsequent infusions as clinically indicated.
•
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements should be collected every 30 minutes (±5 
minutes) and as described above or more frequently if clinically indicated.
7.
ECG during screening required to measure QTc as specified above and 1 ECG is needed while on treatment (pre-durvalumab infusion) and as 
clinically indicated.  ECGs should be obtained after the patient has been in a supine position for 5 minutes and should be recorded while the 
patient remains in that position.  In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead 
ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm prolongation.  If screening laboratory assessments are performed 
within 3 days prior to Day 1, they do not need to be repeated at Day 1.  
8.
Free T3 and free T4 will only be measured if TSH is abnormal.  They should also be measured if there is clinical suspicion of an adverse 
event related to the endocrine system. During maintenance phases 4-7, TSH will be drawn prior to each durvalumab dose and subsequently 4 
weeks and 8 weeks after durvalumab administration.
9.
Can be given without contrast if severe contrast allergy or renal function does not allow contrast administration per institutional 
recommendations. MRIs will be done per PI discretion and when clinically indicated.
10. First void after Vicineum administration in Week 1.
11. First void after the next morning after Vicineum administration in Week 1.
12. Day 8 void prior to Vicineum administration in Week 2.
13. H&P, Labs including renal, liver, complete blood count + platelets, coagulation studies monthly for up to 90 days after last immunotherapy. 
14. End of treatment visit will occur 90 days after the last dose of immunotherapy. If clinically indicated, patients may continue to be followed 
by phone or clinic visits beyond that time and up to a year at the NIH/NCI or their local urologist. 
15.  Per PI discretion, a remote evaluation may be done by phone by a member of the study team. This evaluation will be conducted in 
compliance with NIH guidelines and FDA regulations.  A patient may be asked to come to the NIH Clinical Center or may be referred to 
their local provider for an in-person assessment, if deemed necessary by the PI.  In the case of any visits with participants’ local providers, 
records will be obtained.


3.5
COST AND COMPENSATION 
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by their insurance company.  Medicines that are not part of the study treatment 
will not be provided or paid for by the NIH Clinical Center.    
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete monthly safety 
visits (+/- 7 days) for 90 days following the last dose of study therapy.  These visits will consist 
of H&P and labs (including renal, liver, complete blood count + platelets, coagulation studies).  
Patients will revert to standard of care once coming off study. If clinically indicated, patients 
may continue to be followed by phone or clinic visits beyond that time and up to a year at the 
NIH/NCI or their local urologist.  
3.6.1
Criteria for Removal from Protocol Therapy
Subjects are free to withdraw from further treatment or to withdraw consent to participate in this 
study at any time and without prejudice to further treatment. For subjects who withdraw their 
consent for study participation, no further study specific assessments will be performed and no 
additional study data will be collected. For subjects who withdraw from further treatment only 
will remain on study for further evaluations but receive no additional study treatment. The 
investigator may also withdraw a subject from study treatment or from the study if he or she 
deems it to be in the best interest of the subject or if the subject is unable to comply with the 
study. All subjects withdrawing only from further treatment should have enter the Post-
Treatment Period and have the appropriate assessments performed 90 days after the last dose of 
study drug, unless the subject withdraws consent for the procedures. If clinically indicated, 
patients may continue to be followed by phone or clinic visits beyond that time and up to a year 
at the NIH/NCI or their local urologist. The reasons and details relevant to subject withdrawal 
must be recorded in the source documents and in the CRFs.
In addition, an individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
•
Completion of protocol therapy


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•
Unacceptable toxicity as defined in section 3.3 and Appendix C 
•
Adverse event that, in the opinion of the investigator, contraindicates further dosing 
of either study drug
•
Subject experiences a DLT during the DLT evaluation period (see section 3.1.1)
•
Requirement for prohibited medications/therapies
•
Subject met eligibility criteria at screening but then subsequently is determined to 
have met one or more of the exclusion criteria for study participation and continuing 
investigational therapy might constitute a safety risk
•
Subjects refuses to use contraception as required by the protocol
•
Disease progression (as defined in section 6.2.4.3) or confirmation that the subject is 
no longer benefiting from study treatment
•
Grade 2 or greater hyperbilirubinemia 
•
Participant requests to be withdrawn from active therapy
•
Unacceptable Toxicity as defined as any serious adverse event that is unexpected 
relative to the known safety profile of the investigational agents in the opinion of the 
investigator
•
Sponsor or Manufacturer terminates the study
•
The FDA requests that the sponsor terminate treatment of a specific subject or 
subjects or all subjects
•
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g. refusal to adhere to scheduled visits
•
Investigator discretion
•
Positive pregnancy test or intent to become pregnant or intent to breast-feed or is 
breastfeeding
•
Disease recurrence with high-grade bladder cancer
3.6.2
Off-Study Criteria
The following are off study criteria that will preclude further follow-up:
•
Completed study follow-up period 
•
Participant requests to be withdrawn from study
•
Death
•
Patient is lost to follow-up
•
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3.6.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PERMITTED CONCOMITANT MEDICATIONS
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except 
for those medications identified as “excluded” as listed in Section 4.2.
4.2
EXCLUDED CONCOMITANT MEDICATIONS
The following medications are considered exclusionary during the study. 
1. Any investigational drugs
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy, including investigational therapy for 
cancer treatment.  Concurrent use of hormones for noncancer-related conditions (e.g., 
insulin for diabetes and hormone replacement therapy) is acceptable.  Subjects who enter 
the study with low risk prostate cancer and then progress to require androgen-deprivation 
therapy (ADT) when already enrolled on this trial may continue on trial as per 
investigator discretion.
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled and intranasal corticosteroids is permitted. 
4. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days prior to the 
first dose, during treatment with durvalumab and for 30 days post discontinuation of 
durvalumab.  Inactivated vaccines, such as the injectable influenza vaccine, are permitted.)


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Prohibited & concomitant meds
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [e.g., insulin for 
diabetes and hormone replacement therapy] is 
acceptable.  Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [e.g., by local surgery or radiotherapy])
Live attenuated vaccines 
Should not be given through 30 days after the last 
dose of IP
5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
BIOSPECIMEN COLLECTION 
Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.
5.1.1
Blood studies
5.1.1.1
Serum circulating/Blood cytokine profile
Refer to the table in section 5.2 for volume, tube types and sample collection schedule. Samples 
will be assessed for:
•
IL-1B, IL–2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-18, IFN-y, IL-6, TNF-
alpha, and IL-10.  This will be done with a commercial ELISA kit such as V-plex in 
collaboration with William D. Figg, and Dr. Andrea Apolo.  
•
Soluble PD-L1 (total and free unbound PD-L1)
For Serum collection of samples for cytokines and soluble PDL-1, 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 
biospecimen 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.
5.1.1.2
PBMCs for immune analysis
Samples will be collected at the timeframes indicated in the table in section 5.2
•
Flow cytometry of immune subsets (include CD4+ and CD8+ T-cells, Tregs, NK 


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cells, and MDSCs and PD-L1 expression on immune cells) – This will be processed 
in Dr. Schlom’s laboratory as described below. Dr. Schlom’s laboratory now has the 
ability to analyze 123 peripheral immune cell subsets31 as shown in Appendix D.
•
T-cell clonal expansion assay if appropriate funding and material is available
•
Antigen-specific responses of cytotoxic lymphocytes for tumor associated antigens 
(e.g. brachyury, EPCAM)
•
Immunogenicity Assessment (anti-durvalumab antibodies and anti-vicineum 
antibodies) – Samples will be collected at baseline and stored in Dr. Linehan’s Lab
i. Week 8 for ADA and Week 12 for AVA (separate blood collection at the 
weeks specified – Stored in Dr. Linehan’s Lab
5.1.1.2.1 Sample processing
For PBMCs, green top tubes will be obtained and then processed at the Clinical Services 
Program (CSP) NCI Frederick Cancer Research and Development Center, PO Box B, Frederick, 
MD 21702 in collaboration with Dr. Schlom’s research group.  On days samples are drawn, Jen 
Bangh at CSP should be notified (phone: [301] 846-5893; fax [301] 846-6222).  Once a patient’s 
treatment schedule has been determined, Caroline Jochems should be notified at 
jochemscm@mail.nih.gov for planning purposes.  Dr. Schlom and colleagues recently published 
their ability to analyze PBMCs for 123 subsets of peripheral immune cells using 30 unique 
markers in 5 immune flow cytometry panels.  These subsets are subsets of CD4+ T cells, CD8+ 
T cells, Tregs, B cells, NK cells, NK-T cells, conventional dendritic cells (cDCs), plasmacytoid 
DCs (pDCs), and MDSCs.  A full list is enclosed in Appendix D.  
5.1.2
Research urine studies
5.1.2.1
Urine cytokines 
Urine collection at the timepoints indicated in the table in section 5.2 for correlative/exploratory 
research aims (e.g. inflammatory cells, cytokines) at baseline.  This will be performed through a 
commercial vendor, Luminex, using a platform of 12 urinary cytokines.32
5.1.2.2
Urine EpCAM, Pharmacokinetics and Pharmacodynamics
This will be done in direct collaboration with Dr. Cao’s laboratory
•
Evaluate PK for urinary Vicineum by testing for VB4-845  – see table in section 5.2 
for PK timepoints
•
Evaluate pharmacodynamics (PD) for EpCAM shedding in the urine [baseline, first 
void after drug administration in Week 1, first void the next morning after treatment, 
and the day 8 void prior to start of week 2 treatment, Week 6 before Vicineum, Week 
10 before Vicineum, Week 12 before Vicineum - – see table in section 5.2 for PD 
timepoints
•
Evaluate EpCAM in the urine for the ability to monitor or predict response to therapy 
- see table in section 5.2 for PK timepoints


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5.1.2.3
Sample Processing
For urine collection, it will be processed according to standard protocol (refer to Appendix E) 
and stored in the Urologic Oncology Branch in Dr. Linehan’s lab.  Samples will be batched at 
the end of the trial and then analyzed.  
5.1.3
Tissue studies
Samples will be obtained pre-and post treatment as indicated in the table in section 5.2 to:
•
Perform immunohistochemistry (IHC) or cytogenetic analysis of baseline tissue (FFPE or 
frozen tissue specimen) for EpCAM, PD-1/PD-L1, TILS, CD4, CD8, Tregs, MDSCs, 
Macrophages, and monocytes.  In addition, mesenchymal markers such as vimentin, 
TWIST, Snail, Slug, and Sip1 may also be assessed by immunohistochemistry of baseline 
tissue.  This can be compared to similar IHC of tissue obtained from the last biopsy on trial.  
This analysis will be performed by the NCI Laboratory of Pathology upon accruing at least 
4 patients or by PI’s discretion.  Baseline FFPE slides will be obtained from paraffin-
embedded blocks stored within NCI’s Laboratory of Pathology at a future date when 
analysis will be performed.  In the event that patients have had baseline biopsy at an 
outside institution, every effort will be made to obtain the paraffin-embedded blocks in 
order to generate baseline FFPE slides for further analysis.  
In particular to the current study, we would like to study the T-cell infiltration pattern 
within bladder tumors pre- and post-treatment. Specifically, we will look at: 
1. The presence of CD4 and CD8 T cells in bladder tumor specimens pre- and post-
treatment 
2. The presence of regulatory T cells (Tregs) by double staining with FoxP3 and 
CD4 in bladder tumor specimens pre- and post-treatment
3. The presence of myeloid derived suppressor cells (MDSC) in bladder tumor 
specimens pre- and post-treatment 
4. The presence of myeloid derived suppressor cells (MDSC) in bladder tumor 
specimens pre- and post-treatment 
5. The presence of PD-L1 staining pre- and post-treatment as specified below in 
section 5.1.3.2.
6. The presence of EpCAM and mesenchymal markers.
•
If sufficient tissue is available, cell lines may be generated.  Cell lines may be characterized 
by karyotyping, interphase fluorescence in situ hybridization (FISH) mapping, 
immunohistochemistry, and/or flow cytometry. Differences between cell lines will be 
manipulated to study the various molecular pathways active in nutrient sensing, cell cycle, 
cell signaling, proliferation, apoptosis, angiogenesis, and metastatic potential in urothelial 
cancer.
•
If adequate tissue and funding available, then may perform mutational load analysis 
through a targeted panel (RNAseq or DNA mutation panel) of tumor tissue. This analysis 
will be performed by the NCI CORE facility, NCI collaborator (Paul Meltzer), or outside 
entity (e.g. Foundation Medicine)


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5.1.3.1
Tissue Collection Procedures  
If tissue is clinically available, the Urologic Oncology Branch procedures for tissue collection 
will be followed. This is usually done with standard of care procedures such as such as 
transurethral resection of bladder tumor.  CT guided biopsy is not a procedure by which to 
procure non-muscle invasive bladder tumor and so it will not be performed on this protocol.  A 
procurement form will be completed. The tissue procurement nurse or a UOB-designated 
procurement staff member will work with an NCI pathologist following resection of the 
specimen to obtain tumor tissue from the resected specimen. this will be done using standard of 
care procedures  This will then be delivered by the procurement nurse or UOB Procurement staff 
member to the Urologic Oncology Branch Research Laboratory for individual processing. 
Specimens will be placed in cryovials and also be snap frozen in OCT for frozen tissue sections. 
Tissue sent to pathology will be processed in standard fashion but when formalin-fixed paraffin 
embedded slides made, they will be modified as below in section 5.1.3.2 to allow for PD-L1 
testing in a standardized fashion.  
Pathologic material, such as fixed tissue blocks from surgery performed at the NIH Clinical 
Center, outside surgeries or autopsy materials, may be obtained at the request of, and with 
written permission from the subject, or appropriate relatives. These samples may undergo 
pathologic analysis by individuals in the NCI Laboratory of Pathology to confirm diagnosis and 
may undergo histo-immunologic or other analysis. 
5.1.3.2
Tissue PD-L1 Testing
To ensure comparability of data across all studies of durvalumab and to gain real world experience 
on the performance of this assay, it is strongly encouraged that all studies that include PD-L1 
testing utilize the Ventana SP263 assay.  Testing should be restricted to the Ventana SP263 assay 
and should be performed in accordance with the package insert on the Ventana Benchmark 
platform (Ultra or XT).  
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 assay has a 
fully reproducibility data package supporting cut-off and scoring algorithm.  Following completion 
of ATLANTIC and HAWK clinical trials, the assay will be associated with clinical utility.  In 
other cancer types (bladder, pancreatic, gastric, hepatocellular, triple negative breast, ovarian, 
esophageal, nasopharyngeal, glioblastoma, soft tissue sarcoma, cholangiocarcinoma, small cell 
lung, melanoma and cervical HPV+ cancers), the Ventana SP263 assay has only limited clinical 
performance data.  
5.1.3.2.1 Sample collection for PD-L1 testing
•
The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken at 
this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.  
•
In AstraZeneca studies, the preferred sample for PD-L1 testing was less than or equal to 3 
months old.  In cases where a sample a less than 3 months old was not available, patients 


