Clinical trial NCT04493060
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma Stage IV Pancreatic Cancer AJCC v8
Sponsor: Mayo Clinic
Start date: 2020-12-28; Completion date: 2025-06-01
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well niraparib and dostarlimab work in treating patients with germline or somatic BRCA1/2 and PALB2 mutated pancreatic cancer that has spread to other places in the body (metastatic). Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as dostarlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving niraparib and dostarlimab may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine antitumor activity as measured by disease control rate at 12 weeks (DCR12) as assessed using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) in select homologous recombination repair (HRR) deficient pancreatic cancer patients with HRR deficiency (defined as mutations in BRCA 1/ 2, or PALB2).

SECONDARY OBJECTIVES:

I. To assess adverse events according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) and other safety parameters.

II. To assess the time to next treatment (TTNT), objective response rate (ORR), time to and duration of response and duration of confirmed stable disease according to iRECIST.

III. To assess progression-free survival. IV. To assess overall survival.

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess germline deoxyribonucleic acid (DNA) and serum markers of immune response.

II. To determine changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP inhibitor (i) and a PD-1 inhibitor.

III. To study mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1 inhibitor.

IV. To assess the tumor microenvironment for immune related changes (immune infiltration, PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes \[TIL\]).

V. To assess genetic profile of the tumor pre- and post-treatment. VI. To determine changes in the cytokine profile pre- and post-treatment.

OUTLINE:

Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive dostarlimab intravenously (IV) over 30 minutes on day 1 every 3 weeks (Q3W) for cycles 1-4 and every 6 weeks (Q6W) for subsequent cycles. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months until progressive disease (PD), and then every 6 months for up to 5 years after registration.

Arms: arm 1: Patients receive niraparib PO QD on days 1-21. Patients also receive dostarlimab IV over 30 minutes on day 1 Q3W for cycles 1-4 and Q6W for subsequent cycles. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dostarlimab intervention 2: Niraparib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
ICF_001.pdf: 
 
 
 
 
 
MC1841 / 18-003525 
 
 
Phase II Study of Niraparib and TSR-042 in Patients with 
Germline or Somatic BRCA1/2 and PALB2-related Pancreatic 
Cancer 
 
 
NCT04493060 
 
 
Document Date: 10/19/2023 


 
 
Approval Date:  
October 19, 2023 
Not to be used after: May 25, 2024 
 
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Name and Clinic Number 
Protocol #: MC1841 
Version Date: 07Oct2023 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC1841: Phase II Study of Niraparib and TSR-042 in Patients with Germline or 
Somatic BRCA1/2 and PALB2-related Pancreatic Cancer  
 
IRB#:  
18-003525  
 
Principal Investigator: Dr. Robert McWilliams and Colleagues 
 
 
Key Study Information 
 
 
This section provides a brief summary of the study. It is important for you to understand why 
the research is being done and what it will involve before you decide. Please take the time to 
read the entire consent form carefully and talk to a member of the research team before 
making your decision. You should not sign this form if you have any questions that have not 
been answered. 
It’s Your Choice 
This is a research study. Being in this research study is your choice; 
you do not have to participate. If you decide to join, you can still stop 
at any time. You should only participate if you want to do so. You will 
not lose any services, benefits or rights you would normally have if 
you choose not to take part. 
Research Purpose 
The purpose of this research is to further define genetic identification 
of patients with your condition and to evaluate the treatment 
combination of niraparib and dostarlimab (TSR-042) in patients with 
germline or somatic mutations in BRCA1/2 or PALB2. 
 
You have been asked to take part in this research because you have 
germline or somatic BRCA1/2 or PALB2-related pancreatic cancer. 


 
 
Approval Date:  
October 19, 2023 
Not to be used after: May 25, 2024 
 
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Name and Clinic Number 
Protocol #: MC1841 
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What’s Involved 
Study participation involves a combination treatment of two 
investigational drugs, niraparib and dostarlimab. Niraparib is an oral 
drug (pill form) that will be self-administered daily while on study. 
Dostarlimab is a drug that will be administered intravenously once at 
the beginning of each treatment cycle. 
 
Cycles are 21 days long and subjects will visit the clinic on Day 1 of 
each cycle (plus Day 15 of the first cycle). 
 
Subjects enrolled in this study will be asked to provide both blood 
samples (up to 6) and tissue samples (up to 2 biopsies with an optional 
3rd) for research purposes at time points specified later in this form.  
Key Information 
The most common and expected risks of treatment with niraparib 
include low blood cell counts, high blood pressure, heart palpitations, 
urinary tract infection, shortness of breath, runny or stuffy nose, 
cough, headache, dizziness, feeling weak, lack of energy, difficulty 
sleeping, joint pain, back pain, stomach pain, indigestion, feeling sick, 
vomiting, watery stools (diarrhea), difficulty passing stool 
(constipation), and decreased appetite. 
 
The most common and expected risks of treatment with dostarlimab 
include anemia, nausea vomiting, diarrhea, itchy skin, rash, and 
increased levels in liver function tests. 
 
The risks of the tumor biopsy procedure are mainly pain, bleeding, 
and infection. Depending on the location of the tumor, there is a small 
risk of injury or damage to the nearby organs or tissues. Your doctor 
may use a local anesthetic and/or a medicine to calm your nerves 
before or during the biopsy procedure; there is a possibility that an 
allergic reaction to the anesthetic may occur. There is also a risk of 
scarring at the biopsy site, and there is a possibility of tumor cells 
spreading from the tumor into the nearby area. Your doctor will 
explain the procedure to you and discuss these risks with you. 
 
A complete, detailed list of any/all risks related to study participation 
is located later in this form in section “What are the possible risks or 
discomforts from being in this research study?” 


 
 
Approval Date:  
October 19, 2023 
Not to be used after: May 25, 2024 
 
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Name and Clinic Number 
Protocol #: MC1841 
Version Date: 07Oct2023 
Learn More 
If you are interested in learning more about this study, read the rest of 
this form carefully. The information in this form will help you decide 
if you want to participate in this research or not. A member of our 
research team will talk with you about taking part in this study before 
you sign this form. If you have questions at any time, please ask us. 
 
 
 
Making Your Decision 
 
 
Taking part in research is your decision. Take your time to decide. Feel free to discuss the study 
with your family, friends, and healthcare provider before you make your decision. Taking part in 
this study is completely voluntary and you do not have to participate. 
 
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you either a printed or electronic copy of this form to keep. A 
copy of this form will be put in your medical record. 
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and 
entities. 
 
 
 


 
 
Approval Date:  
October 19, 2023 
Not to be used after: May 25, 2024 
 
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Name and Clinic Number 
Protocol #: MC1841 
Version Date: 07Oct2023 
 
Contact Information 
 
 
If you have questions about … 
You can contact … 
 Study tests and procedures 
 Materials you receive 
 Research-related appointments  
 Research-related concern or complaint 
 Research-related injuries or emergencies 
 Withdrawing from the research study 
Principal Investigators:  
Robert McWilliams, MD (MN) 
Phone: (507) 284-2511 
 
Daniel Ahn, DO (AZ) 
Phone: (480) 301-8000 
 
Hani Babiker, MD (FL) 
Phone: (904) 953-2000 
 
Institution Name and Address: 
Mayo Clinic  
200 1st Street SW 
Rochester, MN 55905 
 
Mayo Clinic Hospital 
5777 E. Mayo Boulevard 
Phoenix, AZ 85054 
 
Mayo Clinic Florida 
4500 San Pablo Road 
Jacksonville, FL 32224 
 Rights of a research participant 
Mayo Clinic Institutional Review Board (IRB)  
Phone: (507) 266-4000 
Toll-Free: (866) 273-4681 
 Rights of a research participant 
 Any research-related concern or complaint 
 Use of your Protected Health Information 
 Stopping your authorization to use your 
Protected Health Information 
 Withdrawing from the research study 
Research Participant Advocate (RPA) 
(The RPA is independent of the Study Team) 
Phone: (507) 266-9372 
Toll-Free: (866) 273-4681 
 
E-mail: researchparticipantadvocate@mayo.edu 
 Billing or insurance related to this research 
study 
Patient Account Services 
Toll-Free: (844) 217-9591  
 
 
 


 
 
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October 19, 2023 
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Name and Clinic Number 
Protocol #: MC1841 
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Other Information:  
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. 
 
 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this research study because you have germline or somatic 
BRCA1/2 and PALB2-related pancreatic cancer. 
 
The plan is to have about 23 people take part in this study at Mayo Clinic. 
 
 
Why is this research study being done? 
 
 
The purpose of this study is to further identify trends in the genetic information of patients with 
your condition and to evaluate the treatment combination of niraparib and dostarlimab (TSR-
042) in patients with germline or somatic mutations in BRCA1/2 or PALB2. 
 
 
Information you should know 
 
 
Who is Funding the Study? 
GlaxoSmithKline (GSK) is funding this study. GSK will pay Mayo Clinic to cover costs related 
to running the study. 
 
Information Regarding Conflict of Interest: 
Your healthcare provider may be referring you to this research study.  If your healthcare provider 
is also an investigator on this study, there is the chance that his or her responsibilities for the 
study could influence his or her recommendation for your participation.  If you prefer, your 
healthcare provider will be happy to refer you to another investigator on the research study team 
for you to decide if you want to participate in the study and to see you for the research study 
activities while you are in the study. 
 
 
 


 
 
Approval Date:  
October 19, 2023 
Not to be used after: May 25, 2024 
 
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How long will you be in this research study? 
 
 
It will take you about 5-6 months to complete this research study. During this time, we will ask 
you to make 12-15 study visits to Mayo Clinic. However, if you are responding well to the study 
treatment, you may continue to remain on study until you decide to stop. 
 
 
What will happen to you while you are in this research study? 
 