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were asked to undergo a new biopsy if considered clinically appropriate by their treating 
physician.  
•
Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy.  Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) to allow 
for adequate PD-L1 immunohistochemistry analyses.  
•
When the collection of a new sample is not clinically appropriate, archival samples may be 
utilized provided the specimen it is not older than 3 years of age.  When archival samples 
are used to assess PD-L1 status, the age of the sample / date of collection should be 
captured.  
•
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for PD-
L1 analysis.  
5.1.3.2.2 Sample data collection for PD-L1 testing
The following fields of data should be collected from the site/institution collecting and if, indicated 
shipping of the samples:  
•
Patient identifier (unique identifier)
•
Specimen identifier (written on the specimen)
•
Site identifier
•
Specimen collection date
•
Type of specimen submitted
•
Quantity of specimen
•
Date of sectioning
•
Archival of fresh tumor
•
Tumor type
•
Primary tumor location
•
Metastatic tumor location (if applicable)
•
Fixative
The following fields of data should be collected from PD-L1 testing laboratory:
•
Are the negative and positive controls stained correctly
•
Is the H&E material acceptable
•
Is morphology acceptable
•
Total percent positivity of PD-L1 in tumor cells
•
PD-L1 status (positive, negative or NA) in tumor cells 
•
Total percent positivity of PD-L1 in infiltrating immune cells
The Ventana SP263 assay to measure PD-L1 in tumors is experimental.  As with all tests, there is 
a chance of false positive (the test shows high PD-L1 when it is not there) or false negative (the 
test does not show PD-L1 when it is there) results may occur.  
5.1.3.2.3 Sample processing for PD-L1 testing


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Preparing Stored samples for testing
•
Where samples already exist, they should be retrieved from the Bio-Bank storage location.  
These blocks should undergo quality review, prior to evaluation or shipment.  Where it is 
not possible or indicated to ship the block to a testing laboratory, unstained slides should 
be prepared from the paraffin-embedded tumor sample block (described below) prior to 
evaluation or shipment.  
Preparing newly acquired samples for PD-L1 testing
•
If patients are undergoing a biopsy procedure that provides the option to submit newly 
acquired samples, this sample should be used to determine PD-L1 status.  Where clinically 
acceptable, a minimum of 2 core biopsies should be collected and processed to FFPE in a 
single block.  The provision of 2 cores is advised in order to provide sufficient tissue for 
PD-L1 assessment. 
•
It is recommended that core needle tumor biopsies are collected using an 18 gauge or larger 
needle and the process should be image-guided.  Excisional or incisional samples are also 
adequate.  If this is not per the institutions normal practice and a smaller gauge needle is 
used then the number of cores collected should be increased to allow sufficient material for 
successful PD-L1 testing (>100 tumor cells) and embedded in the same block.  If available, 
a single excisional biopsy of at least 4 mm in diameter may substitute for all core biopsies. 
Fixation of biopsy samples for PD-L1 testing
•
Previously frozen tissue is not acceptable for processing to FFPE for PD-L1 testing.  To 
fix newly acquired tissue, place immediately (within 30 min of excision) into an adequate 
volume of 10% v/v neutral buffered formalin (NBF).  Samples should remain in fixative 
for 24 – 48 hours at room temperature.  
•
It is vital that there is an adequate volume of fixative relevant to the tissue (at least a 10 
volume excess) and that large specimens (if any) are incised prior to fixation to promote 
efficient tissue preservation.  
Embedding in paraffin for PD-L1 testing
•
An overnight processing schedule into paraffin wax is recommended 
•
Below is the suggested routine overnight processing schedule
Storage of tumor blocks for PD-L1 testing
•
FFPE blocks should be stored at ambient temperature and protected from light until 
shipment by courier at ambient temperature. FFPE blocks are stable under these conditions 
for an indefinite period.
Quality control of samples to be used for PD-L1 testing
•
Tissue should be assessed by the site pathologist prior to PD-L1 testing.  
•
Each sample should be reviewed for:
•
Adequate fixation
•
Good preservation of morphology
•
Presence of tumor tissue


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•
Histopathology consistent with indication
•
Greater than 100 tumor cells are required to determine PD-L1 status – tumor cell 
content must be reviewed prior to testing in order for PD-L1 obtain a valid result.  
If indicated, shipping samples to a PD-L1 testing laboratory
•
When submitting sample to for PD-L1 testing the recommendation is to ship the block in 
order for sectioning to occur at the laboratory.  Blocks should be shipped - containing 
enough material to be provided to allow a minimum of 5, and preferably 10, sections to be 
cut (each 4 micron thick) to be used for PD-L1 testing.   
Sectioning instructions
•
Where it is not possible or indicated to ship the block to laboratory for PD-L1 testing, 
unstained slides should be prepared from the paraffin-embedded tumor sample block as 
described below:  
•
A minimum of 5-10 x 4 micron (μm) thick, unstained sections should be provided 
for PD-L1 testing
•
A new disposable microtome blade must be used for each block to prevent 
contamination between Slides are stable under these conditions for 6 months.
•
patient samples
•
Apply one section per slide to positively-charged Superfrost glass slides 
•
The sections should be dried overnight between room temperature and 37°C. Do 
not dry sections at temperatures above 37°C.
Sections should be stored at ambient temperature and protected from light until use or shipment to 
testing lab by courier at ambient temperature.  It is recommended that slides are cut freshly prior 
to PD-L1 testing and they are used within 90 days of being cut to obtain PD-L1 status
Any additional FFPE tissue obtained that is not used for PD-L1 testing can be used for the 
following additional correlative assays:
1. Tissue Immune Correlates - (FFPE or frozen tissue specimens) - pre-treated and post-
treated samples can be analyzed by IHC (FFPE) for Epcam, TILs, CD4, CD8, Tregs, 
MDSCs, Macrophages, and monocytes.  In addition, mesenchymal markers such as 
vimentin, TWIST, Snail, Slug, and Sip1 may also be assayed by IHC.  
2. Frozen tissue specimens or a single FFPE slide can be analyzed later for tumor 
mutational load through targeted sequencing panel.
Frozen tissue specimens or a single FFPE slide for gene expression using HT Seq immune-
oncology panel of 500+ genes and/or microRNA analysis.


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5.2
SAMPLE COLLECTION SCHEDULE
Test/assay
Volume blood 
(approx)
Type of 
tube a
Collection 
point (+/- 7 
days)
Location of 
specimen analysis
Urine collection 
for Urinary 
Cytokines 
(Section 5.1.2)
50-100 mLs 
Urine 
specimen 
cup
Baseline, 3 
months, 6 
months
Stored and processed 
in Linehan Lab 
(Appendix E) using 
Luminex Assay
Serum collection 
for cytokines
(section 5.1.1)
20 mLs
2 Red Top 
(SST) 
Tubes
Baseline, 2 
weeks, 3 weeks, 
5 weeks
Stored in Dr. Figg’s 
Lab 
Plasma collection 
for soluble PD-L1
(secion 5.1.1)
6 mLs
EDTA
Baseline, 2 
weeks, 3 weeks, 
5 weeks
Stored in Dr. Figg’s 
Lab 
Urinary PK for 
Vicineum
(Section 5.1.2.2)
50-100 mLs
Urine 
specimen 
cup
Baseline, First 
void after Week 
1 Vicineum, 
First void 
morning after 
Week 1 
Vicineum, Day 
8 void prior to 
Week 2 
Vicineum
Stored in Linehan 
Lab (Appendix E) 
Urinary EpCAM
(Section 5.1.2.2)
50-100 mLs
Urine 
specimen 
cup
Baseline, First 
void after Week 
1 Vicineum, 
First void 
morning after 
Week 1 
Vicineum, Day 
8 void prior to 
Week 2 
Vicineum, 
Week 6 before 
Vicineum, 
Week 10 before 
Vicineum, 
Stored in Linehan 
Lab (Appendix E) 


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Test/assay
Volume blood 
(approx)
Type of 
tube a
Collection 
point (+/- 7 
days)
Location of 
specimen analysis
Week 12 before 
Vicineum
Gene Expression
(see section 5.4.1)
Single FFPE 
slide or frozen 
tissue
N/A
Baseline
Stored in Linehan 
Lab and processed by 
NCI DTB CTU lab or 
NCI CORE
Tissue IHC
(see section 5.1.2)
Single FFPE 
slide
N/A
Baseline, Last 
Biopsy on Trial
Will be obtained from 
tissue blocks in 
Laboratory of 
Pathology and 
analyzed by Dr. 
Merino (Laboratory 
of Pathology)
RNAseq and/or 
DNA mutational 
panel for 
mutational load
(see section 5.1.2)
Single FFPE 
slide or frozen 
tissue
N/A
Baseline
NCI CORE facility or 
outside entity 
(Foundation 
Medicine) 
PBMCs for 
immune subsets, 
antigen specific 
responses (section 
5.1.1.2)
60 mL
6 green top 
Tubes
Baseline, 3 
months, 6 
months
Schlom Laboratory 
(Deliver to Frederick 
Lab)
Immunogenic 
Assessment 
(ADA, AVA)
(section 5.1.1.2)
8 mL
2 lithium 
heparin (4 
mL each) 
tubes
Baseline, Week 
8 (ADA), Week 
12 (AVA)
Linehan Laboratory 
in collaboration with 
AZ and Sesen 
Biotherapeutics
a. Please note that tubes and media may be substituted based on availability with the permission of the PI or 
laboratory investigator.
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through 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 the NIH without appropriate approvals and/or agreements, if 
required.


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5.3.1
UOB Research Laboratory
All specimens obtained for research purposes will be coded upon arrival in the UOB research 
laboratory to maintain patient confidentiality.  All samples will be accessioned and entered into a 
database (such as LabMatrix) with access limited to the PI and UOB research data managers.  
The location of all samples will be carefully tracked in the database.  All stored samples will be 
coded and identifying patient information will not be placed on sample containers.  Stored 
samples will be kept in freezers/refrigerators or secure containers located in the Urologic 
Oncology Branch research laboratories or in approved storage facilities.  The research samples 
collected will be used for the correlative/biomarker studies mentioned above in Section 5.1.  
Tissue slides/blocks may be obtained in order to determine protocol eligibility.  Tissues are 
submitted to the NCI Laboratory of Pathology at the NIH Clinical Center for clinical 
determination of histologic features.  Specialized stains/assays may be used to clarify tissue 
phenotype.  After completion of analysis, tissue slides/blocks are either returned to the 
originating pathology department or archived in the Laboratory of Pathology or Urologic 
Oncology Branch and tracked in the UOB database (LabMatrix).  Archived material will be 
retained for the duration of the study unless the originating pathology department requests return.
Coded/anonymous samples with minimal clinical information may be shared with qualified NIH 
and non-NIH researchers who have IRB-approved protocols with similar research objectives.   
No personal identifying information such as name, address, or date of birth will be provided to 
the non-UOB investigator.  In the event a subject is eligible to participate in a clinical trial based 
on tumor characteristics, coded tissue samples may be sent to an outside laboratory.  
5.3.2
Samples (serum samples for cytokines) Stored with Clinical Pharmacology Program 
(Figg Laboratory)
5.3.2.1
Procedures for sample data collection for 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 biospecimen 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.
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in the Labmatrix utilized by the CPP. This is a secure program, with access to 
Labmatrix limited to defined CPP personnel, who are issued individual user accounts. 
Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. 
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. Patient demographics associated with the Clinical Center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 


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5.3.2.2
Procedures for sample storage at the Clinical Pharmacology Program: 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20oC or - 80oC 
according to stability requirements. These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on 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 the IRB approved protocol) and that any unused 
samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
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. 
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 record any loss 
or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2.1.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
5.3.3
Clinical Services Program
All data associated with the patient samples is protected by using a secure database.  All samples 
drawn at the NIH Clinical Center will be transported to the NCI Frederick Central Repository by 
couriers.
Samples will be tracked and managed by the Central Repository database.  All samples will be 
stored in liquid nitrogen.  These freezers are located at NCI Frederick Central Repository in 
Frederick, Maryland.
NCI Frederick Central Repositories (managed under a subcontract) store, among other things, 
biological specimens in support of NIH clinical studies. All specimens are stored in secure, 
limited access facilities with sufficient security, back-up and emergency support capability and 
monitoring to ensure long-term integrity of the specimens for research. 
The subcontractor’s role is limited to clinical research databases and repositories containing 
patient specimens. The subcontractor neither conducts nor has any vested interest in research on 
human subjects, but does provide services and supports the efforts of its customers, many of 
which are involved in research on human subjects. 
It is the intent and purpose of the subcontractor to accept only codedsamples and sample 
information.  If the coded data are linked, the code key will not be accepted.To the best of our 


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ability, every effort will be made to ensure that protected information is not sent electronically or 
by hard copy or on vial labels. 
Sample data is stored in the BioSpecimen Inventory (BSI) System II. This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race 
conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user 
permissions (levels of access) that can be set to control access to the system functions. BSI 
provides audit tracking for processes that are done to specimens including shipping, returning to 
inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of 
specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for 
specimens received by the repository. If a specimen goes out of the inventory, the system 
maintains data associated with the withdrawal request. Vials are labeled with a unique BSI ID 
which is printed in both eye-readable and bar-coded format. No patient-specific information is 
encoded in this ID. 
Investigators are granted view, input and withdrawal authority only for their specimens.  They 
may not view specimen data or access specimens for which they have not been authorized. 
Access to specimen storage is confined to repository staff. Visitors to the repositories are 
escorted by repository staff at all times.
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 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. If the patient withdraws consent, the participants data will 
be excluded from future distributions but data that have already been distributed for approved 
research use will not be able to be retrieved.
Once primary research objectives for the protocol are achieved, intramural researchers can 
request access to remaining samples, provided they have an IRB-approved protocol and patient 
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.
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Proposed Genetic Analysis
Protein, DNA mutational analysis, and miRNA/mRNA for immune gene expression profile 
analysis (quantitative polymerase chain reaction [Q-PCR]) of known and putative targets 
obtained from tumor tissue at baseline if adequate tumor tissue is available for such an analysis.  
The analysis will be performed through one of the following platforms:  


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•
Targeted DNA mutational panel from frozen tissue or FFPE via NCI Core facility, 
collaborator (Paul Meltzer), or outside entity (e.g. Foundation Medicine) if adequate 
funding and tissue available
•
HT seq from single FFPE slide for immune-oncology panel of 500+ genes or 
microRNA analysis – NCI CORE facility or Development Therapeutics Branch 
Clinical Trial Unit (DTB CTU)
•
Nanostring panel for immune oncology related genes obtained from tumor tissue
5.4.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Using a computerized inventory system (LabMatrix), each new specimen collected will be 
assigned a unique barcode identifier that can be linked to the original specimen collected but 
personal identifiers will be removed.  
For each specimen, the corresponding subject demographics and clinical information will be 
assigned in the database as described in section 6.1 and only be accessible by the PI and research 
nurses within the UOB through a password-protected database.
Samples provided to other researchers will be bar coded and these researchers will not have 
access to any information in LabMatrix. Samples will not be sent outside NIH without 
appropriate approvals and/or agreements, if required.
Data from genomic analysis will be deposited in dbGAP.
5.4.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. Subjects will be contacted at 
this time with a request to provide a sample to be sent to a CLIA certified laboratory. If the 
research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling to 
explain this result.  If the subject does not want to come to NIH, a referral to a local genetic 
healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
Note:  incidental findings considered clinically relevant will be discussed among Senior Scientific 
Staff at meetings such as the weekly UOB conference prior to being communicated to subjects.
5.4.4
Genetic counseling
Genetic counseling will be recommended should any clinically relevant incidental findings be 
discovered and consultation with the NCI Genetics Branch will be offered.


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6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR 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.  Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All AEs, 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, Week 1/Day 1, through 90 days after the last administration of 
the study intervention. After 90 days, only adverse events which are serious and related to the 
study intervention need to be recorded.
An abnormal laboratory value will be considered an AE 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
•
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)
•
Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:


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•
An NIH-funded or approved public repository.  Insert name or names: clinicaltrials.gov, 
dbGaP.
•
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
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.2.3
Response Criteria
Patients will be evaluated every 3 months as per standard of care with cystoscopy.  Biopsy will 
be done at PI discretion pending cystoscopic findings.  Any biopsies done will be for clinical 
reasons to rule out tumor recurrence, however, extra biopsy material if available will be used for 
research purposes.  
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with vicineum or durvalumab.  All observed toxicities will be tabulated using CTCAE 
v5.0.  
6.2.4
Evaluable for Objective Secondary Endpoints/Response
Only those patients who have biopsy-proven disease present at baseline, have received at least 
one intravesical dose of Vicineum therapy and one intravenous dose of durvalumab, 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.  
6.2.4.1
Recurrence-free survival
The recurrence-free survival duration will be measured from the start of Vicineum therapy until 
disease recurrence, progression, or death due to any cause.  Recurrence is suspected and/or 
determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a 
TURBT.  Positive cytology in the absence of pathologic confirmation is not considered to be a 
recurrence.  Low grade papillary tumor will not be considered recurrent disease.
6.2.4.2
Complete Response Rate for CIS
In patients with any component of CIS upon study entry, the complete response (CR) rate will be 
determined at 3 months, 6 months, and 12 months from the start of Vicineum therapy.  Complete 
response will be defined as the absence of CIS upon follow-up biospies.  These rates can be 
compared to historical rates of CR for CIS at these various time points. 


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6.2.4.3
Disease Progression & Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. The duration of progression-free survival is measured from the start of 
vicineum therapy until progression or death due to any cause. Disease progression is defined as 
upstaging from a lower stage to a higher stage (e.g., Ta to T1-T4 or T1 to T2-4; CIS to T1 or CIS 
to T2-T4; or any N+ or M+ in these high grade tumors).  
6.2.4.4
Time to Tumor Recurrence
The duration of time measured from the start of Vicineum therapy until recurrence is noted.
6.3
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#ctc_50). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN  
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
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 at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
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 at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.


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In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
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 regular 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. 
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 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
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.


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o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject 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 5.0.
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.
8.1.6
Adverse Events of Special Interest (AESI)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is 


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associated with drug exposure and is consistent with an immune-mediated mechanism of action 
and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
In the event of imAE or suspected imAE, the AstraZeneca study team may request relevant 
clinical information (including images) for those subjects who demonstrate the event, and may 
request the independent review by external experts based on the acquired clinical information. 
AESIs observed with durvalumab include:
•
Diarrhea / Colitis and intestinal perforation
•
Pneumonitis / ILD
•
hepatitis / transaminase increases
•
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus)
•
Rash / Dermatitis
•
Nephritis / Blood creatinine increases
•
Pancreatitis / serum lipase and amylase increases  
•
Myositis / Polymyositis
•
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
•
Intestinal Perforations
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 
etiology include, but are not limited to:
•
Myocarditis
•
Pericarditis
•
Sarcoidosis
•
Uveitis
•
Other events involving the eye and skin
•
Hematological events
•
Rheumatological events
•
Vasculitis
•
Non-infectious meningitis
•
Non-infectious encephalitis
•
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It is possible that events with an inflammatory or immune mediated mechanism could occur in 
nearly all organs. In addition, infusion-related reactions and hypersensitivity/anaphylactic 
reactions with a different underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (e.g., presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochure. More specific guidelines for their evaluation 
and treatment are described in detail in the Dosing Modification and Toxicity Management 
Guidelines (see Appendix C). These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities.  
These guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator.
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 
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 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://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI 
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.


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8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.4.1
Safety Reporting Criteria to AstraZeneca
8.4.1.1
Safety Reports sent by OSRO
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last dose 
of durvalumab or until the initiation of alternative anticancer therapy. The investigator and/or 
Sponsor are responsible for informing the Ethics Committee and/or the Regulatory Authority of 
the SAE as per local requirements.
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 
21 CFR 312.32, and will concurrently forward all such reports to AstraZeneca. A copy of the 
MedWatch/AdEERs report must be emailed to AstraZeneca at the time the event is reported to 
the FDA. It is the responsibility of the sponsor to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement timelines and to 
ensure that these reports are also submitted to AstraZeneca at the same time.
* A cover page should accompany the MedWatch/AdEERs form indicating the following:
•
“Notification from an Investigator Sponsored Study”
•
The investigator IND number assigned by the FDA
•
The investigator’s name and address
•
The trial name/title and AstraZeneca ISS reference number (ESR-##-#####)
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator.
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox:  AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA.
8.4.1.2
Safety Reports sent by the Study Team
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly. 
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the randomization code/ code break information or unblind those SAEs which require expedited 
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On a monthly basis, non-expedited SAEs will be provided to Collaborator Patient Safety 
Department via fax at:  (301) 398-4205 and email  to: drugsafety@medimmune.com and 
AEMailboxClinicalTrialTCS@astrazeneca.com.
8.4.2
Safety Reporting Criteria to Sesen Biotherapeutics  
As soon as the investigator becomes aware that an adverse event meets the criteria for being a 
serious adverse event (SAE) the following is required:
•
The investigator will notify Sesen Biotherapeutics within twenty-four (24) hours of 
becoming aware of the SAE by submitting a completed SAE form and any supporting 
documentation to Sesen Biotherapeutics.  
•
The SAE form and supporting documentation should be scanned and emailed to Sesen 
Biotherapeutics at with joycelyn.entwistle@sesenbio.com and 
rachelle.dillon@sesenbio.com.
•
Follow-up information must be submitted in a timely fashion
All suspected unexpected serious adverse reactions (SUSARs), also called serious and 
unexpected suspected adverse reaction (i.e., serious, unexpected and related SAEs), must be 
reported to all appropriate regulatory authorities and IRBs/Ethics Committees as required by 21 
CFR 312.32 utilizing the MedWatch 3500A form or the CIOMS-1.  The final forms for the 
initial and all follow-up reports must be submitted within two (2) business days of submission to 
the FDA or other health authorities.  These reports should be scanned and emailed to  Sesen 
Biotherapeutics at joycelyn.entwistle@sesenbio.com and rachelle.dillon@sesenbio.com.
8.5
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: https://nih.sharepoint.com/:u:/r/sites/NCI-CCR-OCD-
Communications/SitePages/Forms-and-Instructions.aspx?csf=1&web=1&e=uWBXtI 
8.5.1
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 (section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.5.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 
120 days after the last dose of Durvalumab and Vicineum. 
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies  
occurring from the date of the first dose until 120 days after the last dose should, if possible, be 


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followed up and documented. Pregnant partners may be offered the opportunity to participate in 
an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes.
8.6
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.  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.
8.7
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING PLAN
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 
•
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
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Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s). Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
10.1 STATISTICAL HYPOTHESES
Primary endpoints: 
The primary objective of this trial is to determine whether the use of a combination of Vicineum 
and durvalumab in patients with high grade NMIBC previously treated with BCG is safe and 
tolerable as determined by a 3+3 dose de-escalation trial design.  The primary endpoint will be 
the fraction of patients who have adverse events.
Secondary endpoints:
A secondary endpoint will be to determine if the combination of the two agents can be associated 
with an increase in the disease-free survival (DFS) probability in patients with high grade 
NMIBC previously treated with BCG. If accrual is rapid, an amendment may be made to accrue 
additional patients to evaluate DFS as described in section 10.2.
A secondary objective is whether the combination is associated with changes in a set of immune 
parameters obtained from blood and biopsies. 
A secondary objective is whether the pharmacokinetics of Vicineum can be determined from 
urine samples obtained within the first 7 days of Vicineum treatment.
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A secondary objective is to assess PD-L1 expression and PD-1 expressing T cells in paired 
bladder biopsies pre- and post-treatment with durvalumab and Vicineum as a marker of 
response/benefit.  
10.2 SAMPLE SIZE DETERMINATION
The trial will begin with a 3-patient run-in at the proposed doses of Vicineum and durvalumab 
(1500mg; 30 mg) and if 0/3 or 1/3 patients have a DLT, then the next 3 patients will also be 
treated at the full doses of the agents (1500mg durvalumab; 30 mg Vicineum). If 0/6 or 1/6 has a 
DLT, then the remaining 18 patients will be treated at the full doses if the cumulative fraction of 
patients experiencing a DLT is <1/3. 
If 2 or more patients among 3 to 6 have a DLT at 1500mg durvalumab and 30mg Vicineum, then 
3 patients will be enrolled at the lower dose level (1500mg durvalumab and 20mg Vicineum), 
and if 0/3 or 1/3 patients have a DLT, then the next 3 patients will also be treated at the reduced 
doses of the agents. If 1/6 has a DLT, then the remaining patients will be treated at the lower 
dose level of the agents (1500mg durvalumab and 20mg Vicineum) if the cumulative fraction of 
patients experiencing a DLT is <1/3. 
As the secondary endpoint, all the evaluable patients will have determinations of many immune 
parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from 
blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The 
changes in the parameters obtained from biopsies will be obtained from baseline vs. a single 
second biopsy at 6 months. A very large number of parameters may be evaluated, and unless 
more parameters than anticipated are to be evaluated, we will assume that 24 patients will be 
adequate to evaluate changes in these parameters based on the following.  As an illustration, we 
will assume that a total of 25 paired tests will be considered of equal, primary importance. Paired 
results from 24 evaluable patients, including those used in the initial run-in portion who are 
treated at the highest safe dose, will provide 90% power to detect a change from baseline of 1.0 
SD of the change (effect size=1.0) using a two-sided 0.002 significance level paired t-test, to 
allow an overall 0.05 significance level test, applying a very conservative Bonferroni adjustment 
to the set of approximately 25 paired comparisons.  In practice, comparisons of the paired values 
will likely be performed using a Wilcoxon signed rank test instead of a paired t-test, and a 
Hochberg adjustment may be used instead of an overly stringent Bonferroni adjustment. 
If accrual is sufficiently rapid, that is, if the 24 evaluable patients can be accrued within 2.5 
years, then these 24 patients will be included in an expansion cohort, opened by an amendment 
to the study, designed to evaluate DFS, as follows that would allow for the enrollment of an 
additional 23 patients:
It has been estimated from published trials that the 6 month DFS in patients with high grade 
NMIBC previously treated with BCG is approximately 50%, and that it is 35% at 12 months, and 
25% at 18 months. In this expansion cohort, the goal is to determine if use of a combination of 
Vicineum and durvalumab can be potentially associated with a 50% 1-year DFS probability. 
With 47 evaluable patients receiving the proposed therapy, including those in the initial 6 
patients at the intended dose level as well as those in the evaluation of biologic endpoints, 
assuming accrual would take place over approximately 4 years, and that there would be at least 2 
years of additional potential follow-up after the last patient has begun the therapy, there would be 
80% power to determine whether there is a difference between a 35% 1 year DFS and an 


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improved 50% 1-year DFS, with a one sided 0.10 alpha level test, using the method of 
Brookmeyer and Crowley.33 In practice, Kaplan-Meier curves and appropriate confidence 
intervals at selected time points will be provided to help interpret results relative to the expected 
results.  
It is anticipated that one patient per month may enroll onto this trial; thus, allowing for 6 to 12 
separate patients as a run-in if needed, and 24 evaluable patients at the intended dose level, 
approximately 24-30 months would be the approximate accrual duration for the secondary 
endpoint based on evaluating biologic correlates. To allow for a small number of invaluable 
patients, the accrual ceiling will be set at 40. If the expansion to evaluate DFS will be 
undertaken, this will be modified by an amendment.
10.3 POPULATIONS FOR ANALYSIS
Modified intention to treat: all patients who receive at least one dose of the two drugs will be 
included in the statistical analyses performed.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
For the toxicity evaluation, the fraction of patients with toxicity will be determined and reported 
at each of the dose levels explored. The immune parameters will be obtained at baseline, 3 
months, and 6 months and for each parameter, the change between baseline and the later time 
points will be calculated and evaluated for the statistical significance of the change. If the 
disease-free survival (DFS) is evaluated, a Kaplan-Meier curve for DFS will be constructed.
10.4.2 Analysis of the Primary Endpoint
All patients will be evaluated for the grades of toxicity identified, and the number of patients will 
DLTs at each dose level will be reported. The MTD will be identified based on being the dose 
level at which 0 or 1 patient in 6 has a DLT. All toxicities will be tabulated for all 24 or more 
patients to be enrolled onto the trial. 
10.4.3 Analysis of the Secondary Endpoints
Efficacy:  A DFS curve will be created using the Kaplan-Meier method based on all patients 
considered to be evaluable based on having received protocol treatment, provided that adequate 
patients are enrolled in order to address this following an amendment to increase accrual.
The response to treatment will be determined for patients who receive treatment; the response 
rate for those patients who are evaluable for response, along with a 95% two-sided confidence 
interval will be reported.
As another secondary endpoint, all the evaluable patients will have determinations of many 
immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained 
from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The 
changes in the parameters obtained from biopsies will be obtained from baseline vs. a single 
second biopsy at 6 months. As an illustration, we will assume that a total of 25 paired tests will 
be considered of equal, primary importance. Paired results from 24 evaluable patients, including 
those used in the initial run-in portion who are treated at the highest safe dose, will be formed 
and tested for a difference from zero using a two-sided 0.002 significance level paired t-test, to 