 
If you agree to be in the study, you will be asked to participate in the following:  
 
Screening Visit 
During this visit, we will do some tests and procedures to see if you are eligible to take part in 
this research study. The Principal Investigator will review the results of these tests and 
procedures. If you aren’t eligible, the Principal Investigator will tell you why. At this visit we 
will: 
• Ask you about your medical history 
• Give you a physical exam, including height, weight, and “vital signs” (blood pressure, 
temperature, heart and breathing rates) 
• Draw a blood sample for clinical care testing 
• Test your blood for pregnancy if you are able to become pregnant 
• Ask you to provide a urine sample 
• Conduct scan of your tumor (CT, MRI, or bone scan).  
 
These exams, tests or procedures are part of regular clinical care and may be done even if you do 
not join the study. If you have had some of them recently, they may not need to be repeated. This 
will be up to the Principal Investigator. 
 
Study Treatment Visits (every treatment cycle during this study is 21 days long) 
Cycle 1: Day 1 
At this visit we will:  
• Give you a physical exam, including measurements of your height, weight, and “vital 
signs” (blood pressure, temperature, heart and breathing rates) 
• Ask you about any health problems since your last visit 
• Provide you a medication diary for the oral study drug (niraparib) 
• Provide a supply of the oral study drug and instructions for self-administration 


 
 
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• Draw a blood sample for clinical care testing 
• Test your blood for pregnancy if you are able to become pregnant 
• Draw a blood sample for research 
• Ask you to provide a urine sample 
• Conduct a biopsy of your tumor 
• Administer study drug (dostarlimab) intravenously 
 
Cycle 1: Day 8 
• Ask you about any side effects or health problems since your last visit 
• Draw a blood sample for clinical care testing 
 
Cycle 1: Day 15 
At this visit we will: 
• Ask you about any side effects or health problems since your last visit 
• Draw a blood sample for research 
 
Cycle 2: Day 1 (and Day 1 of all remaining cycles) 
At this visit we will: 
• Give you a physical exam, including measurements of your weight and “vital signs” 
(blood pressure, temperature, heart and breathing rates) 
• Ask you about any side effects or health problems since your last visit 
• Review your medication diary 
• Provide a supply of the oral study drug  
• Draw a blood sample for clinical care testing 
• Test your blood for pregnancy if you are able to become pregnant every third cycle after 
Cycle 1 (day 1 of Cycles 3, 6, 9, etc.) 
• Draw a blood sample for research (Day 1 of Cycles 2, 3, 5 and last treatment visit only) 
• Ask you to provide a urine sample 
• Administer study drug (dostarlimab) intravenously 
• Conduct scan of your tumor (CT, MRI, or bone scan). These scans will be done every 6 
weeks starting with your screening visit (Day 1 of Cycles 2, 4, 6, etc.). 
• Conduct a biopsy of your tumor (Day 1 of Cycle 5 and last treatment visit only; biopsy 
conducted during last treatment visit is optional) 
 
Clinical Follow-up Visit (approximately 30 days after last treatment visit) 
At this visit we will: 
• Give you a physical exam, including measurements of your weight and “vital signs” 
(blood pressure, temperature, heart and breathing rates) 
• Ask you about any side effects or health problems since your last visit 


 
 
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• Draw a blood sample for clinical care testing 
• Test your blood for pregnancy if you are able to become pregnant 
• Ask you to provide a urine sample 
 
Event Monitoring Visits 
These visits will begin 3 months after the Clinical Follow-up Visit and will occur every three 
months after. During these visits, we will ask you about any health problems since your last visit. 
 
Blood Pressure and Heart Rate Monitoring 
During the first 8 weeks of study treatment, you will be asked to monitor your blood pressure 
and heart rate at least once a week. You will be provided a diary for recording your blood 
pressure and heart and you will be asked to record those values at the beginning of each week 
(Days 1, 8, and 15 of Cycles 1, 2, and 3). If you are in the clinic for a study visit during any of 
those days, your blood pressure and heart rate will be recorded by the study staff and you will 
not have to record it in your diary. 
 
Collection of Blood and Tissue Samples for Research 
Tissue and blood specimens are mandatory for this study. You will be asked to have biopsies to 
collect tissue, and blood draws (taken at the same times as your clinical blood tests) for this 
study. 
 
You will be informed of any clinically relevant research results. Any results reported to you 
individually, will also be placed in your medical record. Study results will be reported on 
ClinicalTrials.gov after the study is completed. 
 
Birth Control Requirements 
If you are sexually active and able to become pregnant, or able to cause pregnancy of someone 
able to become pregnant, you must agree to use one of the birth control methods listed below: 
• Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or 
implants 
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, 
cream, or gel that kills sperm) 
• Intrauterine device (IUD) 
• Abstinence (no sex) 
 
If you are of childbearing potential, you must use birth control for the entire study and for at least 
180 days after your last dose of Niraparib and 180 days after your last dose of dostarlimab.  
 


 
 
Approval Date:  
October 19, 2023 
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If you are a male subject and are sexually active with a person of childbearing potential, you 
must use birth control for the entire study and for at least 180 days after your last dose of 
Niraparib and 180 days after your last dose of dostarlimab.  
 
If you are already using a method of birth control, your Study Doctor or the study staff will 
discuss with you whether your current method of birth control is acceptable for use during this 
study. 
 
 
What are the possible risks or discomforts from being in this research study? 
 
 
Niraparib (Formerly MK-4827) 
Niraparib has moderate influence on the ability to drive or use machines. Patients who take 
niraparib may experience weakness, fatigue, difficulty concentrating and dizziness. Patients who 
experience these symptoms should observe caution when driving or using machines. 
 
Known side effects of niraparib are listed below: 
 
Very Common occurrence (may affect more than 1 in 10 people) 
• Decrease in a type of blood cell called platelets that help stop bleeding; this may increase 
your risk of bleeding (thrombocytopenia)  
• Decrease in red blood cells that carry oxygen; this may make you feel tired or short of 
breath (anemia)  
• Decrease in a type of white blood cell called a leukocyte that fight infection; this may 
decrease your ability to fight infections (leukopenia) 
• Decrease in a type of white blood cell called neutrophils that fight infection; this may 
decrease your ability to fight infections and may be associated with fever, and may lead 
to a potentially life-threatening condition caused by the body’s response to an infection, 
triggering changes that can damage multiple organ systems (neutropenia, febrile 
neutropenia) 
• Increased blood pressure (hypertension) 
• Noticeably rapid, strong, or irregular heartbeat (palpitations) 
• Pain or burning when urinating which may indicate an infection (urinary tract infection) 
• Breathlessness or difficulty breathing (dyspnea) 
• Runny or stuffy nose (nasopharyngitis) 
• Cough 
• Headache 
• Feeling lightheaded or like you are about to faint (dizziness) 


 
 
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October 19, 2023 
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• Feeling weak (asthenia) 
• Feeling tired, lack of energy (fatigue)  
• Sleeplessness, trouble sleeping (insomnia) 
• Joint pain (arthralgia) 
• Back pain 
• Pain in your belly (abdominal pain)   
• Indigestion (dyspepsia) 
• Feeling sick to your stomach (nausea) 
• Vomiting 
• Frequent watery stools (diarrhea) 
• Difficulty with emptying the bowels, often because of hard stools (constipation)  
• Reduced desire to eat (decreased appetite)  
 
Common occurrence (may affect up to 1 in 10 people) 
• 
Infection due to low white blood cell counts (neutropenic infection) 
• Low blood cell counts due to a problem in the bone marrow or blood cancer starting from 
the bone marrow (Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML]) 
• An irritation or infection in the tubes that carry air in and out of the lungs, that causes a 
cough (bronchitis) 
• An abnormally rapid heart rate (tachycardia) 
• An accumulation of fluid that causes swelling in lower extremities such as lower legs, 
hands and feet (peripheral edema) 
• Muscle pain (myalgia) 
• Rash 
• Decrease in weight  
• Feelings of sadness, depressed (depression) 
• Feelings of worry, nervousness, or unease (anxiety) 
• Impaired concentration, understanding, memory, and thinking (cognitive impairment) 
• Inflammation of the white area of the eye (conjunctivitis) 
• Nosebleed (epistaxis) 
• Sore, red mouth (stomatitis) 
• Swelling or irritation of the lining of the mouth, throat, esophagus, stomach, or intestines 
(mucosal inflammation/mucositis)  
• Abnormal taste in mouth (dysgeusia) 
• Dry mouth 
• Increased sensitivity of the skin to sunlight (photosensitivity) 
• Decrease in levels of potassium in your blood (hypokalemia) 
• Increased level of creatinine in your blood; this may be a sign of kidney damage (blood 
creatinine increase) 


 
 
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October 19, 2023 
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• Increased liver enzymes in the blood; aspartate transaminase (“AST”), alanine 
aminotransferase (“ALT”), gamma glutamyl transferase increased (“GGT”), or alkaline 
phosphatase (ALP); this may be a sign of damage to liver cells  
• Allergic reaction (hypersensitivity, including anaphylaxis) 
 
Uncommon Occurrence (may affect up to 1 in 100 people) 
• Fever with low white blood cell count (febrile neutropenia) 
• Severe life-threatening infection due to low white cell counts [associated with low blood 
pressure and possible organ failure (for example, heart, kidney and/or liver)] (neutropenic 
sepsis) 
• Decrease in number of all types of blood cells (pancytopenia) 
• Confusion (confusional state/disorientation) 
• Seeing or hearing things that are not really there (hallucination)  
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing 
(non-infectious pneumonitis) 
 
Rare Occurrence (may affect up to 1 in 1000 people) 
• Severe increase in blood pressure (hypertensive crisis) 
• A brain condition with symptoms including seizures, headache, confusion, and changes 
in vision (posterior reversible encephalopathy syndrome [PRES]) 
 