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allow an overall 0.05 significance level test, applying a very conservative Bonferroni adjustment 
to the set of approximately 25 paired comparisons.  In practice, comparisons of the paired values 
will likely be performed using a Wilcoxon signed rank test instead of a paired t-test, and a 
Hochberg adjustment may be used instead of an overly stringent Bonferroni adjustment. 
Another secondary objective is to evaluate the pharmacokinetic parameters of Vicineum 
obtained by urine samples. This will be a descriptive analysis and will report sample statistics 
such as mean, standard error, median, minimum, maximum and other descriptive measures only.
Urinary EpCAM will be measured and will be compared between patients who have a clinical 
response to therapy vs. those who do not respond. The results will be presented for both response 
categories using descriptive statistics such as mean, standard error, median, minimum, maximum 
and other descriptive measures. Although it is expected to have low power, a comparison of the 
EpCAM levels may be compared between the two response categories using a Wilcoxon rank 
sum test, with the resulting p-value intended to help describe the differences noted.
PD-L1 and PD-1 levels will be obtained at baseline and after treatment with both agents. The 
change in levels will be determined between the two measurements, and these changes will be 
compared between responders and non-responders, as well as between those who respond or 
have SD (clinical benefit=CR+PR+SD) and those with PD. Although it is expected to have low 
power, in each case the comparisons between the two response categories will be made using a 
Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences 
noted.
10.4.4 Safety Analyses
All patients will be evaluated for the grades of toxicity identified, and the number of patients will 
DLTs at each dose level will be reported. The MTD will be identified based on being the dose 
level at which 0 or 1 patient in 6 has a DLT. All toxicities will be tabulated. 
10.4.5 Baseline Descriptive Statistics
Demographic and clinical characteristics of all patients will be reported.
10.4.6 Planned Interim Analyses
None will be performed.
10.4.7 Subgroup Analyses
None will be performed.
10.4.8 Tabulation of Individual Participant Data
None will be provided.
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
This Protocol will be carried out under a collaboration between NCI, Sesen Biotherapeutics Inc. 
and AstraZeneca AB. Sesen Biotherapeutics will provide Vicineum (VB4-845) under NCI 
CRADA #3149, and AstraZeneca will provide Durvalumab (MEDI 4736) under NCI CRADA 
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12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Subjects from all racial/ethnic groups and both sexes are eligible for this study if they meet the 
eligibility criteria.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible for participation in this study based on the 
fact that patients under 18 are unlikely to have this disease and there are unknown toxicities in 
pediatric patients.
12.3 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 (section 12.4), 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 to assess ongoing capacity of the subject and to identify an LAR.
Please see section 12.5.1 for the consent procedure. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Patients may benefit from the study as treatment may delay or avoid having the bladder removed. 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  Patients will be examined and evaluated prior to enrollment. All evaluations to monitor 
the treatment of patients will be recorded in the patient chart.  If patients suffer any physical 
injury as a result of the participation in this study, immediate medical treatment is available at 
the Clinical Center, National Cancer Institute, Bethesda, Maryland. 
Although no compensation is available, any injury will be evaluated and treated in keeping with 
the benefits or care to which patients are entitled under applicable regulations. In all publications 
and presentations resulting from this trial, patients’ anonymity will be protected to the maximum 
extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and 
Drug Administration (FDA) or other regulatory authorities may have access to research files in 
order to verify that patients’ rights have been safeguarded. In addition, patient names will be 
given to the Central Registration to register and verify patients’ eligibility.
12.4.1 Study Agents Risks
Potential adverse reactions attributable to the administration of the study agents utilized in this 
trial are discussed in sections 14.1.2 and 14.2.2. Additional information is located in the 
investigator brochures.


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12.4.2 Research Blood Sampling Risks
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
12.4.3 Risks from Bladder Procedures
Risks associated with cystoscopy, TURBT, biopsies and catheterization include:  burning when 
passing urine, blood-tinged urine, bladder infection or the need to urinate frequently following 
the procedures.  The insertion of a catheter into the bladder through the urethra may cause 
discomfort. There is also a small risk that these procedures, particularly cystoscopy, TURBT and 
biopsies, could damage the lining of the bladder or cause a perforation of the bladder.  This could 
lead to urine or drugs leaking out of the bladder causing severe side effects.  
12.4.4 Non-Physical Risks of Genetic Research
•
Risk of receiving unwanted information: Anxiety and stress may arise as a result of the 
anticipation of unwanted information regarding disease.   Subjects will be clearly informed 
that the data related to genetic analysis is coded, investigational and will not be shared with 
family members or health care providers.  However, as specified above in Section 5.4.3, 
subjects who have indicated a desire to be informed of these data will be given an 
opportunity.  
•
Risk related to possibility that information may be released: This includes the risk that data 
related to genotype or risk for disease tendency or trait can be released to members of the 
public, insurers, employers, or law enforcement agencies.  
•
Risk to family or relatives: Family members or relatives may or may not want to be aware of 
familial tendencies or genetic risks of disease which may cause anxiety about possible future 
health problems.    
12.4.5 Radiation Risks
The risk of radiation exposure is expected from up to 1 CT scan a year.  The total estimated 
effective dose for one year is approximately 1.4 rem.
12.4.6 CT Contrast Risks
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath 
and swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT 
can cause kidney problems for certain patients, such as those with impaired kidney function.
12.4.7 Electrocardiogram Risks
Other than possibly experiencing some minor skin irritation from the electrodes, there are no 
anticipated risks related to complete the electrocardiogram and/or the echocardiogram.
12.5 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document 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 


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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 used in compliance with 
policy, including HRPP Policy 303) 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.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or on the electronic document.  
Signatures on electronic documents are described below.  Note: FDA only regulates electronic 
signatures (i.e., an electronic timestamp is generated at the time of signature) in FDA regulated 
research.  
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found https://nih.sharepoint.com/sites/NCI-CCR-OCD-
Communications/SitePages/OEC-Administrative---Clinical-Research-(ADCR).aspx?Mode=Edit.
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in section 12.5. 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 


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investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the NIH has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.


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13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site and by NCI CCR research staff will be secured and password protected. 
At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION  
14.1 DURVALUMAB (IND #: 136199)
14.1.1 Source 
Durvalumab will be supplied by the Investigational Products supply section of 
AstraZeneca/MedImmune under NCI CRADA #3155.  There are no manufacturing differences 
between the clinical supply that will be used in this study and the supply of marketed agent.


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14.1.2 Toxicity
For additional information, refer to the investigator brochure.
Table 1. Frequency of ADRs for Durvalumab Monotherapy From Pooled Data Across Multiple 
Tumour Types (N=3006)
SOC
PT/medical concept
MedDRA (v24.0)
CIOMS frequency 
indicator a/
overall frequency all 
CTC grades 
All 
CTCAE 
Grades
n (%)
Grade 3 
or 4
n (%)
Cough/productive cough b
Very common 
646 (21.5)
11 (0.4)
Pneumonitis  b,c
Common 
114 (3.8)
26 (0.9)
Dysphonia
Common
93 (3.1)
2 (<0.1)
Respiratory, 
thoracic, and 
mediastinal 
disorders
ILD
Uncommon
18 (0.6)
4 (0.1)
ALT increased/AST increased 
b, c
Common 
244 (8.1)
69 (2.3)
Hepatobiliary 
disorders
Hepatitis b, c
Uncommon
25 (0.8)
12 (0.4)
Diarrhea
Very common 
491 (16.3)
19 (0.6)
Abdominal pain b
Very common
383 (12.7)
53 (1.8)
Colitis b
Uncommon 
28 (0.9)
10 (0.3)
Gastrointestinal 
disorders
Pancreatitis b
Uncommon
6 (0.2)
5 (0.2)
Hypothyroidism b
Very common 
345 (11.5)
5 (0.2)
Hyperthyroidism b
Common 
164 (5.5)
0
Thyroiditis b
Uncommon
23 (0.8)
2 (<0.1)
Adrenal insufficiency
Uncommon
18 (0.6)
3 (<0.1)
Type 1 diabetes mellitus 
Rare
1 (<0.1)
1 (<0.1)
Hypophysitis/Hypopituitarism 
b
Rare
2 (<0.1)
2 (<0.1)
Endocrine 
disorders
Diabetes insipidus
Rare
1 (<0.1)
1 (<0.1)
Blood creatinine increased
Common
105 (3.5)
3 (<0.1)
Dysuria 
Common
39 (1.3)
0
Renal and 
urinary disorders
Nephritis b
Uncommon 
9 (0.3)
2 (<0.1)
Rash b
Very common
480 (16.0)
18 (0.6)
Pruritus 
Very common
325 (10.8)
1 (<0.1)
Night sweats 
Common
47 (1.6)
1 (<0.1)
Dermatitis b
Uncommon
22 (0.7)
2 (<0.1)
Skin and 
subcutaneous 
tissue disorders
Pemphigoid b
Rare
3 (<0.1)
0
Cardiac disorders
Myocarditis
Rare
1 (<0.1)
1 (<0.1)
Pyrexia
Very common
414 (13.8)
10 (0.3)
General 
disorders and 
administration 
site conditions
edema peripheral b
 Common
291 (9.7)
9 (0.3)


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SOC
PT/medical concept
MedDRA (v24.0)
CIOMS frequency 
indicator a/
overall frequency all 
CTC grades 
All 
CTCAE 
Grades
n (%)
Grade 3 
or 4
n (%)
Upper respiratory tract 
infections b
Very common 
407 (13.5)
6 (0.2)
Pneumonia b,c
Common
269 (8.9)
106 (3.5)
Oral candidiasis 
Common
64 (2.1)
0
Dental and oral soft tissue 
infections b
Common
50 (1.7)
1 (<0.1)
Infections and 
infestations
Influenza
Common
47 (1.6)
2 (<0.1)
Myalgia 
Common
178 (5.9)
2 (<0.1)
Myositis b
Uncommon
6 (0.2)
1 (<0.1)
Musculoskeletal 
and connective 
tissue disorders
Polymyositis d
Not determined
-
-
Myasthenia gravis b, e
Not determined
-
-
Nervous system 
disorders
Encephalitis b, f
Not determined
-
-
Injury, 
poisoning, and 
procedural 
complications
Infusion related reaction b
Common
49 (1.6)
5 (0.2)
Blood and 
lymphatic system 
disorders
Immune thrombocytopenia c
Rare
2 (<0.1)
1 (<0.1)
a
The corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as: 
(1) very common (≥1/10); (2) common (≥1/100 to <1/10); (3) uncommon (≥1/1000 to <1/100); (4) rare 
(≥1/10000 to <1/1000); (5) very rare (<1/10000); not determined (cannot be estimated from available data).
b
Denotes a medical concept. See Table 31 of investigator brochure for individual PTs.
c
Fatal events have been reported. 
d
Polymyositis (fatal) was observed in a patient treated with durvalumab from an ongoing AstraZeneca-
sponsored clinical study outside of the pooled dataset.
e
Reported frequency from AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare, with no 
events at Grade >2.
f
Reported frequency from ongoing AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare 
and includes 2 events of encephalitis, one fatal (PT: Immune-mediated encephalitis) and one Grade 2 (PT: 
Autoimmune encephalitis).
ADR = adverse drug reaction; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CIOMS = 
Council for International Organisations of Medical Sciences; CTCAE = Common Terminology Criteria for Adverse 
Events; ILD = interstitial lung disease; MedDRA = Medical Dictionary for Regulatory Activities; n = number of 
patients; PT = preferred term; SOC = system organ class.


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Table 2. Serious Adverse Reactions for Durvalumab Monotherapy Considered Expected 
for Safety Reporting Purposes
Number (%) of subjects 
exposed (N=5208)
MedDRA (v25.0) 
SOC
PT
Suspected 
SARs n 
(%) a
Occurrence of 
life-threatening 
suspected SARs
n (%) b
Occurrence 
of fatal 
suspected 
SARs
n (%) b
Pneumonitis
43 (0.8)
0
0
Respiratory, 
thoracic, and 
mediastinal 
disorders
Interstitial lung disease
10 (0.2)
0
0
Injury, poisoning, 
and procedural 
complications
Infusion related reaction
7 (0.1)
0
0
Pneumonia
16 (0.3)
0
0
Infections and 
infestations
Pneumocystis jirovecii 
pneumonia
2 (<0.1)
0
0
Colitis
12 (0.2)
0
0
Diarrhoea
13 (0.2)
0
0
Abdominal pain
3 (<0.1)
0
0
Enterocolitis
3 (<0.1)
0
0
Pancreatitis
2 (<0.1)
0
0
Gastrointestinal 
disorders
Proctitis
2 (<0.1)
0
0
Adrenal insufficiency
6 (0.1)
0
0
Hyperthyroidism
3 (<0.1)
0
0
Hypopituitarism
3 (<0.1)
0
0
Endocrine disorders
Hypothyroidism
3 (<0.1)
0
0
Hepatitis
5 (<0.1)
0
0
Hepatobiliary 
disorders
Autoimmune hepatitis
3 (<0.1)
0
0
Nephritis
3 (<0.1)
0
0
Renal and urinary 
disorders
Blood creatinine 
increased
2 (<0.1)
0
0
AST increased
6 (0.1)
0
0
ALT increased
5 (<0.1)
0
0
Hepatic enzyme 
increased
2 (<0.1)
0
0
Investigations
Transaminases 
increased
2 (<0.1)
0
0


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Number (%) of subjects 
exposed (N=5208)
MedDRA (v25.0) 
SOC
PT
Suspected 
SARs n 
(%) a
Occurrence of 
life-threatening 
suspected SARs
n (%) b
Occurrence 
of fatal 
suspected 
SARs
n (%) b
General disorders 
and administration 
site conditions
Pyrexia
5 (<0.1)
0
0
Musculoskeletal and 
connective tissue 
disorders
Myositis
4 (<0.1)
0
0
Skin and 
subcutaneous tissue 
disorders
Rash
4 (<0.1)
0
0
Blood and lymphatic 
system disorders
Immune 
thrombocytopenia
2 (<0.1)
0
0
Metabolism and 
nutrition disorders
Type 1 diabetes 
mellitus
2 (<0.1)
0
0
Nervous system 
disorders
Myasthenia 
gravis
2 (<0.1)
0
0
a   n = number of patients who have experienced the SAR.
b  All fatal and all life-threatening events for durvalumab monotherapy are considered unexpected for 
reporting purposes and are excluded from this table. Pooled dataset from studies CD-ON-MEDI4736-1108, 
ATLANTIC, MYSTIC, EAGLE, ARCTIC, CONDOR, HAWK, PACIFIC, D4190C00002, BISCAY, 
STRONG, PACIFIC 6, DANUBE, HIMALAYA, KESTREL, NeoCOAST, D4190C00007, D4190C00021, 
D4190C00022, and D4198C00001.
Only patients exposed to 10 mg/kg Q2W or 20 mg/kg Q4W durvalumab, or equivalent fixed dosing of durvalumab 
750 mg Q2W or 1500 mg Q4W schedule, are included.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; DCO = data cut-off; MedDRA = 
Medical Dictionary for Regulatory Activities; PT = preferred term; Q2W = every 2 weeks; Q4W = 
every 4 weeks; SAR = serious adverse reaction; SOC = system organ class.
14.1.2.1 Other Potential Risks for Durvalumab Monotherapy and the Durvalumab Plus 
Tremelimumab Combination
Hypersensitivity Reactions and Anaphylaxis
Hypersensitivity reactions and anaphylaxis are considered potential risks for durvalumab 
monotherapy and the durvalumab + tremelimumab combination. In the durvalumab monotherapy 
pooled dataset (N=3006), hypersensitivity/anaphylactic reactions (grouped term including 


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reported PTs of hypersensitivity, drug hypersensitivity, drug eruption, anaphylactic shock, and 
anaphylactic reaction), were uncommonly reported in 28 patients (0.9%); 5 patients had Grade 3 
or 4 events. Of the 28 patients, 16 patients had events of drug hypersensitivity (1 patient had a 
Grade 4 event), 5 patients had events of drug eruption (2 patients had Grade 3 events), 4 patients 
had events of hypersensitivity (Grade 1 or 2 events), 3 patients had events of anaphylactic 
reaction (1 patient had a Grade 4 event), and 1 patient had a Grade 2 event of anaphylactic shock.
Subcutaneous Injection Site Reaction
Subcutaneous injection site reactions can occur via immune or non-immune mechanisms.
A potential immunogenic mechanism could be due to antigen presentation and processing by 
lymph node and migratory cutaneous dendritic cells in the subcutaneous space. Non-immune 
mechanisms by which injection site reactions may arise can be related to biophysical 
characteristics of the drug and preservative/stabilizing agents. Patients should be closely 
monitored for signs and symptoms of subcutaneous injection site reactions including, but not 
limited to pain, blistering, induration, burning, and erythema at the site of injection.
Immunogenicity
As with the administration of any therapeutic protein, there is a potential for an immune 
response. The incidence of durvalumab ADA-positive patients in clinical studies is low. Overall, 
of the 4045 patients who were treated with durvalumab monotherapy 10 mg/kg Q2W, 20 mg/kg 
Q4W, or 1500 mg Q4W, 3069 patients were evaluable for the presence of ADAs, of which 6.2% 
(191/3069) patients were ADA-positive at any visit and 2.7% (84/3069) patients were treatment-
emergent ADA-positive. Neutralising antibodies against durvalumab were detected in 0.5% 
(16/3069) patients. The presence of ADAs did not have a clinically relevant effect on PK. The 
presence of durvalumab ADA did not have an influence on durvalumab exposure metric, and 
there was no apparent effect on the safety of durvalumab.
Other Rare or Less Frequent Immune-mediated Adverse Events
Events with an inflammatory or immune mediated mechanism could occur in nearly all organs. 
Potential risks with an immune-mediated aetiology that are rare or less frequent include, but are 
not limited to, Guillain-Barre Syndrome, pericarditis, sarcoidosis, uveitis, cholangitis sclerosing, 
immune-mediated cystitis and other events involving the eye (eg, keratitis and optic neuritis), 
skin (eg, scleroderma and vitiligo), haematological (eg, hemolytic anaemia and immune-
mediated neutropenia), rheumatological events (polymyalgia rheumatica and autoimmune 
arthritis), vasculitis, non-infectious meningitis and psoriasis.
14.1.3 Formulation, packaging and storage  
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 
275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The 
nominal fill volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Durvalumab must be used within the individually assigned 
expiration date on the label.


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14.1.4 Study Drug Preparation
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 
•
24 hours at 2°C to 8°C (36°F to 46°F)
•
4 hours at room temperature
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. 
14.1.5 Study Drug Administration
See section 3.2.1
14.1.6 Incompatibilities
There are no incompatibilities for durvalumab.  
14.1.7 Accountability and dispensation
The investigator is responsible for keeping accurate records of the clinical supplies received, the 
amount dispensed to and returned by the subjects and the amount remaining at the conclusion of 
the trial.
14.1.8 Disposition of unused investigational study drug
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.
14.2 VICINEUM (IND #: 136199)
14.2.1 Source 
Vicineum (investigational supply) will be supplied by Sesen Biotherapeutics under NCI CRADA 
#3149. Commercial supply will be provided for the study after the 31st Aug 2021. 
14.2.2 Toxicity 
14.2.2.1 Phase 1/2 clinical trial (Study No. VB4-845-02-I)
The most frequently reported treatment-related AEs were those associated with renal and urinary 
disorders (23.4% of subjects). Within this class, dysuria (14.1% of subjects) and hematuria 
(10.9% of subjects) were reported most frequently. All other AEs assessed as possibly, probably, 
or definitely related to Vicineum occurred in less than 10% of the subject population. Of the 
related systemic AEs, fatigue was reported as an AE by 7.8% of subjects and myalgia was 
reported by 4.7% of subjects. 


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14.2.2.2 Phase 2 trial (Study No. VB4-845-02-IIA)
The most commonly reported treatment-emergent adverse events regardless of causality were 
associated with renal and urinary disorders, including dysuria (60.9% of subjects), hematuria 
(26.1% of subjects), pollakiuria (23.9% of subjects), micturition urgency (21.7% of subjects), 
nocturia (15.2% of subjects), incontinence (urge incontinence and urinary incontinence; 13.0% 
of subjects), urinary tract infections (13.0% of subjects), and bladder pain (10.9% of subjects). 
Other treatment related AEs that occurred in 10% or more of subjects were fatigue (21.7%), flu-
like symptoms (10.9%), fever (10.9%), joint pain (13%), and dizziness (10.9%).
14.2.2.3 Phase 3 trial (Study No. VB4-845-02-IIIA)
Table 3. Treatment-Emergent Adverse Events Considered Related to Vicineum occurring in 
≥5% of subjects, VB4-845-02-IIIA
Adverse Event
Grade 1 – 2
Grade 3 – 4
Grade 5
Total
Any Event Related to Vicineum
61 (46%)
4 (3%)
1 (1%)
66 (50%)
Renal and Urinary Disorders
45 (34%)
1 (1%)
1 (1%)
47 (35%)
Dysuria
18 (14%)
0
0
18 (14%)
Haematuria
17 (13%)
0
0
17 (13%)
Pollakiuria
15 (11%)
0
0
15 (11%)
Micturition Urgency
15 (11%)
0
0
15 (11%)
General Disorders and 
Administration Site Conditions
12 (9%)
0
0
12 (9%)
Fatigue
10 (8%)
0
0
10 (8%)
Gastrointestinal Disorders
9 (7%)
0
0
9 (7%)
Infections and Infestations
15 (11%)
2 (2%)
0
17 (13%)
Urinary Tract Infection
14 (11%)
2 (2%)
0
16 (12%)
Investigations
7 (5%)
3 (2%)
0
10 (8%)
Note: Treatment-emergent adverse events were assessed as possibly, probably, or definitely related to study treatment 
per Investigator
Data Source: VB4-845-02-IIIA Interim CSR Table 28
Table 4. Serious Adverse Events, VB4-845-02-IIIA
Age/ 
Sex
Adverse Event
(MedDRA Preferred Term)
Relationship 
to Study 
Druga
Severity
Day of 
Onsetb
Duration 
(days)
Outcome
70 / M
Pyelonephritis
Not related
Gr. 3
Day 17
4
Recovered/Resolved
76 / M
Asthma
Not related
Gr. 3
Day 264
9
Recovered/Resolved
Hepatitis cholestatic
Related
Gr. 4
Day 46
Ongoing
Not recovered/Not 
resolved
91 / M
Renal failure
Related
Gr. 5
Day 46
24
Fatal


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81 / M
Small intestinal obstruction
Not related
Gr. 3
Day 212
5
Recovered/Resolved
59 / M
UTI
Not related
Gr. 3
Day 72
3
Recovered/Resolved
Acute kidney injury
Related
Gr. 3
Day 20
3
Recovered/Resolved
74 / M
Acute kidney injury
Related
Gr. 3
Day 29
6
Recovered/Resolved
Esophageal obstruction
Not related
Gr. 3
Day 140
3
Recovered/Resolved
70 / M
Fall
Not related
Gr. 3
Day 407
3
Recovered/Resolved
Hematuria
Not related
Gr. 2
Pre-drug
4
Recovered/Resolved
Urinary retention
Not related
Gr. 2
Pre-drug
10
Recovered/Resolved
UTI
Not related
Gr. 2
Pre-drug
25
Recovered/Resolved
Pericardial effusion
Not related
Gr. 3
Day 61
4
Recovered/Resolved
UTI
Not related
Gr. 3
Day 61
4
Recovered/Resolved
82 / M
Small intestinal obstruction
Not related
Gr. 1
Day 75
3
Recovered/Resolved
86 / M
Hematuria
Not related
Gr. 1
Day 475
3
Recovered/Resolved
73 / M
Lung neoplasm surgery
Not related
Gr. 4
Day 287
15
Recovered/Resolved with 
sequelae
70 / M
Pyrexia
Related
Gr. 2
Day 32
2
Recovered/Resolved
Acute kidney injury
Not related
Gr. 3
Day 121
3
Recovered/Resolved
75 / F
Small intestinal obstruction
Not related
Gr. 3
Day 380
3
Recovered/Resolved
83 / M
Rib fracture
Not related
Gr. 3
Day 85
Ongoing
Not recovered/Not 
resolved
Hematuria
Not related
Gr. 3
Pre-drug
2
Recovered/Resolved
Acute kidney injury
Not related
Gr. 2
Day 32
3
Recovered/Resolved
77 / M
Cystitis
Not related
Gr. 3
Day 32
4
Recovered/Resolved
75 / F
Urinary retention
Not related
Gr. 2
Day 102
5
Recovered/Resolved
89 / M
Hematuria
Not related
Gr. 3
Day 214
2
Recovered/Resolved
76 / M
Tachycardia
Not related
Gr. 3
Day 17
4
Recovered/Resolved
82 / M
Aortic valve disease
Not related
Gr. 4
Day 694
2
Recovered/Resolved with 
sequelae
77 / F
Pelvic pain
Not related
Gr. 3
Day 36
3
Recovered/Resolved
F = female; M = male; MedDRA = Medical Dictionary for Regulatory Activities; UTI = urinary tract infection
a Investigator’s assessment
b Initial dose of Vicineum = Day 1
Data source: VB4-845-02-IIIA Interim CSR Table 26
 
14.2.3 Formulation, packaging and storage 
Vicineum™ (oportuzumab monatox, VB4-845) is a clear, colorless solution for intravesical 
administration. It is provided as a frozen product in a glass vial, and then thawed at room 
temperature prior to preparation for administration. Cloudiness, a change in color and/or the 
presence of particulate matter may indicate the product has deteriorated. If this occurs, Sesen 


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Biotherapeutics should be contacted immediately and the product must not be used.  Vicineum is 
packaged in a 10 mL glass borosilicate vial containing 7 mL of study drug at a concentration of 5 
mg/mL. Each vial is sealed with grey butyl stoppers and covered with an aluminum cap center 
tear-off seal.
Vicineum will be mixed with phosphate buffered saline prior to intravesical administration.  
Refer to the Vicineum Dose Preparation and Administration Manual for details.
14.2.4 Product preparation
Refer to the Vicineum Dose Preparation and Administration Manual for details.
14.2.5 Administration procedures
See section 3.2.2 and Vicineum Dose Preparation and Administration Manual.
14.2.6 Incompatibilities
Vicineum is administer intravesically via a catheter.  Only material indicated as qualified in the 
Vicineum Dose Preparation and Administration Manual in Section 6 should be used.
14.2.7 Accountability and dispensation 
The Investigator agrees that the study drug will be administered only to subjects who have 
provided written informed consent, have met all entry criteria, and are enrolled in the study. The 
Investigator must not loan or dispense clinical study material to another Investigator or site.
Drug accountability records will be maintained by the Investigator or authorized site staff for all 
clinical trial supplies (includes Vicineum and phosphate buffered saline). Sesen Biotherapeutics . 
or designee will provide the Investigator with drug accountability logs to document receipt and 
dispensing. Any discrepancy and/or deficiency must be recorded, reported to Sesen 
Biotherapeutics or designee, and a plan for resolution documented. If at any point in the conduct 
of the study a vial is deemed unacceptable for use, the site will document the damage on the drug 
accountability log and immediately notify Sesen Biotherapeutics or designee. Sesen 
Biotherapeutics  or designee will monitor the completeness and accuracy of all accountability 
records throughout the study and verify product accountability against site documentation. 
14.2.8 Disposition of unused investigational study drug
Any expired Vicineum, or Vicineum vial deemed unacceptable for use or any Vicineum supply 
remaining at the end of the study should be destroyed at each clinical site in accordance with the 
site’s drug destruction policy.   