Side Effects Requiring Immediate Medical Attention: 
The side effects listed below require IMMEDIATE MEDICAL ATTENTION OR ADVICE. 
Call the study staff right away if you have any of these side effects: 
• Allergic reactions can be life-threatening. Symptoms may include difficulty breathing, 
shortness of breath, low blood pressure (feeling lightheaded, dizziness), tingling around 
the mouth, rash. 
• Low platelet counts may increase your risk of bleeding and bruising. Bleeding may 
require urgent medical attention, including a transfusion (receiving blood or blood 
products by vein). 
• Low red blood cell counts may make you feel tired or short of breath and symptoms may 
require a blood transfusion. 
• Low neutrophil counts may be associated with infection, sometimes severe and life-
threatening (neutropenic infection, neutropenic sepsis): 
o Symptoms of severe life-threatening infection may include fever, feeling of low blood 
pressure (lightheadedness, dizziness), decreased urination, rapid pulse, rapid 
breathing or shortness of breath 
• Decrease in the number of all types of blood cells (pancytopenia) 
• Low blood cell counts due to a problem in the bone marrow or blood cancer starting from 
the bone marrow (MDS or AML). MDS/AML, including fatal cases, have been reported 


 
 
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with use of niraparib. If you experience prolonged haematological toxicities, contact your 
study doctor for haematologist evaluation. 
• High blood pressure (hypertension) including severe increase in blood pressure 
(hypertensive crisis) has been reported with the use of niraparib. If you have pre-existing 
hypertension, the physician will determine if your blood pressure is adequately controlled 
before starting niraparib treatment.  
o Symptoms of a severe increase in blood pressure may include blurry vision, 
headache, nausea, vomiting, confusion, passing out, seizures, weakness or numbness 
on one side of body or in one arm or leg and/or difficulty talking (symptoms of a 
stroke), trouble breathing, chest pain, pain in the upper or lower back, urine that is 
brown or bloody 
• Posterior Reversible Encephalopathy Syndrome (PRES), a rare neurological side effect 
has been reported with niraparib treatment. 
o If you have headache, vision changes, confusion or seizure with or without high 
blood pressure, please contact your doctor. 
 
Class Effects: 
Class effects are potential risks that are associated with a particular group of drugs.  Niraparib 
belongs to the group known as poly (ADP-ribose) polymerase inhibitors (PARP) inhibitors.  
These class effects are potential risks for the group of drugs but have not yet been identified as 
side effects for niraparib.   
 
Secondary Primary Malignancy: 
PARP inhibitors may also cause a new primary cancer (that is, a cancer other than the one for 
which you have been treated). In 2 studies comparing niraparib to placebo (sugar pill), new 
primary cancers were observed in a small number of patients who took niraparib or placebo.  
 
Safe Handling: 
Niraparib may have adverse effects on an unborn baby. Wash your hands after handling the 
Study Drug. If a caregiver is giving the Study Drug to you, he or she should wear disposable 
gloves. Notify your Study Doctor if it appears that the Study Drug is damaged or defective in any 
way. 
 
Dostarlimab (TSR-042) 
As of April 2023, dostarlimab has been studied in about 3000 patients with advanced or recurrent 
solid tumors in clinical trials, with about 2300 of these patients receiving dostarlimab in 
combination with other medicines Your study doctor will explain the risks, side effects, and 
discomforts that may be experienced related to non-study drugs which are part of usual care. 
Some of the side effects mentioned below can be life-threatening or fatal. 
 


 
 
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These side effects are considered very common in patients who took dostarlimab (may affect 
more than 1 in 10 people):  
• Decrease in the number of red blood cells that carry oxygen. Low red blood cell count 
may make you feel tired or short of breath and symptoms may require a blood transfusion 
(anemia) 
• Feeling sick to the stomach (nausea) 
• Vomiting 
• Frequent watery stools (diarrhea)  
• Itchy skin (pruritus) 
• Rash 
• Fever (pyrexia) 
• Increased levels of substances in the blood produced by the liver which may be a sign of 
liver injury (AST increased, ALT increased) (transaminases increased) 
• Underactive thyroid gland (hypothyroidism) 
 
These side effects are considered common in patients who took dostarlimab (may affect up to 1 
in 10 people): 
• Decreased production of adrenal hormones resulting in possible weakness and/or low 
blood pressure (adrenal insufficiency) 
• Muscle pain (myalgia) 
• Overactive thyroid gland (hyperthyroidism) 
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing 
(pneumonitis) 
• Inflammation of the pancreas causing pain in the upper abdomen. This could become 
severe and cause nausea and vomiting, fever, and rapid heart rate (pancreatitis) 
• Inflammation of the colon that can cause stomach pain or diarrhea (colitis) 
• Chills 
• Inflammation of the liver (hepatitis) 
 
These side effects are considered uncommon in patients who took dostarlimab (may affect up to 
1 in 100 people): 
• Destruction of red blood cells which can cause tiredness, dizziness, yellow skin or fast 
heart rate (autoimmune hemolytic anemia) 
• Inflammation of the thyroid gland (thyroiditis) 
• Pituitary gland inflammation (hypophysitis) 
• Severe high blood sugar due to uncontrolled diabetes (diabetic ketoacidosis) 
• Diabetes requiring insulin (Type 1 diabetes mellitus) 
• Inflammation of the eye which can cause redness, blurred vision or vision loss (uveitis) 
• Muscle pain involving several muscles (polymyalgia rheumatica) 


 
 
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• Kidney inflammation (nephritis) 
• Immune-mediated arthritis  
• Myasthenia gravis 
• Inflammation in the brain (encephalitis) 
• Inflammation of the heart muscle (myocarditis) 
• Inflammation of the lining of the stomach (gastritis) 
• Inflammation of the food pipe (esophagitis) 
• Inflammation of the small intestine (enteritis) 
• Inflammation of blood vessels in the gastrointestinal tract (vasculitis gastrointestinal) 
• Inflammation of the muscle which can cause weakness, swelling and pain (myositis) 
• Inflammation throughout the whole body leading to high or low temperatures, low blood 
pressure, increased heart rate, increased rate of breathing and low or high white blood cell 
count (Systemic Inflammatory Response Syndrome) 
• Infusion-related reactions which can occur within 24 hours after receiving an intravenous 
infusion, or which can be delayed for up to about 2 weeks.  Infusion-related reactions 
may include dizziness or fainting, flushing, rash, fever, chills, shortness of breath, 
increased or decreased blood pressure, increased heart rate, swelling of the lips, tongue or 
face, feeling sick to your stomach, back pain or pain at the site of infusion. Although 
infusion-related reactions are usually reversible, they can be severe or life threatening. 
(Infusion related reactions) 
 
There are rare but serious immune-related adverse events which have been seen when 
dostarlimab was used alone or in combination with other medicines:  
• Overactive immune-system cells which damage body tissues and organs leading to signs 
of uncontrolled fever, enlarged spleen, low blood count and liver test abnormalities. This 
disease can be fatal. (Hemophagocytic Lymphohistiocytosis). 
• A neurological disorder where the immune system attacks part of the peripheral nervous 
system that can cause tingling in the feet and hands, pain, muscle weakness, and 
problems with coordination (Guillain-Barre syndrome). 
• Muscle weakness, twitching, cramping, or inability to move (peripheral motor 
neuropathy) 
• Muscle pain and weakness; swollen, red, or thickened skin (eosinophilic fasciitis) 
 
There may be other risks called “class effects” that have been seen in patients receiving other 
drugs that work like dostarlimab. These effects could also occur with dostarlimab. They are 
potential risks but not known as side effects for dostarlimab so far. The most significant class 
related side effects are “immune-related”, meaning side effects caused by increased activity of 
the immune system, which can affect multiple organs of the body including bowels 
(gastrointestinal tract), hormone glands (endocrine system), heart (cardiovascular system), lungs, 


 
 
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liver, skin, muscles and joints (musculoskeletal system), and nerves (nervous system). These 
other immune-related side effects may be life-threatening or fatal. 
 
The side effects listed below require immediate medical attention or advice. Call the study 
doctor right away if you have any of these side effects. 
 
• Respiratory: shortness of breath, rapid breathing, new or worse cough 
• Gastrointestinal: diarrhea, stools that are black or bloody, stomach area pain, nausea or 
vomiting 
• Kidneys: dark or bloody urine, urinating more often than usual 
• Musculoskeletal: chest pain, muscle pain or weakness 
• Cardiac: fast or unusual heartbeat 
• Skin: rash, itching, blisters, pale or yellow skin 
• Eyes: yellowing of the whites of your eyes, blurry vision 
• Brain: abnormal thinking, confusion, personality changes, headache and neck stiffness. 
• General: bleeding or bruising more easily than normal, feeling cold, hair loss, dizziness 
or fainting, feeling tired or weak, fever or chills. 
 
Risks related to pregnancy and breastfeeding 
Dostarlimab may cause harm to the unborn baby when it is used by a pregnant person. You 
should not join this study if you are pregnant or planning to become pregnant. You should not 
join this study if you are breastfeeding. 
 
If you are a woman able to have children, you will be given a pregnancy test at screening, and if 
the result is positive, you will not be able to participate in this study. 
 
You will be required to use one highly effective form of contraception with your partner starting 
with the Screening Visit through 180 days after the last dose of study therapy. If you are already 
using a method of birth control, your Study Doctor or the study staff will discuss with you 
whether your current method of birth control is acceptable for use during this study. 
 
The following are considered highly effective forms of contraception: hormonal contraceptives 
that include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents), 
intrauterine device (IUD), vasectomized partner, and abstinence, if this is the established and 
preferred contraception for the patient.  
 
If, during this study, you or your partner become pregnant or think you may be pregnant, stop 
taking the Study Drug and let the Study Doctor know right away. You will be asked to withdraw 
from the study. Information about your pregnancy and its outcome will be collected and used to 


 
 
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learn more about the effects of the Study Drug on pregnancy. Payment for all aspects of 
obstetrical care, child, or related care will be your responsibility.  
 
Female study participants who are pregnant or breast-feeding, or any study participant unable or 
unwilling to use effective contraception as required by study instructions should not use 
dostarlimab. 
 
All drugs have a potential risk of an allergic reaction, which if not treated promptly, could 
become life-threatening. 
 
Other less common side effects have been reported. The Study Doctor or staff can discuss these 
with you. 
 
Reproductive Risks 
The effect of the combination of niraparib and dostarlimab on a fetus (developing baby still in 
the womb), or on a breastfeeding infant, is unknown and may be harmful. Because of these risks, 
persons of childbearing potential cannot take part in this study if they are pregnant or 
breastfeeding. 
 