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16 APPENDICES
16.1
 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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16.2 APPENDIX B: DURVALUMAB DOSE CALCULATIONS
Durvalumab Dosing
The durvalumab dosing should be done depending on subject weight (if subject is < 30kg)):
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 50 (mg/mL) 
where 50 mg/mL is durvalumab nominal concentration 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle only needed for greater than 10% change in weight.
5. The theoretical number of vials required for dose preparation is the next greatest whole 
number of vials from the following formula:
Number of vials = Dose (mL) / 10 (mL/vial)
Example: 
1. Cohort dose: 10 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL
5. The theoretical number of vials required for dose preparation: 
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials


16.3 APPENDIX C: DURVALUMAB DOSING MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES
These guidelines are standardized for durvalumab trials.  However, these guidelines are superseded and should be superceded by any 
protocol-specific DLTs as as specified in section 3.1.1.  This is specifically the case for toxicities such as hyperbilirubinemia, 
encephalopathy, neurotoxicity, peripheral neuromotor syndromes, and transaminase elevation as well as others. 
General Considerations Regarding Immune-Mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs). 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators are 
advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European 
Society of Medical Oncology (ESMO)) in the management of these events.  Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general 
guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section.
Early identification and management of imAEs is essential to ensure safe use of the study drug.  Monitor patients closely for symptoms and signs that may be clinical 
manifestations of underlying imAEs. Patients with suspected imAEs  should be thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, 
concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated.  Institute medical 
management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen  for severe (Grade 3) imAEs. Permanently discontinue 
study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to 
reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid 
should be tapered over ≥ 28 days.  More potent immunosuppressive agents should be considered for events not responding to systemic steroids. Alternative 
immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant guidelines. With long-
term steroid and other immunosuppressive use, consider the need for glucose monitoring.
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable study 
protocol.
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy
•
Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation
•
Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy
•
Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .


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General Considerations Regarding Immune-Mediated Reactions
Relevant Society Guidelines for Management of imAEs
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versions of these 
guidelines at the time of updating TMGs. Please refer to the most up to date version of these guidelines.
1.
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother 
Cancer 2021;9:e002435
2.
Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical 
Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-1768.
3.
Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guidelines for diagnosis, 
treatment, and follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142.
4.
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341.
5.
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version1.2022. Published February 
28, 2022.
Pediatric Considerations Regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTCAE grade/severity is the same for pediatric patients as it is for adult patients, 
as well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of initiating corticosteroids. 
−
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
−
The recommendations for steroid dosing (i.e., mg/kg/day) provided for adult 
patients should also be used for pediatric patients.
−
The recommendations for intravenous immunoglobulin (IVIG) and 
plasmapheresis use provided for adult patients may be considered for 
pediatric patients.
−
The infliximab 5 mg/kg IV one time dose recommended for adults is the 
same as recommended for pediatric patients ≥ 6 years old. For subsequent 
dosing and dosing in children < 6 years old, consult a pediatric specialist.
−
For pediatric dosing of mycophenolate mofetil, consult a pediatric specialist.
−
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology with similar 
clinical presentation (e.g. infection, 
progressive disease).
−
Monitor patients for signs (e.g. tachypnoea) 
and symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath or 
cough). Evaluate patients with imaging and 
pulmonary function tests, including other 
diagnostic procedures as described below. 
−
Suspected pneumonitis should be confirmed 
with radiographic imaging and other 
infectious and disease-related etiologies 
excluded, and managed as described below.
−
Initial work-up may include clinical 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up (including clinically 
relevant culture specimens to rule out 
infection), and high- resolution computed 
tomography (CT) scan.
−
Consider Pulmonary and Infectious Diseases 
consults.
Grade 1
No dose modifications required. However, consider holding 
study drug/study regimen dose as clinically appropriate and 
during diagnostic work-up for other etiologies.
For Grade 1 
−
Monitor and closely follow up in 2 to 4 days 
for clinical symptoms, pulse oximetry 
(resting and exertion), and laboratory work-
up, and then as clinically indicated.
Pneumonitis/Interstitial 
Lung Disease (ILD)
Grade 2
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1.
•
If toxicity improves to Grade ≤1, then the decision to 
reinitiate study drug/study regimen will be based upon 
treating physician’s clinical judgment and after 
For Grade 2
−
Monitor symptoms daily and consider 
hospitalization as clinically indicated.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
completion of steroid taper (<10 mg prednisone or 
equivalent).
−
Consider Pulmonary and Infectious Diseases 
Consults.
−
Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent).
−
Consider HRCT or chest CT with contrast, 
Repeat imaging as clinically indicated.
−
If no improvement within 2 to 3 days, 
additional workup should be considered and 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started.
−
If no improvement within 2 to 3 days despite 
IV methylprednisolone at 2 to 4 mg/kg/day, 
promptly start immunosuppressive therapy. 
such as tumor necrosis factor (TNF) 
inhibitors (e.g., infliximab at 5 mg/kg IV 
once, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
−
Consider discussing with Clinical Study 
Lead.
Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Hospitalize the patient
−
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent.
−
Obtain Pulmonary and Infectious Diseases 
Consults; consider discussing with Clinical 
Study Lead, as needed.
−
Consider starting anti-infective therapy if 
infection is still a consideration on the basis 


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
of other diagnostic testing despite negative 
culture results
−
Supportive care (e.g., oxygen).
−
If no improvement within 2 days, additional 
workup should be considered and prompt 
treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab.
Diarrhea/Colitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections), including testing for Clostridium 
difficile toxin, etc.
−
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such 
as increased frequency over baseline or 
blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, 
and ileus).
−
Consider further evaluation with imaging 
study with contrast.
−
Consult a gastrointestinal (GI) specialist for 
consideration of further workup
−
WHEN SYMPTOMS OR EVALUATION 
INDICATE AN INTESTINAL 
PERFORATION IS SUSPECTED, 
CONSULT A SURGEON 


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
EXPERIENCED IN ABDOMINAL 
SURGERY IMMEDIATELY WITHOUT 
ANY DELAY. 
−
PERMANENTLY DISCONTINUE 
STUDY DRUG FOR ANY GRADE OF 
INTESTINAL PERFORATION. 
−
Steroids should be considered in the absence 
of clear alternative etiology, even for low-
grade events, in order to prevent potential 
progression to higher grade events, including 
intestinal perforation. 
−
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis.
Grade 1
No dose modifications.
For Grade 1
−
Monitor closely for worsening symptoms.
−
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), loperamide, and other 
supportive care measures. 
−
If symptoms persist, consider checking 
lactoferrin; if positive, treat as Grade 2 
below. If negative and no infection, continue 
Grade 1 management.
Grade 2
Hold study drug/study regimen until resolution to Grade ≤1
•
If toxicity improves to Grade ≤1, then study drug/study 
regimen can be resumed after completion of steroid taper 
(<10 mg prednisone, or equivalent).
For Grade 2
−
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide.
−
Consider further evaluation with imaging 
study with contrast.


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
−
Consider consult of a gastrointestinal (GI) 
specialist for consideration of further 
workup.
−
Promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
−
If no improvement within 3 days despite 
therapy with 1 to 2 mg/kg IV prednisone 
equivalent, reconsult GI specialist and, if 
indicated, promptly start additional 
immunosuppressant agent such as infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of 
the treating provider or relevant practice 
guidelines. Caution: it is important to rule 
out bowel perforation and refer to infliximab 
label for general guidance before using 
infliximab.
−
If perforation is suspected, consult a 
surgeon experienced in abdominal 
surgery immediately without any delay.
−
Consider, as necessary, discussing with 
Clinical Study Lead if no resolution to Grade 
≤1 in 3 to 4 days.
Grade 3 or 4
Grade 3
•
For patients treated with durvalumab monotherapy, 
hold study drug/study regimen until resolution to 
Grade ≤1; study drug/study regimen can be resumed 
after completion of steroid taper (<10 mg prednisone 
per day, or equivalent).  
•
For patients treated with durvalumab in combination 
with other products (not tremelimumab), decision to 
be made at the discretion of the study investigator, in 
discussion with AstraZeneca Clinical Study Lead.
•
For patients treated with durvalumab in 
combination with tremelimumab or 
For Grade 3 or 4
−
Urgent GI consult and imaging and/or 
colonoscopy as appropriate.
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Monitor stool frequency and volume and 
maintain hydration.
−
If still no improvement within 2 days, 
continue steroids and promptly add further 
immunosuppressants. (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 weeks 


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
tremelimumab monotherapy, permanently 
discontinue both durvalumab and tremelimumab 
for 1) Grade 3 diarrhea colitis or 2) Any grade of 
intestinal perforation.  
Grade 4 
Permanently discontinue study drug/study regimen.
after initial dose at the discretion of the 
treating provider or relevant practice 
guidelines). Caution: Ensure GI consult to 
rule out bowel perforation and refer to 
infliximab label for general guidance before 
using infliximab. 
−
If perforation is suspected, consult a 
surgeon experienced in abdominal 
surgery immediately without any delay.
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant 
medications).
−
Monitor and evaluate transaminases 
(aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline 
phosphatase [ALP], and total bilirubin.
ALT or AST ≤ 3 x 
ULN or total 
bilirubin ≤ 1.5 x 
ULN
•
No dose modifications.
•
If it worsens, then consider holding therapy.
−
Continue transaminase and total bilirubin 
monitoring per protocol.
Hepatitis 
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis.
ALT or AST > 3 ≤ 5 
x ULN or total 
bilirubin > 1.5 ≤ 3 x 
ULN 
•
Hold study drug/study regimen dose until  ALT or AST ≤ 
3 x ULN or total bilirubin ≤ 1.5 x ULN. Resume study 
drug/study regimen after completion of steroid taper (<10 
mg prednisone or equivalent).
•
Permanently discontinue study drug/study regimen for any 
case meeting Hy’s law laboratory criteria (AST or ALT 
>3 × ULN AND bilirubin >2 × ULN without initial 
−
Regular and frequent checking of 
transaminases and total bilirubin (e.g., every 
1 to 2 days) until LFT elevations improve or 
resolve.
−
If no resolution to  ALT or AST ≤ 3 x ULN 
or total bilirubin ≤ 1.5 x ULN  in 1 to 2 days, 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in 
hepatocellular 
carcinoma (HCC) 
patients (or 
secondary tumour 
involvement of the 
liver with abnormal 
baseline values 
[BLV])


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Event 
Dose Modifications
Toxicity Management
findings of cholestasis (i.e., elevated ALP) and in the 
absence of any alternative cause.
consider discussing with Clinical Study 
Lead, as needed.
−
If event is persistent (>2 to 3 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
ALT or AST > 5-≤ 
10 x ULN
•
Hold study drug/study regimen . Resume study drug/study 
regimen if elevations downgrade to ALT or AST ≤ 3 x 
ULN or total bilirubin ≤ 1.5 x ULN after completion of 
steroid taper (<10 mg prednisone, or equivalent). 
•
If in combination with tremelimumab, do not restart 
tremelimumab.
−
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent.
−
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day methylprednisolone 
IV or equivalent, promptly start treatment 
with an additional immunosuppressant.(e.g., 
mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with 
hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead 
if mycophenolate is not available. Infliximab 
should NOT be used.
Concurrent ALT or
AST > 3 x ULN and
total bilirubin
> 2 x ULN d
ALT or AST
> 10 x ULN OR total
bilirubin > 3 x
ULN
Permanently discontinue study drug/study regimen.
−
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day 
or equivalent.
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with an 
additional immunosuppressant.(e.g.,  
mycophenolate  mofetil 0.5 – 1 g every 
12 hours then taper in consultation with 
hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study 
Lead if mycophenolate is not available. 
Infliximab should NOT be used.


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
−
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate.
Any Elevations of 
AST, ALT, or T. Bili 
as Described Below
General Guidance
For Any Elevations Described
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis 
[e.g., portal vein thrombosis]).
−
Monitor and evaluate liver function test: 
AST, ALT, ALP, and T. Bili.
−
For hepatitis B (HBV) + patients: evaluate 
quantitative HBV viral load, quantitative 
Hepatitis B surface antigen (HBsAg), or 
Hepatitis B envelope antigen (HBeAg).
−
For hepatitis C (HCV) + patients: evaluate 
quantitative HCV viral load.
−
Consider consulting Hepatology or 
Infectious Diseases specialists regarding 
changing or starting antiviral HBV 
medications if HBV viral load is >2000 
IU/ml.
−
Consider consulting Hepatology or 
Infectious Diseases specialists regarding 
changing or starting antiviral HCV 
medications if HCV viral load has increased 
by ≥2-fold.
−
For HCV+ with Hepatitis B core antibody 
(HBcAb) +: Evaluate for both HBV and 
HCV as above.
Hepatitis 
(elevated  
transaminases and total
bilirubin)
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis. 
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
 Isolated AST or ALT 
>ULN and ≤2.5 BLV 
•
No dose modifications.
•
If ALT/AST elevations represents significant worsening 
based on investigator assessment, then treat as  described 
for elevations in the row below.
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients (or 
secondary tumour 
involvement of the 
liver with abnormal 
baseline values 
[BLV])


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Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
•
For all  transaminase elevations , see instructions at 
bottom of shaded area if transaminase rise is not isolated 
but (at any time) occurs in setting of either increasing 
bilirubin or signs of DILI/liver decompensation
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
AST or ALT >2.5 
BLV and ≤5×BLV 
and ≤ 20 ULN
•
Hold study drug/study regimen dose until  resolution to 
AST or ALT ≤2.5×BLV.
•
If toxicity worsens, then treat as  described for elevations 
in the rows below. If toxicity improves to  AST or ALT 
≤2.5×BLV, resume study drug/study regimen after 
completion of steroid taper (<10 mg prednisone, or 
equivalent).
−
Regular and frequent checking of 
Transaminases and total bilirubin (e.g., 
every 1 to 3 days) until elevations of these 
are improving or resolved.

Recommend consult hepatologist; consider 
abdominal ultrasound, including Doppler 
assessment of liver perfusion.
−
Consider, as necessary, discussing with 
Clinical Study Lead.
−
If event is persistent (>2 to 3 days) or 
worsens, and investigator suspects toxicity 
to be an imAE, start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day of prednisone PO 
or IV equivalent, consider additional 
workup. If still no improvement within 2 to 
3 days despite 2mg/kg/day of IV 
methylprednisolone, consider additional 
abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and 
consider starting additional 
immunosuppressants. (e.g., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or 
relevant practice guidelines). Discuss 
Clinical Study Lead if mycophenolate 
mofetil is not available. Infliximab should 
NOT be used.