Subjects of Childbearing Potential: 
If you are able to become pregnant, you must have a negative pregnancy test in order to 
participate in this study unless you cannot become pregnant. 
 
To participate in the study, patients who can become pregnant must adhere to the birth control 
requirements.  
 
If you become pregnant or think you may be pregnant during the study, you must stop taking 
the study drugs and contact the Study Doctor’s site right away. You will be asked to withdraw 
from the study. The Study Doctor is required to follow up and document the course and the 
outcome of all pregnancies, even if you withdraw from the study or if the study has finished. 
 
You must not breast-feed an infant (or store breastmilk for use) during the study and for 90 days 
after receiving the final dose of Niraparib and for 180 days after receiving the final dose of 
dostarlimab. 
 
Subjects Able to Father a Child: 
To participate in the study, male study patients must adhere to contraception requirements.  
 
You must not donate sperm for 180days after your last dose of Study Drug:  
If your partner thinks they might have become pregnant within one month of beginning the 
study, while you are in the study, or for 180 days after your last dose of dostarlimab or 180 days 


 
 
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after your last dose of niraparib, you must tell the Principal Investigator immediately. The 
Principal Investigator may ask for your partner’s permission to collect information about the 
outcome of the pregnancy and the newborn. You won’t have to stop taking the study drug or stop 
taking part in the study if your partner becomes pregnant. 
 
Other Risks 
Blood Draw Risks 
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, 
infection at the site of the needle stick. 
 
MRI Risks 
There is no radiation associated with MRI, but people who have metal devices like pacemakers 
cannot have an MRI and will not be able to participate in the study. Some people with 
claustrophobia may feel too closed in and may not tolerate MRI scanning. If you feel too 
confined in the MRI scanner you can inform the technologist and the MRI scan will be stopped. 
The MRI machine makes loud knocking sounds when it is scanning. Because of this you will be 
asked to wear earplugs while getting your MRI scan. The earplugs minimize discomfort from 
noise and keep the MRI noise within the safety range. 
 
The contrast agent you will receive is FDA-approved and used routinely for MRI exams. It 
contains a material called gadolinium, a rare metal. About 1 in 100 people may notice 
discomfort, tingling or warmth in the lips, metallic taste in the mouth, tingling in the arm, 
nausea, or headache. These side effects usually last only for a short time and go away as your 
body adjusts to the gadolinium. There is a small risk of an allergic reaction to gadolinium. 
However, a severe allergic reaction occurs in less than one in 300,000 people. The needle placed 
in your vein to give you the gadolinium may cause minor pain, bruising and/or infection at the 
injection site. Studies have shown that small amounts of gadolinium may remain in the body of 
patients who have received these injections. The effect of this, if anything, is unknown at this 
time. 
 
Radiation Risk 
You will be exposed to radiation from the CT scans of your tumor. The amount of radiation has a 
low risk of harmful effects. 
 
Biopsy Risks 
The risks of the tumor biopsy procedure are mainly pain, bleeding, and infection. Depending on 
the location of the tumor, there is a small risk of injury or damage to the nearby organs or tissues. 
Your doctor may use a local anesthetic and/or a medicine to calm your nerves before or during 
the biopsy procedure; there is a possibility that an allergic reaction to the anesthetic may occur.  


 
 
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There is also a risk of scarring at the biopsy site, and there is a possibility of tumor cells 
spreading from the tumor into the nearby area. Your doctor will explain the procedure to you and 
discuss these risks with you. 
 
Complications from biopsies can be life threatening. As with any interventional procedure, other 
potentially serious complications from bleeding or organ damage may occur. These might 
require additional surgical intervention. 
 
The risks described above may be different for you depending on your health and the location of 
the tumor. These risks should be discussed with your study doctor or person performing the 
biopsy. 
 
You will be exposed to radiation during the CT-guided biopsies. The amount of radiation has a 
low risk of harmful effects. 
 
Bone and Bone Marrow Sample 
If your doctor wants you to be tested for Myelodysplastic Syndrome and Acute Myeloid 
Leukemia (MDS/AML), then you will have a bone/bone marrow biopsy collected for testing by 
a local haematologist. Your local haematologist may ask you to sign another consent form before 
the procedure. This procedure may take about 30 minutes, including the preparation of the 
biopsy site.  Before the procedure, you will be given local anaesthesia or IV sedation (to numb 
the place where the biopsy will be taken).   A needle will be placed either into your breastbone or 
a pelvic bone to obtain the liquid bone marrow sample.  A second sample will be also collected 
by removing a small piece of the bone along with the marrow inside the bone. The doctor will be 
sure that you have recovered from the anaesthesia before you leave the doctor’s office.  Risks of 
the procedure may include a brief sharp pain during the procedure, bleeding (if you have low 
platelets (blood cells)), infection or discomfort at the site of biopsy. 
 
Genetic Testing Risks 
This study involves testing your DNA, which is the genetic information you inherited from your 
parents (also known as genetic testing). You will not be notified of the genetic test results and 
they will not be put into your medical record. 
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes 
it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the 
following ways:  
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  
• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.  


 
 
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• Employers with 15 or more employees may not use your genetic information when 
making a decision to hire, promote, or fire you or when setting the terms of your 
employment.  
All health insurance companies and group health plans must follow this law.  
 
Be aware that this new Federal law doesn’t protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
 
Standard of Care Risks 
Your doctor will discuss the risks of tests and procedures that are part of your standard clinical 
care. 
 
Confidentiality Risk 
As with all research, there is a chance that confidentiality could be compromised; however, we 
take precautions to minimize this risk.  
 
Additional Costs 
Taking part in this research study may lead to added costs to you. In some cases, insurance will 
not pay for services ordinarily covered because these services were performed in a research 
study. You should check with your insurance company to see what services will be covered and 
what you will be responsible to pay. 
 
Unknown Risks 
There may be other side effects or risks that we cannot predict. Many side effects may go away 
shortly after the study medication or procedure is stopped. However, in some cases they can be 
serious, long-lasting, permanent, and/or fatal. 
 
 
Are there reasons you might leave this research study early? 
 
 
If you decide to stop taking part in the study for any reason, we will ask you to make a final 
study visit. At this visit, we will: 
• Ask you about side effects or health problems since your last visit 
• Draw a blood sample for research 
• Review your study drug diary 
• Collect any unused study drug 
 
You may decide to stop at any time. You should tell the Principal Investigator if you decide to 
stop and you will be advised whether any additional tests may need to be done for your safety.  


 
 
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In addition, the Principal Investigator or Mayo Clinic may stop you from taking part in this study 
at any time: 
• if it is in your best interest,  
• if you don’t follow the study procedures,  
• if the study is stopped.  
 
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
We will tell you about any new information that may affect your willingness to stay in the 
research study. 
 
 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will 
offer care for research-related injuries, including first aid, emergency treatment and follow-up 
care as needed. 
 
Who will pay for the treatment of research related injuries? 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance. Treatment costs for research-related injuries not covered by your insurance will be 
paid by Mayo Clinic. 
 
 
What are the possible benefits from being in this research study? 
 
 
Others with pancreatic cancer may benefit in the future from what we learn in this research 
study. 
 
 
 


 
 
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What alternative do you have if you choose not to participate in this 
research study? 
 
 
You don’t have to be in this study to receive treatment for your condition. For example: 
• You may choose to try another treatment option determined by your doctor.  
• You may choose to take part in a different study, if one is available. 
• You choose not to receive treatment. 
 
For patients who have only had one prior line of therapy for pancreatic cancer, there are other 
chemotherapy regimens with demonstrated benefit for second line treatment. You and your 
oncologist should discuss pros and cons to these alternatives. 
 
Talk to the Principal Investigator or your doctor if you have any questions about any of these 
treatments or procedures. 
 
 
What tests or procedures will you need to pay for if you take part in this 
research study? 
 
 
You won’t need to pay for tests and procedures which are done just for this research study. These 
tests and procedures are: 
• Supply and administration of the study drugs (niraparib and dostarlimab) 
• Collection and testing of blood samples for research 
• Collection and testing of tissue samples for research 
 
However, you and/or your insurance will need to pay for all other tests and procedures that you 
would have as part of your clinical care. These tests and procedures are: 
• Physical exams and health assessments (including blood tests conducted as part of your 
clinical care) 
• Scans of your tumor (CT, MRI, or bone scans) 
• Pregnancy testing 
 
You will also be responsible for any co-payments and deductibles.  
 
If you have billing or insurance questions call Patient Account Services at the telephone 
number provided in the Contact Information section of this form. 
 


 
 
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October 19, 2023 
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{{$QNS1Y}} 
{{$QNS1N}}
{{$QNS1IN}} 
{{$QNS1D                                                                                                    }} 
 
Will you be paid for taking part in this research study? 
 
 
You won’t be paid for taking part in this study. 
 
There is a very small chance that some commercial value may result from the use of your 
sample. This could include new products like a drug or a test to diagnose a disease. If that 
happens, you will not be offered a share in any profits. 
 
 
Will your information or samples be used for future research? 
 
 
Blood and tissue samples will be used for research related to the study and study drug. These 
samples may be analyzed at Mayo Clinic or sent externally to complete the testing. Research 
results will not be returned to you. 
 
We would also like to keep your sample for future research. You can still take part in this current 
study even if you don’t want your sample used for future research. If you agree to give your 
sample, it will be the property of Mayo Clinic. 
 
Other researchers at Mayo Clinic who aren’t involved with this study may ask to use your 
sample for future research. Researchers at other institutions may also ask for a part of your 
sample for future studies. If you approve release of your sample by checking ‘yes’ below, Mayo 
may send the sample(s) and some information about you to researchers who request them, but 
Mayo will not send your name, address, phone number, social security number, or any other 
identifying information with the sample. Your sample will be sent to researchers in a coded 
format, which protects your identity. 
 
Some future studies may examine your DNA, which is the genetic information you inherited 
from your parents (genetic testing). The Principal Investigator may contact you if there are 
findings which may be useful for your health care. You would be given general information on 
the potential risks, benefits, and costs of choosing to learn about the findings. 
 
Please read the following statements and mark your choices: 
1.  I permit my sample to be stored and used in future research of pancreatic cancer at Mayo 
Clinic: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 


 
 
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{{$QNS2D                                                                                                  }} 
{{$QNS3Y}} 
{{$QNS3N}}
{{$QNS3IN}} 
{{$QNS3D                                                                                                     }} 
{{$QNS4Y}} 
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{{$QNS4IN}} 
{{$QNS4D                                                                                                     }} 
{{$QNS5Y}} 
{{$QNS5N}}
{{$QNS5IN}} 
{{$QNS5D                                                                                                     }} 
2.  I permit my sample to be stored and used in future research at Mayo Clinic to learn about, 
prevent, or treat any other health problems:  
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
3.  I permit Mayo Clinic to give my sample and related information to researchers at other 
institutions:  
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
4.  I permit Mayo Clinic to conduct an additional biopsy at the end of study treatment to 
collect tissue for research testing purposes: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
Optional Research Biopsy 
If your cancer returns, we would like to obtain a portion of the biopsy tissue for research testing. 
These tests will be done in order to understand how your cancer responds to treatment. It is 
hoped that this will help investigators better understand how to make this therapy more effective. 
The results of these tests will not be sent to you or your study doctor and will not be used in 
planning your care. These tests are for research purposes only, and you will not have to pay for 
them. 
 
You can take part in the treatment portion of this study without taking part in these research 
laboratory tests. 
 
5.   If my cancer comes back, I agree to an additional, optional biopsy to provide tissue 
sample(s) from my biopsy to Mayo Clinic for research testing planned as part of this study. 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
There is a very small chance that some commercial value may result from the use of your 
donated sample. If that happens, you won’t be offered a share in any profits. 
 
You may request to have your sample destroyed by writing to the Principal Investigator. 
The address is found in the “Contact Information" section of this consent form. 
 
Your information and/or samples would be removed from any repository where they are stored, 
if possible. Information and/or samples already distributed for research use will not be retrieved. 
Because we cannot predict how your sample will be used in the future, we cannot promise that 
samples can be retrieved and destroyed.  


 
 
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How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. All of your research samples will be labeled with a code 
number and kept in locked storage.  
 
Only your study doctor will be able to link your samples with your identity. No one working 
with your samples will know your identity. If the results of the research are made public, 
information that identifies you will not be used. 
 
During this research, information about your health will be collected.  Under Federal law called 
the Privacy Rule, health information is private.  However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so.  Information about you and your health cannot be used in this 
research study without your written permission.  If you sign this form, it will provide that 
permission (or “authorization”) to Mayo Clinic. 
 
Your health information may be collected from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and 
questionnaires. 
 
Your health information will be used and/or given to others to: 
• Do the research. 
• Report the results. 
• See if the research was conducted following the approved study plan, and applicable rules 
and regulations. 
 
Your health information may be used and shared with: 
• Mayo Clinic research staff involved in this study.  
• Other Mayo Clinic staff involved in your clinical care. 
• Researchers involved in this study at other institutions. 
• The sponsor(s) of this study and the people or groups hired by the sponsor(s) to help 
perform this research. 
• The Mayo Clinic Institutional Review Board that oversees the research.  
 


 
 
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• Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research. 
• A group that oversees the data (study information) and safety of this research.  
 
How your information may be shared with others: 
While taking part in this study, you will be assigned a code that is unique to you, but does not 
include information that directly identifies you. This code will be used if your study information 
is sent outside of Mayo Clinic. The groups or individuals who receive your coded information 
will use it only for the purposes described in this consent form. 
 
If the results of this study are made public (for example, through scientific meetings, reports or 
media) information that identifies you will not be used. 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic may be 
allowed to review your health information included in past, present, and future medical and/or 
research records. This review may be done on-site at Mayo Clinic or remotely (from an off-site 
location). These records contain information that directly identifies you. However, the 
individuals will not be allowed to record, print, copy (using paper, digital, photographic or other 
methods), or remove your identifying information from Mayo Clinic. 
 
Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will 
remain private and it may no longer be protected by the Privacy Rule. 
 
 
Your Rights and Permissions 
 
 
Participation in this study is completely voluntary. You have the right not to participate at all.  
Even if you decide to be part of the study now, you may change your mind and stop at any time.  
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
Deciding not to participate or choosing to leave the study will not result in any penalty.  Saying 
‘no’ will not harm your relationship with your own doctors or with Mayo Clinic. 
 
If you cancel your permission for Mayo Clinic to use or share your health information, your 
participation in this study will end and no more information about you will be collected; 
however, information already collected about you in the study may continue to be used. 


 
 
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You can cancel your permission for Mayo Clinic to use or share your health information at any 
time by sending a letter to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN:  Notice of Revocation of Authorization 
201 Building 4-60 
200 1st Street SW 
Rochester, MN  55905 
 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research 
Participant Advocate at: researchparticipantadvocate@mayo.edu. 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission for Mayo Clinic to use and share your health information lasts until the end of 
this study, unless you cancel it. The study does not end until all data has been collected, checked 
(or audited), analyzed, and reported. Because research is an ongoing process, we cannot give you 
an exact date when the study will end. Sometimes this can be years after your study visits and/or 
activities have ended. 
 
There is no expiration or end date related to the Sponsor’s use of your health information 
received from Mayo Clinic as part of this study. 
 
 
 


 
 
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{{$prtPartName                                          }} 
{{$dteParticipantSig                                }} 
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{{$sigParticipant                    }} 
{{$prtPOCName                                       }} 
{{$dtePOCSig                                        }} 
{{$sigPOC                                 }} 
 
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Prot_SAP_002.pdf: 
 
 
 
 
 
MC1841 / 18-003525 
 
 
Phase II Study of Niraparib and TSR-042 in Patients with 
Germline or Somatic BRCA1/2 and PALB2-related Pancreatic 
Cancer 
 
 
NCT04493060 
 
 
Document Date: 05/18/2021 


MC1841 
Protocol Version Date: 18May2021 
Mayo Clinic Cancer Center 
MC1841: Phase II Study of Niraparib and TSR-042 in Patients with Germline or Somatic BRCA1/2 
and PALB2-related Pancreatic Cancer 
Sponsor/Principal Investigator: Robert R McWilliams MD 
Mayo Clinic 
200 First Street SW 
Rochester MN 55905 
507/284-2511 
Co-Principal Investigators: 
Kabir Mody MD 
Mayo Clinic 
4500 San Pablo Rd 
Jacksonville FL 32224 
904/953-2790 
Daniel H Ahn DO 
Mayo Clinic  
13400 East Shea Boulevard  
Scottsdale AZ 85259  
480/301-8000 
Co-Investigators: 
Fergus J Couch PhD√ 
Haidong Dong MD PhD √ 
Svetomir N Markovic MD PhD√ 
Statistician: 
Nathan R Foster MS√ 
FDA IND #:  141914 
Trial Supported by:  
Funding: GSK  
Drug Availability:  
Supplied Investigational Agents: niraparib, TSR-042 
Drug Company Supplied: niraparib, TSR-042 (GSK) 
√Study contributor(s) not responsible for patient care 
Document History 
Effective Date 
Amendment 1 
29Dec2020 
Activation 
29Dec2020 
Amendment 2 
pending 
 
 
 
 
 
 
 
 
 
 


MC1841 
2 
Amendment 2 
Protocol Version Date: 18May2021 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions 
/adjustments, dose modifications, 
adverse events, forms completion 
and submission 
Sharon F Solinger 
Quality Assurance Specialist 
Phone: 507/266-1714 
E-mail: solinger.sharon@mayo.edu 
Drug administration, infusion 
pumps, nursing guidelines 
Lisa Kottschade, APRN CNP 
Phone: 507/266-3570 
E-mail: kottschade.lisa@mayo.edu  
Forms completion and submission  Angela Gosch 
MCR Data Coordinator 
Phone: 507/538-0415 
Email: gosch.angela@mayo.edu  
Nhi Baltazar 
MCR Clinical Coordinator 
Phone: 507/422-6953 
Email: baltazar.nhi@mayo.edu  
LaTarra Davis 
MCF Data Coordinator 
Phone: N/A 
Email:Davis.LaTarra@mayo.edu  
Kaitlin Marrache 
MCF Clinical Coordinator 
Pager: 904/953-4404 
Email:marrache.kaitlin@mayo.edu 
Vincent Vu 
MCA Data Coordinator 
Phone: 480/342-1740 
Email: Vu.Vincent@mayo.edu  
Morgan Hope 
MCA Clinical Coordinator 
Phone: 480/342-6010 
Email: Hope.Morgan@mayo.edu 
Protocol document, consent form, 
regulatory issues 
Mitchell Perrizo, Senior Research Protocol Specialist (Rochester) 
Phone: 507/284-9104 
Email: perrizo.mitchell@mayo.edu 
Laurie Mihalik, Senior Research Protocol Specialist (Arizona) 
Phone: 480/342-3256 
Email: mihalik.laurie@mayo.edu  
Marnisha James, Research Protocol Specialist (Florida) 
Phone: N/A 
Email: James.Marnisha@mayo.edu 
Non-paraffin biospecimens 
Biospecimens Accessioning and Processing (BAP) Service Center 
Website: biospecimens-accessioning-processing-rst  
Phone: 507/538-7898 
Serious Adverse Event Reporting Patricia G McNamara, SAE Coordinator 
E-mail: RSTP2CSAES@mayo.edu  
*No waivers of eligibility allowed 


MC1841 
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Protocol Version Date: 18May2021 
Table of Contents 
MC1841: Phase II Study of Niraparib and TSR-042 in Patients with Germline or Somatic BRCA1/2 and 
PALB2-related Pancreatic Cancer ................................................................................................................. 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 11 
3.0 
Registration Patient Eligibility .................................................................................................... 12 
4.0 
Test Schedule .............................................................................................................................. 16 
5.0 
Stratification Factors OR Grouping Factor: ................................................................................ 18 
6.0 
Registration/Randomization Procedures ..................................................................................... 18 
7.0 
Protocol Treatment ...................................................................................................................... 20 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 21 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 27 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 31 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 43 
12.0 
Descriptive Factors ..................................................................................................................... 51 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 51 
14.0 
Body Fluid Biospecimens ........................................................................................................... 53 
15.0 
Drug Information ........................................................................................................................ 55 
16.0 
Statistical Considerations and Methodology ............................................................................... 59 
17.0  
Pathology Considerations/Tissue Biospecimens ......................................................................... 63 
18.0 
Records and Data Collection Procedures .................................................................................... 65 
19.0  
Budget ......................................................................................................................................... 66 
20.0 
References ................................................................................................................................... 66 
Appendix I 
ECOG Performance Status ............................................................................................... 68 
Appendix II 
Patient Medication Diary .................................................................................................. 69 
Appendix III 
Examples of confirmed progression ................................................................................. 70 
Appendix IV 
PAXgene Manufacturer’s Recommendations ................................................................... 71 
Appendix V 
Patient Blood Pressure and Heart Rate Monitoring Diary ................................................ 75 
.


MC1841 
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Protocol Version Date: 18May2021 
Schema 
 
Registration 
 
 
↓ 
 
 
Treatment with niraparib and TSR-
042 
 
 
↓ 
 
 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
 
↓ 
 
 
Clinical Follow-up 
 
 
↓ 
 
 
Survival Follow-up 
 
Cycle = 21 days  
Treatment with niraparib and TSR-042 will continue until confirmed progressive disease according to 
iRECIST, clinical progression, intolerable adverse effects or patient/investigators decision, whichever is 
applicable. 
 
Generic name: niraparib 
Brand name(s): ZEJULA® 
Availability: Investigational 
Generic name: TSR-042, dostarlimab 
Brand name(s): N/A 
Availability: Investigational 
 
 
 


MC1841 
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1.0 
Background  
Pancreatic cancer is currently the 4th leading cause of cancer death in the US and will soon cause 
the death of more Americans than breast cancer. Therapies are very limited and largely 
ineffective. In our own data sequencing 3,000 patients with pancreatic cancer (accepted in 
JAMA), approximately 3% of pancreatic cancer patients harbor germline mutations in DNA 
repair genes such as BRCA1/2 and PALB2, and are therefore potential candidates for PARP-
inhibitor therapy. In addition, somatic mutations in Homologous Recombination Repair (HRR) 
genes can confer sensitivity as well, and have been reported to double the number of patients 
potentially eligible for such therapy. Recently, Waddell et al defined 5 subtypes of pancreatic 
adenocarcinoma, with BRCA-like tumors, categorized as such by genomic instability, comprising 
15-20% of pancreatic cancer, with the latter identified as a potential target for immunotherapy 
strategies. (1) In breast and ovarian BRCA-mutant tumors, neoantigen load alone did not 
correlate with T-cell infiltration, suggesting that other therapies to disrupt the tumor 
microenvironment may be necessary to induce an immune response. (2) The Keynote-162 study 
of niraparib and pembrolizumab has validated this approach, with early reports of impressive 
efficacy. Of the first 8 platinum-resistant ovarian cancer patients, 4 had confirmed responses, and 
4 had stable disease. One triple negative breast cancer patient (of 5) had SD for 10 cycles. (3) 
Although unselected trials in pancreatic cancer with immunotherapy alone have yet to be 
successful, we hypothesize that induced genetic variation with PARP inhibition disrupting the 
tumor microenvironment and increasing neoepitope expression can sensitize tumors to immune 
checkpoint inhibition. 
We are currently funded by a Project in our NCI Pancreas SPORE grant to more fully define 
genetic identification of this subset of patients and develop a therapeutic strategy. We have 
developed preliminary data (Figure 1) with RNAseq suggesting that potent PARP inhibition (in 
this case, talazoparib) is associated with gain of novel mutations in pancreas cell lines, even 
compared to cisplatin alone, or irinotecan alone. In addition, double-stranded break repair 
deficient tumors are associated with increased expression of genes involved in antitumor 
immunity, including CD8 positive T cell activators and regulatory molecules, in a similar pattern 
of that seen with MMR deficient tumors. (4)  
We propose that a combination of PARP inhibition and anti-PD1 therapy has valuable therapeutic 
potential in this subset of pancreatic cancer. The strong activity seen in the dose escalation phase 
of Keynote 162 in refractory ovarian and TNBC cancer hold promise for pancreatic cancer as 
well, as long as properly selected patients are enrolled. No reports have been published for the 
combination of PARP inhibition and checkpoint blockade in pancreatic cancer to date. However, 
given the potential for neoepitope formation in patients with defective HRR deficiency upon 
exposure to PARP inhibition, we propose that there could be an additive or synergistic effect of 
the combination in HRR deficient pancreatic cancer. HRR deficient pancreatic cancer has largely 
been defined to date based on mutations in well-established genes such as BRCA1/2 and PALB2. 
However, more DNA repair associated genes are becoming associated with risk for pancreatic 
cancer and may well impact tumor phenotype.  
Therefore, we propose this single arm-cohort study. The goal would be to evaluate the 
combination of niraparib and TSR-042 in patients with germline or somatic mutations in 
BRCA1/2 or PALB2.  


MC1841 
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Pre-clinical data: 
There are in vitro studies to suggest that the immunotherapy in combination with PARP 
inhibition provides synergy.(Higuchi, Flies et al. 2015) In a syngeneic model of breast cancer, 
PARP inhibition was shown to increase PD-L1 expression (Figure 1 from Jiao et al). (Jiao, Xia et 
al. 2017) Additionally in the same set of experiments, to corroborate these findings of extent of 
PARP inhibition (through measurement of PARylation enzyme activity, which are inhibited by 
PARP inhibitors), showed an inverse correlation (Figure 2 – see below). This supports that high 
level of PARP activity suppresses PD-L1 expression or stated another way, PARP inhibition was 
led to increased PD-L1 expression in these tumors.(Jiao, Xia et al. 2017) 
 
 


MC1841 
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Protocol Version Date: 18May2021 
 
Figure 1: PARPi upregulates PD-L1 expression in xenograft tumors. A–C, BT549 (A), SUM149 
(B), andMDA-MB-231 cells (C)were inoculated into the mammary fad pad of nude mice, and the 
mice with established tumors were treated with olaparib or rucaparib. Tumors were then isolated 
to evaluate PD-L1 expression by immunoblotting (A and B) or IHC staining (C). Black 
arrowheads, detected PD-L1 signals. Scale bar, 50 mm.  
[From Open Access Article Jiao et al: (Jiao, Xia et al. 2017)] 
 


MC1841 
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Figure 2: Inverse correlation between PAR and PD-L1 in surgical specimens of breast cancer. 
Top, representative images of IHC staining of PAR and PD-L1 in human breast cancer tissues (n 
¼ 116). Scale bar, 50 mm; bottom, correlation analysis between PAR and PD-L1 was analyzed 
using the Pearson c2 test (P ¼ 0.02). A P value of less than 0.05 was considered to be statistically 
significant. 
[From Open Access Article Jiao et al: (Jiao, Xia et al. 2017)] 
 
PARP inhibition combinatorial strategies: 
PARP inhibitors are being explored in various clinical trials in combination with various other 
classes of drugs.(Drean, Lord et al. 2016) These include chemotherapies, targeted therapies, novel 
targeted therapies, as a radiation sensitizer, endocrine therapies and most recently several trials 
exploring the combination with immunotherapies.(Schaefer, James et al. 2011, Drean, Lord et al. 
2016, Papa, Caruso et al. 2016) This as noted above has been of particular interest in patients with 
homologous-repair related breast and/or ovarian cancers as well as increased interest to study this 


MC1841 
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now in prostate and pancreas cancers.(Javle, Golan et al. 2016, Ang and Tan 2017, Golan and 
Javle 2017, Ramakrishnan Geethakumari, Schiewer et al. 2017, Turk and Wisinski 2018) 
Furthermore, there is some data to support use of immunotherapy for BRCA-related tumors 
whereby immunotherapy alone could potentially be effective.(Matsuo, Spragg et al. 2018) The 
addition of PARP inhibition to further help augment responses in an aggressive disease like 
pancreas cancer would be of further value with rationale to supports its use as outlined. Figure 3 
from a recent review summarizes some of the ways how some of the ‘DNA-damaging’ drugs 
including PARP inhibition can affect the immunogenicity of tumors.(Brown, Sundar et al. 2018)    
 
Figure 3: Mechanisms by which DNA damaging agents affect the immunogenicity of tumors 
From Open Access Article (Brown, Sundar et al. 2018) 
 
Current PARP inhibitor and immunotherapy combination trials: 
At present, there are several clinical trials trying to explore this combination in various tumor 
types where HR-deficiency plays a role. These include but are not limited to the following: 


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Protocol Version Date: 18May2021 
 
From Open Access Article: (Brown, Sundar et al. 2018) Ongoing combination trials with DDR 
and immune checkpoint inhibitors (www.clinicaltrials.gov) 
 
Resources available: 
Mayo Clinic Cancer Center operates in 3 physical sites – Rochester, MN, Phoenix, AZ, and 
Jacksonville, Fl. We have pancreatic cancer expertise at all 3 sites, with annual unique pancreatic 
adenocarcinoma patients seen upwards of 700 patients. TEMPUS, FoundationOne, Carris or 
equivalent testing will be performed on patients as part of standard of care testing. We anticipate 
5-8% of patients to be eligible for cohort based on our experience and published data on 
frequency of BRCA1/2, and PALB2 mutations. Given genomic testing is now done as part of 
standard of care, we anticipate rapid accrual. 