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ALT or AST
>5-7X BLV and ≤ 
20X ULN OR 
concurrent 2.5-5X 
BLV and ≤20XULN 
and total bilirubin       
> 1.5 - < 2 x ULN d
•
Withhold durvalumab and permanently discontinue 
tremelimumab 
•
Resume study drug/study regimen if elevations 
downgrade to AST or ALT ≤2.5×BLV and after 
completion of steroid taper (<10 mg prednisone, or 
equivalent).
•
Permanently discontinue study drug/study regimen if the 
elevations do not downgrade to AST or ALT ≤2.5×BLV 
within 14 days
−
Regular and frequent checking of LFTs (e.g., 
every 1-2 days) until elevations of these are 
improving or resolved.
−
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, 
including Doppler assessment of liver 
perfusion; and consider liver biopsy.
−
Consider discussing with Clinical Study 
Lead, as needed.
−
If investigator suspects toxicity to be 
immune-mediated, promptly initiate empiric 
IV methylprednisolone at 1 to 2 mg/kg/day 
or equivalent.
−
If no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not 
been done already) and promptly start 
treatment with an additional 
immunosuppressant.  (e.g. mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with a hepatologist or relevant 
practice guidelines). Discuss with Study 
Clinical Lead if mycophenolate is not 
available. Infliximab should NOT be used.
 ALT or AST
> 7 X BLV OR > 20
ULN whichever 
occurs
first OR bilirubin >
3ULN 
Permanently discontinue study drug/study regimen.
Same as above 
(except recommend obtaining liver biopsy early)
Nephritis and/or renal 
dysfunction
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, infections, recent IV 
contrast, medications, fluid status).
−
Consider Consulting a nephrologist.
−
Consider imaging studies to rule out any 
alternative etiology.


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Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 1
No dose modifications.
For Grade 1
−
Monitor serum creatinine weekly and any 
accompanying symptoms.
•
If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol.
•
If creatinine worsens, depending 
on the severity, treat as Grade 2, 3, 
or 4.
−
Consider hydration, electrolyte replacement, 
and diuretics, as clinically indicated.
−
Consider nephrologist consult if not resolved 
within 14 days, or earlier as clinically 
indicated
Grade 2
Hold study drug/study regimen until resolution to Grade ≤1 or 
baseline. 
•
If toxicity improves to Grade ≤1 or baseline, then resume 
study drug/study regimen after completion of steroid taper 
(<10 mg prednisone, or equivalent).
For Grade 2
−
Consider including hydration, electrolyte 
replacement, and diuretics as clinically 
indicated.
−
Follow urine protein/creatinine ratio every 3-
7 days.
−
Carefully monitor serum creatinine and as 
clinically warranted.
−
Consult nephrologist and consider renal 
biopsy if clinically indicated.
−
Start prednisone 0.5 – 1 mg/kg/day if other 
causes are ruled out.
−
If event is persistent beyond 5 days or 
worsens, increase to prednisone up to 2 
mg/kg/day PO or IV equivalent.
−
If event is not responsive within 5 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consider 
additional workup. When event returns to 


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
baseline, resume study drug/study regimen 
and routine serum creatinine monitoring per 
study protocol.
Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Carefully monitor serum creatinine daily.
−
Follow urine protein/creatinine ratio every 3-
7 days.
−
Consult nephrologist and consider renal 
biopsy if clinically indicated.
−
Promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
−
If event is not responsive within 3 to 5 days 
of steroids or worsens despite prednisone at 
1 to 2 mg/kg/day PO or IV equivalent, 
consider additional workup and prompt 
treatment with an immunosuppressant.
Rash or Dermatitis
(Including Pemphigoid)
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology.
−
Monitor for signs and symptoms of 
dermatitis (rash and pruritus).
−
HOLD STUDY DRUG IF GRADE 3 
PEMPHIGOID OR SEVERE 
CUTANEOUS ADVERSE REACTION 
(SCAR) IS SUSPECTED. 
−
PERMANENTLY DISCONTINUE 
STUDY DRUG IF SCAR OR GRADE 3 
PEMPHIGOID IS CONFIRMED.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 1
No dose modifications.
For Grade 1
−
Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy 
(e.g., emolient, lotion, or institutional 
standard).
Grade 2
For persistent (>1 week) Grade 2 events, hold scheduled study 
drug/study regimen until resolution to Grade ≤1 or baseline.
•
If toxicity improves to Grade ≤1 or baseline, then resume 
drug/study regimen after completion of steroid taper (<10 
mg prednisone, or equivalent).
For Grade 2
−
Consider dermatology consult and skin 
biopsy, as indicated.
−
Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy 
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions 
occurs within 1 week or is worsening despite 
symptomatic treatment and/or use of 
moderate strength topical steroid, consider 
discussing with Clinical Study Lead, as 
needed, and promptly start systemic steroids 
such as prednisone 1 to 2 mg/kg/day PO or 
IV equivalent.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 3
For Grade 3
•
Hold study drug/study regimen until resolution to Grade 
≤1 or baseline.
•
If toxicity improves to Grade ≤1 or baseline, then resume 
drug/study regimen after completion of steroid taper (<10 
mg prednisone, or equivalent).
  
For Grade 3
−
Reconsult dermatologist. Consider skin 
biopsy (preferably more than 1) as clinically 
feasible. 
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Consider hospitalization.
−
Monitor the extent of rash [Rule of Nines].
−
Consider, as necessary, discussing with 
Clinical Study Lead.
Grade 4
For Grade 4
Permanently discontinue study drug/study regimen.
For Grade 4
−
Reconsult a dermatologist. Consider skin 
biopsy (preferably more than 1) as clinically 
feasible.
−
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.
−
Consider hospitalization.
−
Monitor the extent of rash [Rule of Nines].
Consider, as necessary, discussing with Clinical Study 
Lead.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency)
Any Grade
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression including brain 
metastases, or infections).
−
Consider consulting an endocrinologist for 
endocrine events.
−
Consider discussing with Clinical Study 
Lead, as needed.
−
Monitor patients for signs and symptoms of 
endocrinopathies. (Non-specific symptoms 
include headache, fatigue, behaviour 
changes, mental status changes, 
photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and 
weakness.)


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 1
No dose modifications.
For Grade 1
−
Monitor patient with appropriate endocrine 
function tests.
−
For suspected hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to 
guide assessment of early-morning 
adrenocorticotropin hormone (ACTH), 
cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test 
(though it may not be useful in diagnosing 
early secondary adrenal insufficiency).
−
If TSH < 0.5 × LLN, or TSH >2 × ULN, or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 2, 3, or 4

For Grade 2-4 endocrinopathies other than hypothyroidism 
and type 1 diabetes mellitus (T1DM), consider holding 
study drug/study regimen dose until acute symptoms 
resolve.

Study drug/study regimen can be resumed once patient 
stabilizes and after completion of steroid taper (<10 mg 
prednisone, or equivalent).

Patients with endocrinopathies who may require prolonged 
or continued steroid replacement (e.g., adrenal 
insufficiency) can be retreated with study drug/study 
regimen if the patient is clinically stable as per investigator 
or treating physician’s clinical judgement.
For Grade 2, 3, or 4 
−
Consult endocrinologist to guide evaluation 
of endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan.
−
For all patients with abnormal endocrine 
work up, except those with isolated 
hypothyroidism or T1DM, and as guided by 
an endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant 
hormone replacement.
−
Isolated hypothyroidism may be treated 
with replacement therapy, without study 
drug/study regimen interruption, and 
without corticosteroids.
−
Isolated T1DM may be treated with 
appropriate diabetic therapy, and without 
corticosteroids. Only hold study 
drug/study regimen in setting of 
hyperglycemia when diagnostic workup is 
positive for diabetic ketoacidosis. 
−
For patients with normal endocrine workup 
(laboratory assessment or magnetic 
resonance imaging (MRI) scans), repeat 
laboratory assessments/MRI as clinically 
indicated.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Amylase/Lipase 
increased
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
Grade 1
No dose modifications.
Grade 2, 3, or 4
For Grade 2, 3, or 4
In consultation with relevant gastroenterology specialist, 
consider continuing study drug/study regimen if no 
clinical/radiologic evidence of pancreatitis ± improvement in 
amylase/lipase.
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g. disease 
progression, viral infection, concomitant 
medications, substance abuse).
−
For modest asymptomatic elevations in 
serum amylase and lipase, corticosteroid 
treatment is not indicated as long as there are 
no other signs or symptoms of pancreatic 
inflammation. 
−
Assess for signs/symptoms of pancreatitis 
−
Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if 
clinical suspicion of pancreatitis and no 
radiologic evidence on CT)
−
If isolated elevation of enzymes without 
evidence of pancreatitis, continue 
immunotherapy.  Consider other causes of 
elevated amylase/lipase
−
If evidence of pancreatitis, manage 
according to pancreatitis recommendations 
Acute Pancreatitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology.
−
Consider Gastroenterology referral 
Grade 2
Consider holding study drug/regimen.
Grade 2
−
Consider IV hydration
−
Consider Gastroenterology referral


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 3, or 4
For Grade 3
Hold study drug/study regimen until resolution  of elevated 
enzymes and no radiologic findings.
If no elevation in enzymes or return to baseline values, then 
resume study drug/study regimen after completion of steroid 
taper (<10 mg prednisone, or equivalent).
For Grade 4
Permanently discontinue study drug/study regimen.
For Grade 3, or 4
−
Promptly start systemic steroids prednisone 
1 to 2 mg/kg/day PO or IV equivalent.
−
IV hydration
Nervous System Disorders
Aseptic Meningitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
−
Symptoms may include headache, photophobia, and 
neck stiffness, nausea/ vomiting which may resemble 
an infectious meningitis.
−
Patients may be febrile.
−
Mental status should be normal
For Any Grade
−
Consider neurology consult
−
Consider MRI brain with and without 
contrast with pituitary protocol and a lumbar 
puncture for diagnosis.
−
Exclude bacterial and viral infections. (ie 
HSV)
−
Consider IV acyclovir until polymerase 
chain reactions are available
Any Grade
Permanently discontinue study drug/study regimen
For Any Grade
−
Consider neurology consult
−
Consider MRI brain with and without 
contrast with pituitary protocol and a lumbar 
puncture for diagnosis.
−
Exclude bacterial and viral infections. (ie 
HSV)
−
Consider IV acyclovir until polymerase 
chain reactions are available
−
Consider, as necessary, discussing with 
Clinical Study Lead.( Last bullet)
−
Consider hospitalization.
−
Once infection has been ruled out promptly 
initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Encephalitis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
− Symptoms may include Confusion, altered behaviour, 
headaches, seizures, short-term memory loss, depressed level 
of consciousness, focal weakness, and speech abnormality.
For Any Grade 
−
Consider neurology consult
−
Consider testing including MRI of the brain 
with and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for 
subclinical seizures, ESR, CRP, 
antineutrophil cytoplasmic antibody 
(ANCA) (if vasculitic process suspected), 
thyroid panel including TPO and 
thyroglobulin and additional autoantibodies 
to rule out paraneoplastic disorders.
−
Exclude bacterial and viral infections. (i.e.
−
HSV) Consider IV acyclovir until 
polymerase chain reactions are available.
Grade 2
For Grade 2
Permanently discontinue study drug/study regimen.
For Grade 2
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
−
Once infection has been ruled out 
methylprednisolone 1–2 mg/kg/day
−
For progressive symptoms or if oligoclonal 
bands are present consider 
methylprednisolone 1 g IV daily for 3–5 days 
plus IVIG or plasmapheresis
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Consider, as necessary, discussing with 
Clinical Study Lead.
−
Consider hospitalization.
−
Once infection is ruled out, start 
methylprednisolone 1 g IV daily for 3–5 
days for progressive symptoms consider 
adding IVIG or plasmapheresis 


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Transverse Myelitis
Any Grade
General Guidance
−
Permanently discontinue immunotherapy
−
Consider MRI of the spine and brain
−
Once imaging is complete, consider lumbar 
puncture
Consider testing to rule out additional aetiologies: B12, 
HIV, rapid plasma reagin (RPR), ANA, anti-Ro/La 
antibodies, aquaporin-4 IgG, myelin oligodendrocyte 
glycoprotein (MOG) IgG, paraneoplastic panel for anti-
Hu and anti-CRMP5/CV2
For Any Grade
−
Consider neurology consult
−
Inpatient care
−
Consider prompt initiation of high 
methylprednisolone pulse dosing
−
Strongly consider IVIG or plasmapheresis
Peripheral neuropathy
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be evaluated to rule out any 
alternative etiology for neuropathy (e.g., 
disease progression, infections, metabolic 
syndromes or medications). It should be 
noted that the diagnosis of immune-mediated 
peripheral neuromotor syndromes can be 
particularly challenging in patients with 
underlying cancer, due to the multiple 
potential confounding effects of cancer (and 
its treatments) throughout the neuraxis. 
Given the importance of prompt and 
accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological 
consult.
−
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve conduction 
investigations) are routinely indicated upon 
suspicion of such conditions and may be best 
facilitated by means of a neurology 
consultation.