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All 3 sites are fully capable of research blood draws and biopsies. Tissue will be managed in 
FFPE, which will not require special handling or shipping. Fresh samples would also be collected 
for xenograft and/or organoid development and potentially RNA-Seq. There is one Mayo Clinic 
IRB and Cancer Center approval process, and though all 3 sites contract independently, there is 
an internal requirement for budgets to align within a tight range of one another. We have recently 
hired a program coordinator for our pancreas cancer group to speed timelines for trial 
development.  
Publication plan: 
ASCO/ASCI GI, Journal of Clinical Oncology likely in 2019/20 
 
2.0 
Goals  
2.1 
Primary Goal 
To determine antitumor activity as measured by disease control rate at 12 weeks 
(DCR12) as assessed using iRECIST in select homologous recombination repair 
(HRR) deficient pancreatic cancer patients with HRR deficiency (defined as 
mutations in BRCA 1/ 2, or PALB2)  
2.2 
Secondary Goals 
2.21 
To assess adverse events according to the current National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) and 
other safety parameters. 
2.22 
To assess the time to next treatment (TTNT), objective response rate 
(ORR), time to and duration of response and duration of confirmed stable 
disease according to iRECIST. 
2.23 
To assess progression-free survival. 
2.24 
To assess overall survival. 
2.3 
Correlative Research 
2.31 
To assess germline DNA and serum markers of immune response. 
2.32 
To determine changes in circulating tumor DNA (ctDNA) profile after 
therapy with a PARPi and a PD-1 inhibitor. 
2.33 
To study mechanisms of resistance in ctDNA profile after therapy with a 
PARPi and a PD-1 inhibitor. 
2.34 
To assess the tumor microenvironment for immune related changes 
(immune infiltration, PD-L1 and PD-1 expression, tumor-infiltrating 
lymphocytes [TIL]). 
2.35 
To assess genetic profile of the tumor pre- and post-treatment. 
2.36 
To determine changes in the cytokine profile pre- and post-treatment. 
 


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3.0 
Registration Patient Eligibility 
3.1 
Registration - Inclusion Criteria 
3.11 
Presence of either a germline deleterious mutation or somatic deleterious 
mutation in any one of the genes in our proposed gene-panel as 
determined by any of the commercially available or institutional testing 
platforms. 
Note: The somatic mutation could be either on a tissue-based test or the 
circulating tumor DNA (ctDNA)-based assay. The 6 genes that would 
determine eligibility would be: BRCA1/2, PALB2, BARD1, RAD51c, 
RAD51d.  
3.12 
Provide written informed consent 
3.13 
Age ≥ 18 years 
3.14 
Histological/cytological confirmation of diagnosis of metastatic pancreatic 
ductal adenocarcinoma 
3.15 
At least one but no more than two prior lines of systemic therapy for 
metastatic disease (maintenance therapy is not considered a line of 
treatment).  
Note: Patients who have not had any prior chemotherapy can refuse 
chemotherapy and be considered eligible. This refusal and their reason for 
refusal would have to be documented.  
3.16 
Received a platinum agent as part of first or second line treatment (unless 
contraindicated). 
3.17 
ECOG performance status of 0 or 1 
3.18 
Adequate hematologic and end-organ function as evidenced by the 
following ≤14 days prior to registration: 
a. Serum creatinine ≤1.5 x ULN or eGFR ≥60mL/min using the 
Cockroft-Gault Equation  
b. Hemoglobin ≥9.0 g/dL 
c. Absolute neutrophil count ≥1500/μL 
d. Platelets ≥100x109/L 
e. Total bilirubin ≤1.5 x ULN, (2.0 x ULN for subjects with Gilbert’s 
disease) 
f. Aspartate Transaminase (AST) and Alanine Transaminase (ALT) 
≤2.5x ULN (for subjects with hepatic metastases ≤5 x ULN) 
Note: One time repeat testing to meet eligibility is allowed. If more 
testing is required, discuss with PI. 
g. International normalized ratio (INR) or prothrombin time (PT) ≤1.5× 
ULN unless patient is receiving anticoagulant therapy as long as PT or 
partial thromboplastin (PTT) is within therapeutic range of intended 
use of anticoagulants. Activated partial thromboplastin time (aPTT) 
≤1.5× ULN unless patient is receiving anticoagulant therapy as long as 


MC1841 
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Protocol Version Date: 18May2021 
PT or PTT is within therapeutic range of intended use of 
anticoagulants 
3.19a Evaluable or measurable disease per iRECIST (See Section 11.0). 
3.19b Life expectancy of ≥3 months 
3.19c Willingness to consent to translational studies 
3.19d Willingness to undergo repeat biopsies of tumor lesions amenable to 
biopsy.  
Note: While biopsies are mandatory, subjects are allowed to participate if 
no lesions are amenable to biopsy, or if biopsy is not possible due to 
safety.  
3.19e Willingness to not donate blood during the study or for 90 days after the 
last dose of study treatment 
3.19f Willingness to not breastfeed during the study or for 90 days after the last 
dose of study treatment 
3.19g Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
3.2 
Registration - Exclusion Criteria 
3.21 
Known hypersensitivity to any component of study treatments (either 
niraparib and/or TSR-042 or similar medications).  
3.22 
Prior treatment with the combination of PARP inhibition and 
immunotherapy (either CTLA-4 or anti-PD1/PD-L1 therapies). Prior 
treatment consisting of monotherapy with either PARP inhibitors and/or 
with immunotherapy are allowed. Treatment with PARPi or PD1 inhibitor 
as the most recent treatment prior to enrollment is not allowed.   
3.23 
Patient experienced ≥ Grade 3 immune-related AE with prior 
immunotherapy, with the exception of non-clinically significant lab 
abnormalities. 
3.24 
Radiotherapy ≤ 2 weeks prior to first study treatment or radionuclide 
treatment ≤ 4 weeks of first study treatment. 
3.25 
Live attenuated vaccine administration within 30 days prior to registration 
and/or expected during study period. 
3.26 
Known brain metastases, uncontrolled seizure disorder, or active 
neurologic disease which in the opinion of the investigator would impede 
participation within the trial. Subjects with treated brain metastases are 
allowed to enroll. 
3.27 
Allogenic bone marrow transplantation or high-dose chemotherapy 
requiring hematopoietic stem cell rescue. 
3.28  Received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to 
registration. 


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NOTE: patients are also deemed ineligible if they have received a 
transfusion ≤ 4 weeks prior to first dose of niraparib. 
3.29a  Received colony-stimulating factors (eg, granulocyte colony-stimulating 
factor, granulocyte macrophage colony-stimulating factor, or recombinant 
erythropoietin) ≤ 4 weeks prior to registration. 
NOTE: patients are also deemed ineligible if they have received 
colony-stimulating factors ≤ 4 weeks prior to first dose of niraparib. 
3.29b  Known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to 
prior chemotherapy that persisted > 4 weeks and was related to the most 
recent treatment. 
3.29c  Known history of myelodysplastic syndrome (MDS) or acute myeloid 
leukemia (AML) 
3.29d ≤ 4 weeks since receiving treatment with another investigational drug, or 
anti-cancer therapy, or within a time interval less than at least 5 half-lives 
of the investigational agent (whichever is shorter), or insufficient recovery 
(to the judgement of the investigator) from adverse events due to such a 
previously administered agent, except for alopecia prior to initiating 
protocol therapy. Bisphosphonate therapy and RANKL inhibitors are not 
considered anti-cancer therapy.  
3.29e Inadequate recovery from toxicity and/or complications from previous 
interventions, including due to major surgery to the judgement of the 
investigator. Minor surgery allowed up to 3 weeks from registration.  
3.29f Primary or secondary immunodeficiency, including immunosuppressive 
disease, and immunosuppressive doses of corticosteroids (e.g., prednisone 
> 20 mg per day during 2 weeks prior to first study treatment) or other 
immunosuppressive medications at dose levels that to the judgement of the 
investigator would preclude participation within the past 4 weeks prior to 
registration. Subjects with HIV who are stable on highly active 
antiretroviral therapy (HAART) will not be excluded. 
3.29g Participant has known active hepatitis B (e.g., hepatitis B surface antigen 
[HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic 
acid [qualitative] is detected). 
3.29h  Pregnant or lactating. 
3.29i Clinically significant, active, bacterial infections that, to the judgement of 
the investigator makes it undesirable for the subject to participate in the 
study. 
3.29j Persons of childbearing potential (POCBP) or those capable of causing 
pregnancy whose sexual partners are POCBP who are unwilling or unable 
to use an effective method of contraception for at least 1 month prior to 
study entry, for the duration of the study, and for at least 180 days after the 
last dose of study drug. 


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Nonchildbearing potential is defined as follows (by other than medical 
reasons): 
• ≥45 years of age and has not had menses for >1 year 
• Patients who have been amenorrhoeic for <2 years without history 
of a hysterectomy and oophorectomy must have a follicle 
stimulating hormone value in the postmenopausal range upon 
screening evaluation 
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal 
ligation. Documented hysterectomy or oophorectomy must be 
confirmed with medical records of the actual procedure or 
confirmed by an ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure, otherwise the patient must 
be willing to use an adequate barrier method throughout the study, 
starting with the screening visit through 180 days after the last 
dose of study treatment. Information must be captured 
appropriately within the site’s source documents. Note: Abstinence 
is acceptable if this is the established and preferred contraception 
for the patient. 
3.29k History or active TB (Bacillus Tuberculosis) that in the investigator’s 
opinion would preclude participation within the study. 
3.29l Any gastro-intestinal conditions that to the judgement of the investigator 
would interfere with the absorption of niraparib. 
3.29m Active, known or suspected unstable auto-immune disease, are excluded 
from this study. Exceptions to this criterion are all auto-immune disease 
that have remained stable within the past 3 months on corticosteroids (≤ 
prednisone 20 mg or equivalent) prior to first study treatment are allowed 
to enroll. Patients with autoimmune diseases that do not require active 
immunosuppression are also allowed to enroll. 
Note: Paraneoplastic disease as a cause of auto-immune phenomenon 
will not be considered as auto-immune disease and are allowed to enroll. 
3.29n Evidence of serious uncontrolled medical disorder, active infection or 
mental disorder that, to the judgement of the investigator, makes it 
undesirable for the subject to participate in the study or that would 
jeopardize compliance with the protocol. Examples include, but are not 
limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal 
cord compression, superior vena cava syndrome, or any psychiatric 
disorder that prohibits obtaining informed consent 
3.29o Prior malignancy which required active systemic treatment within 2 years 
prior to first study treatment. Exceptions are: successfully treated 
squamous cell carcinoma of the skin, superficial bladder cancer, and in 
situ carcinoma of the cervix. Since patients with BRCA 1/2 or PALB2 can 
have other tumors, as long as they have been definitively treated, it would 
not be considered an exclusion.  


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Protocol Version Date: 18May2021 
4.0 
Test Schedule 
4.1 
Test schedule for niraparib and TSR-042 in Pancreatic Cancer 
 
Screening1 
Baseline2 
Cycle 1 
End of Each 
Cycle 
Clinical Follow-up 
(30 days after EOT) 
Tests and procedures 
≤30 days prior to 
Registration 
≤14 days prior to 
Registration 
Day 8 
Day 15 
Window* 
-30 days 
-14 days 
 
±3 days 
±3 days 
±3 days 
±5 days 
History, physical exam, PS3 
 
X 
X 
 
 
X 
X 
Height 
 
X 
 
 
 
 
 
MSI/MMR status4 
 
X 
 
 
 
 
 
Adverse event assessment 
 
X 
X 
X5 
X6 
X 
X 
Pregnancy test7 
 
X 
X 
 
 
X 
X 
Hematology8 
 
X 
X9 
X 
X 
X 
X 
Chemistry10 
 
X 
X11 
 
 
X 
X 
Thyroid Panel 
 
X 
 
 
 
X12 
X 
Urinalysis 
 
X 
X 
 
 
X 
X 
HBV/HCV test 
X 
 
 
 
 
 
 
PT/PTT/INR 
 
X 
 
 
 
X13 
 
 
1 One time retesting of single or multiple screening assessments is allowed per investigator’s discretion in case patient does not meet specified inclusion and exclusion criteria. 
2 Patients are deemed ineligible if they have received a transfusion or colony-stimulating factors ≤ 4 weeks prior to first dose of niraparib. (refer to Sections 3.28 and 3.29a) 
3 Physical examination includes vital signs (temperature, blood pressure, pulse) and weight; and should be performed at screening and on the days treatment is being administered, 
prior to TSR-042 treatment. Blood pressure and heart rate monitoring will be required weekly for the first 2 months of therapy (until C3D15). After the first 2 months of therapy, 
blood pressure and heart rate monitoring only needs to be checked on D1 of each new cycle. For the weekly checks, monitoring at or near home is acceptable. 
4 Collect and record MSI/MMR status (if known) 
5 Cycle 1 Day 8 Adverse Event Assessments will be done clinically but they will not be captured in Rave until end of cycle for worst grade in the cycle. 
6 Cycle 1 Day 15 Adverse Event Assessments will be done clinically but they will not be captured in Rave until end of cycle for worst grade in the cycle. 
7 Persons of childbearing potential: a serum pregnancy test must be performed ≤7 days prior to registration followed by a confirmatory urine pregnancy test ≤7 days prior to study 
treatment start (if necessary). Pregnancy test will be performed before initiating protocol therapy, every 3 cycles (i.e. end of Cycles 3 and 6), and at Clinical Follow-Up visit. 
8 Hematology includes: hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with differential and platelet count. Blood sampling for all safety 
laboratory tests should be performed at the end of the cycle, prior to the next treatment administration. 
NOTE: hematology testing must be performed on Cycle 1 Day 1 
9 Labs do not need to be repeated if collected ≤ 7 days prior to start of Cycle 1. 
10 Chemistry includes: SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin, creatinine, calcium, phosphate, glucose, sodium (Na), and potassium (K). Blood sampling 
for all safety laboratory tests should be performed at the end of the cycle, prior to the next treatment administration. Baseline labs do not need to be repeated if collected ≤ 7 days 
prior to Cycle 1 Day 1. 
11 Labs do not need to be repeated if collected ≤ 7 days prior to start of Cycle 1. 
12 Thyroid panel to include TSH, T3 or FT3, and FT4. Done at the end of Cycle 1 and every 6 weeks thereafter through the remainder of the study (can be done up to 7 days prior 
to TSR-042 administration) and at End of Treatment Visit. 
13 Testing required only when clinically indicated. Will require coagulation tests (PT/PTT/INR) prior to biopsies. 


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Screening1 
Baseline2 
Cycle 1 
End of Each 
Cycle 
Clinical Follow-up 
(30 days after EOT) 
Tests and procedures 
≤30 days prior to 
Registration 
≤14 days prior to 
Registration 
Day 8 
Day 15 
Window* 
-30 days 
-14 days 
 
±3 days 
±3 days 
±3 days 
±5 days 
CA19-9 
 
X 
 
 
 
X 
 
Bone marrow aspirate and 
biopsy 
 
 
X14 
 
Tumor measurement by 
CT, MRI, or Bone Scan15 
X 
 
 
 
 
X 
 
Patient Medication Diary 
 
 
 
 
 
X 
 
Research Collections 
 
 
 
 
 
 
 
Research blood samplesR 
 
 
X 
 
X 
X16 
 
Research tissue samples17, R 
 
 
X 
 
 
X 
 
Cycle = 21 days; R = Research funded 
 
4.2 
Survival Follow-up 
 
Survival Follow-up 
q. 3months 
until PD 
At PD 
After PD  
q. 6 months Death 
New Primary 
Survival Follow-up 
X 
X 
X 
X 
X 
1. If a patient is still alive 5 years after registration, no further follow-up is required 
 
 
14 For any patient diagnosed with MDS/AML while on study, a bone marrow aspirate/biopsy must be completed by a local hematologist. A copy of the hematologist's report of 
aspirate/biopsy findings including a classification according to WHO criteria and other sample testing results related to MDS/AML will be provided to the PI and to GSK. 
Testing completed as part of standard of care is sufficient as long as the methods are acceptable to GSK. Will only be collected once while on study. Upload this documentation 
into the Supporting Documents form within Rave. 
15 All lesions identified at screening should be followed using the same imaging procedure (i.e. either CT or MRI). A bone scan should only be done if clinically indicated and 
performed as needed if the patient develops symptoms or signs of bone disease. If bone metastases are present at screening, bone scans during treatment should be performed in 
addition to and at the same time as the CT/MRI-scans only to confirm complete response. Response should be assessed based on iRECIST criteria. Starting at screening and then 
at 6-week intervals while on study treatment and until immune confirmed objective progressive disease (iCPD) according to iRECIST (See Section 11.0). 
16 Research blood sample collected at end of Cycles 1, 2, 4, and (last day) End of Treatment (ie. progression) (See Section 14.1). 
17 Research tissue sample collection to be performed at baseline (after registration, prior to treatment), end of Cycle 4, and (last day) End of Treatment (ie. progression). The (last 
day) End of Treatment collection is optional. Only allowed to be omitted if there are no lesions amenable to biopsy or if biopsy is not possible due to patient safety. Will require 
coagulation tests (PT/PTT/INR) prior to biopsies. 


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5.0 
Stratification Factors OR Grouping Factor:  
Grouping factor: Platinum unexposed vs platinum exposed but not refractory vs platinum 
resistant. 
6.0 
Registration/Randomization Procedures 
6.1 
Registration /Registering a patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application. The registration/ randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the website. If unable to access the website, call the Mayo 
Clinic Research Site Management Office at (507) 284-2753 between the hours of 8 a.m. 
and 4:30 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page (http://ccswww/training/index.html) and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and an MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MC Research Site Management Office (507) 284-2753. If the patient 
was fully registered, the MC Research Site Management Office staff can access 
the information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Site Management Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Site Management Office 
(fax: 507-284-0885). If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Site Management Office is no longer necessary. 
 
 


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6.4 
Correlative Research Mandatory 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19b, 14.1 and 17.1). 
6.5 
Banking 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of pancreatic cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.6 
Treatment on protocol 
Treatment on this protocol must commence at a Mayo Clinic Rochester/Arizona/Florida 
institution under the supervision of a medical oncologist. 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤30 days after registration. 
6.8 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9b 
Study drug 
Study drug is available on site.  
6.9c 
Blood draw kits (Include if kits must be used for this study) 
Blood draw kit is available on site (See Section 14.0).  
6.9d 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
 


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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
Use actual weight or estimated dry weight if fluid retention 
• 
Quality Control and Definitions of Deviations will be done according to the 
guidelines in Appendix IV 
7.11 
Treatment medication table 
Agent 
Dose Level 
Route 
ReRx 
Days* 
niraparib 
200 mg 
Oral 
Once daily 
1-21 
TSR-042 
Cycles 1-4: 500 mg  
IV 
Q3W 
1 
 
Cycles 5+: 1000 mg 
IV 
Q6W 
1 
*Each cycle is 21 days. 
7.12 
TSR-042 
TSR-042 will be administered via a 30-minute (-5-minute/+15-minute infusion 
window allowed) IV infusion on Day 1 of every 21-day cycle (i.e., Q3W) at 
500 mg for the first 4 doses, followed by 1,000 mg on Day 1 of every other 
21-day cycle (i.e., Q6W) thereafter until the patient discontinues study treatment. 
7.13  
Niraparib 
Niraparib will be administered as a flat-fixed, continuous daily dose. Niraparib 
should be swallowed whole and not opened, crushed or chewed. Food does not 
significantly affect the absorption of niraparib; therefore, niraparib may be taken 
without regard to meals. Participants should take doses at approximately the 
same times each day. Bedtime administration may be a potential method for 
managing nausea. 
Vomited doses should not be made up. 
If a participant misses a dose (greater than 12 hours from normal dosing time) of 
niraparib, they should skip that dose and take their next dose at its regularly 
scheduled time.  
If niraparib is dose reduced, participants should be instructed to continue using 
their current supply at their new dose until their supply has been exhausted.  
Participants must be instructed to return unused study drugs to the site at 
discontinuation or completion of treatment. The site personnel must ensure that 
the appropriate dose of each study drug is administered and that the drug 
accountability is performed and documented. 
7.14 
Drug Release Instructions 
When enrolling a patient to the study, the patient must be enrolled to the Tesaro 
platform (4G Prancer RTSM) to assign vial and bottle numbers for the study 
drugs. To do so, you must: 
• 
Log into the platform at https://tesaro.4gclinical.com