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Grade 1
No dose modifications.
For Grade 1
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Monitor symptoms for interference with 
ADLS, gait difficulties, imbalance, or 
autonomic dysfunction
Grade 2
Hold study drug/study regimen dose until resolution to Grade 
≤1.
For Grade 2
−
Consult a neurologist.
−
Consider EMG/NCS
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Observation for additional symptoms  
decompensation or consider initiating 
prednisone 0.5–1 mg/kg orally
−
− If progression, initiate methylprednisolone 
2–4 mg/kg/day and treat as GBS.
−
Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 
(e.g., gabapentin or duloxetine).
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4 
−
Consider discussing with Clinical Study 
Lead, as needed.
−
Recommend hospitalization.
−
Monitor symptoms and consult a 
neurologist.
−
Treat per Guillain-Barré Syndrome 
recommendations


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
Guillain-Barré 
Syndrome (GBS)
General Guidance
−
Recommend hospitalization
−
Obtain neurology consult
−
Obtain MRI of spine to rule out compression 
lesion
−
Obtain lumbar puncture
−
Antibody tests for GBS variants
−
Pulmonary function tests
−
Obtain electromyography (EMG) 
and nerve conduction studies
−
Frequently monitor pulmonary function 
tests and neurologic evaluations
−
Monitor for concurrent autonomic dysfunction
−
Initiate medication as needed for neuropathic 
pain
Grade 2-4
Grade 2-4
Permanently discontinue
Start IVIG or plasmapheresis in addition to 
methylprednisolone 1 gram daily for 5 days, then 
taper over 4 weeks.
Myasthenia gravis
General Guidance
−
Obtain neurology consult
−
Recommend hospitalization
−
Obtain pulmonary function tests
−
Obtain labs: ESR, CRP, creatine 
phosphokinase (CPK), aldolase and anti-
striational antibodies
−
Consider cardiac exam, ECG, troponin, 
transthoracic echocardiogram for possible 
concomitant myocarditis
−
Obtain electromyography (EMG) and nerve 
conduction studies
−
Consider MRI of brain/spine to rule out 
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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
−
Avoid medications that might exacerbate 
MG (e.g. beta blockers, some antibiotics, IV 
magnesium)
Grade 2
Permanently discontinue
−
Consider pyridostigmine 30mg three times 
daily and gradually increase based on 
symptoms (max dose 120mg four times 
daily)
−
Consider starting low dose prednisone 20mg 
daily and increase every 3-5 days. (Target 
dose 1mg/kg/day. Max dose 100mg daily)
Grade 3-4
Permanently discontinue
−
Start methylprednisolone 1-
2mg/kg/day. Taper steroids based on 
symptom improvement
−
Start plasmapheresis or IVIG
−
Consider rituximab if refractory to 
plasmapheresis or IVIG
−
Frequent PFT assessments
−
Daily neurologic evaluations
Myocarditis
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
Discontinue drug permanently if biopsy-proven immune-
mediated myocarditis.
For Any Grade
−
Initial work-up should include clinical 
evaluation, B-type natriuretic peptide (BNP), 
cardiac enzymes, electrocardiogram (ECG), 
echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up 
as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed.
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections)
−
The prompt diagnosis of immune-mediated 
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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
patients with baseline cardiopulmonary 
disease and reduced cardiac function. 
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest 
pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can 
overlap with lung toxicities, simultaneously 
evaluate for and rule out pulmonary toxicity 
as well as other causes (e.g., pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). Consult a 
cardiologist early, to promptly assess 
whether and when to complete a cardiac 
biopsy, including any other diagnostic 
procedures.
−
as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed. 
Grade 2, 3 or 4

If Grade 2-4, permanently discontinue study 
drug/study regimen.
For Grade 2-4
−
Monitor symptoms daily, hospitalize.
−
Consider cardiology consultation and a 
prompt start of high-dose/pulse 
corticosteroid therapy
−
Supportive care (e.g., oxygen).
−
If no improvement consider additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab), IVIG or 
plasmapheresis or other therapies depending 
on the clinical condition of the patient, based 
on at the discretion of the treating specialist 
consultant or relevant practice guidelines. 
Caution: It is important to rule out sepsis 


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
and refer to infliximab label for general 
guidance before using infliximab.  
Infliximab is contraindicated for patients 
who have heart failure.
 Myositis/ Polymyositis 
Any Grade
(Refer to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTCAE 
grade/severity)
General Guidance
For Any Grade
−
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, or 
infections).
−
Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, 
hips, neck and back, also difficulty breathing 
and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings 
of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting 
up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or 
reaching up.
−
If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with 
prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with 
poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, 
refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but 
previously unknown) autoimmune disorder, 
consider Rheumatology consultation.
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
−
Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, lactate 
dehydrogenase (LDH), blood urea nitrogen 


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Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
(BUN)/creatinine, erythrocyte sedimentation 
rate or C-reactive protein (CRP) level, urine 
myoglobin, and additional laboratory work-
up as indicated, including a number of 
possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could guide 
need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition 
particle antibodies). Confirmatory testing 
may include electromyography, nerve 
conduction studies, MRI of the muscles, 
and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or 
dysphonia.
Grade 1

No dose modifications.
For Grade 1
−
Monitor and closely follow up in 2 to 4 days 
for clinical symptoms and initiate evaluation 
as clinically indicated.
−
Consider Neurology consult.
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
Grade 2

Hold study drug/study regimen dose until resolution to 
Grade ≤1.

Permanently discontinue study drug/study regimen if it 
does not resolve to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency.
For Grade 2
−
Monitor symptoms daily and consider 
hospitalization.
−
Consider Rheumatology or Neurology 
consult, and initiate evaluation.
−
Consider, as necessary, discussing with the 
Clinical Study Lead.
−
If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 


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Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
systemic steroids along with receiving input 
from Neurology consultant 
−
If clinical course is not rapidly progressive, 
start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent); if no 
improvement within 2 to 3 days, continue 
additional work up and start treatment with 
IV methylprednisolone 2 to 4 mg/kg/day
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
3 days, consider additional 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab ) IVIG or 
plasmapheresis, or other therapies based on 
the discretion of the specialist consultant or 
relevant practice guideline. Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab.
Grade 3 
For Grade 3

Hold study drug/study regimen dose until resolution to 
Grade ≤1.

Permanently discontinue study drug/study regimen if 
Grade 3 imAE does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory insufficiency.
For Grade 3 
−
Monitor symptoms closely; recommend 
hospitalization.
−
Consider Rheumatology or Neurology 
consult
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with 
receiving input from Neurology consultant.
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 
2 to 3 days, consider starting another 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab at 5 mg/kg IV, 
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1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized Exanthematous Pustulosis, Drug Reaction 
with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome.
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event 
Dose Modifications
Toxicity Management
initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab.
−
Consider whether patient may require IV IG, 
plasmapheresis.
Grade 4
For Grade 4
Permanently discontinue study drug/study regimen.
Grade 4
−
Monitor symptoms closely; recommend 
hospitalization.
−
Consider Rheumatology and/or Neurology 
consult
−
Consider discussing with the Clinical Study 
Lead, as needed.
−
Promptly start IV methylprednisolone 2 
to 4 mg/kg/day systemic steroids along 
with receiving input from Neurology 
consultant.
−
If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 2 to 3 days, 
consider starting another 
immunosuppressive therapy such as a 
TNF inhibitor (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion 
of the treating provider or relevant 
practice guidelines). Caution: It is 
important to rule out sepsis and refer 
to infliximab label for general guidance 
before using infliximab.


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Other–Immune-Mediated Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTCAE 
grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all 
organs, some of them are not noted specifically in these 
guidelines (e.g. immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis).
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections). 
−
The Clinical Study Lead may be contacted for immune-
mediated reactions not listed in the “specific immune-
mediated reactions” section
−
Consultation with relevant specialist
−
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Monitor as clinically indicated
Grade 2
•
Hold study drug/study regimen until resolution to 
≤Grade 1 or baseline.
•
If toxicity worsens, then treat as Grade 3 or Grade 4.
•
Study drug/study regimen can be resumed once event 
stabilizes to Grade ≤1 after completion of steroid 
taper.
•
Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they 
do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
Grade 3
Hold study drug/study regimen 
Grade 4
Permanently discontinue study drug/study regimen 
For Grade 2, 3, or 4
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and society guidelines. (See 
page 4).
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Clinical Study Lead.”


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Infusion-Related Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade
−
Manage per institutional standard at the discretion of investigator.
−
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia).
Grade 1 or 2
For Grade 1
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event.
For Grade 2
•
The infusion rate of study drug/study regimen may 
be decreased 50% or temporarily interrupted until 
resolution of the event.
•
Subsequent infusions may be given at 50% of the 
initial infusion rate.
For Grade 1 or 2
−
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator.
−
Consider premedication per institutional standard or study protocol 
prior to subsequent doses.
−
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions.
Grade 3 or 4
For Grade 3 or 4
Permanently discontinue study drug/study regimen.
For Grade 3 or 4
−
Manage severe infusion-related reactions per institutional standard, 
appropriate clinical practice guidelines, and society guidelines. 


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Non-Immune-Mediated Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTCAE grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant.
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Treat accordingly, as per institutional standard.
Grade 2-3
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
Treat accordingly, as per institutional standard.
Grade 4
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.).
Treat accordingly, as per institutional standard.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Clinical Study Lead.”


16.4 APPENDIX D: COMPLETE LIST OF PERIPHERAL IMMUNE CELL SUBSETS31
Complete list of 123 peripheral immune cell subsets analyzed by flow cytometry. Nine classic subsets
were identified as well as 114 refined subsets relating to maturation and function within the classic subsets.
1. Total CD4+ T cells
• PD-L1+ CD4
• PD-1+ CD4
• EOMES+ CD4
• TCR+ CD4
• Tbet+ CD4
• BATF+ CD4
• CTLA-4+ CD4
• Tim-3+ CD4
• ICOS+ CD4
o PD-L1+ ICOS+ CD4
o PD-1+ ICOS+ CD4
• Total naïve (CCR7+CD45RA+) CD4
o PD-L1+ naïve CD4
o PD-1+ naïve CD4
o CTLA-4+ naïve CD4
o Tim-3+ naïve CD4
• Total central memory  (CCR7+ 
CD45RA-) CD4
o PD-L1+ CM CD4
o PD-1+ CM CD4
o CTLA-4+ CM CD4
o Tim-3+ CM CD4
• Total effector memory (CCR7-
CD45RA-) CD4
o PD-L1+ EM CD4
o PD-1+ EM CD4
o CTLA-4+ EM CD4
o Tim-3+ EM CD4
• Total EMRA (CCR7-CD45RA+) CD4
o PD-L1+ EMRA CD4
o PD-1+ EMRA CD4
o CTLA-4+ EMRA CD4
o Tim-3+ EMRA CD4
2. Total CD8+ T cells
• PD-L1+ CD8
• PD-1+ CD8
• EOMES+ CD8
• TCR+ CD8
• Tbet+ CD8
• BATF+ CD8
• CTLA-4+ CD8
• Tim-3+ CD8
• Total naïve (CCR7+CD45RA+) CD8
o PD-L1+ naïve CD8
o PD-1+ naïve CD8
o CTLA-4+ naïve CD8
o Tim-3+ naïve CD8
• Total central memory (CCR7+CD45RA-) 
CD8
o PD-L1+ CM CD8
o PD-1+ CM CD8
o CTLA-4+ CM CD8
o Tim-3+ CM CD8
• Total effector memory (CCR7-
CD45RA-) CD8
o PD-L1+ EM CD8
o PD-1+ EM CD8
o CTLA-4+ EM CD8
o Tim-3+ EM CD8
• Total EMRA (CCR7-CD45RA+) CD8
o PD-L1+ EMRA CD8
o PD-1+ EMRA CD8
o CTLA-4+ EMRA CD8
o Tim-3+ EMRA CD8
3. Total Tregs
• PD-L1+ Tregs
• PD-1+ Tregs
• CTLA-4+ Tregs
• ICOS+ Tregs
• CD45RA+ Tregs
• CD49d- Tregs
4. Total B cells
• PD-L1+ B cells
• PD-1+ B cells
• CTLA-4+ B cells
• Tim-3+ B cells
5. Total NK
• PD-L1+ NK
• PD-1+ NK
• Tim-3+ NK
• Total mature (CD16+ CD56dim) NK
o PD-L1+ mature NK
o PD-1+ mature NK
o Tim-3+ mature NK
• Total functional intermediate (CD16+
CD56br) NK
o PD-L1+ functional intermediate NK
o PD-1+ functional intermediate NK
o Tim-3+ functional intermediate NK
• Total immature (CD16- CD56br) NK
o PD-L1+ immature NK
o PD-1+ immature NK
o Tim-3+ immature NK
• Total unconventional (CD16- CD56dim) 
NK
o PD-L1+ unconventional NK
o PD-1+ unconventional NK
o Tim-3+ unconventional NK
6. Total NK-T
• PD-L1+ NK-T
• PD-1+ NK-T
• Tim-3+ NK-T
7. Total cDC
• PD-L1+ cDC
• PD-1+ cDC
• CD83+ cDC
• Tim-3+ cDC
8. Total pDC
• PD-L1+ pDC
• PD-1+ pDC
• CD83+ pDC
• Tim-3+ pDC
9. Total MDSC
• PD-L1+ MDSC
• PD-1+ MDSC
• CD16+ MDSC
• Total monocytic (CD14+ CD15-) MDSC
o PD-L1+ mMDSC
o PD-1+ mMDSC
o CD16+ mMDSC
• Total granulocytic (CD14- CD15+) 
MDSC
o PD-L1+ gMDSC
o PD-1+ gMDSC
o CD16+ gMDSC
• Total lineage negative (CD14- CD15-) 
MDSC
o PD-L1+ lin neg MDSC
o PD-1+ lin neg MDSC
o CD16+ lin neg MDSC
BATF, basic leucine zipper transcription factor ATF-like; cDC, conventional dendritic cells; CM, central memory; CTLA-4, 
cytotoxic T lymphocyte-associated protein-4; EM, effector memory; EMRA, terminally differentiated effector memory;
EOMES, eomesodermin; FoxP3, forkhead box P3; gMDSCs, granulocytic mononuclear derived suppressor cells;  ICOS, 
inducible T cell co-stimulator; lin neg MDSCs, lineage negative MDSCs; mMDSCs, monocytic MDSCs; NK, natural killer;
pDC, plasmacytoid DC; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; Tbet, T box expressed in T
cells; TCR, T cell receptor; Tim-3, T cell immunoglobulin and mucin domain-3; Tregs, regulatory T cells.


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16.5 APPENDIX E: URINE COLLECTION 
The following protocol is used in the Linehan Laboratory:
Urine Protocol
A. Urine will be collected at room temperature from patients through voiding or instrumentation 
and transported to laboratory staff on ice.  Collection will be 30-100 mL of urine in a sterile 
urine container.
B. Centrifuge urine at 1200xg (2491 rpm for 20 minutes using our 5810R Eppendorf 
Centrifuge) at 4°C in 50 mL conical tube.
C. Filter the supernatant (cell-free urine) with .45 μm filter to remove large debris.  Save cell 
pellet.
D. Store filtered urine as cell-free, filtered urine in 6 vials (1.8 mL cryovial each) at -80°C 
without any cryopreservative.  
E. Resuspend urine cell pellet in 1 mL of 5% DMSO (95% MEM media) and transfer to 1.8 mL 
cryovial tube.
F. Spin this cryovial at 1200xg for 20 minutes at 4°C and leave cell pellet packed. 
G. Do slow freeze of cell pellet with Mr. Frosty and then store at -80.   
H. Schematic: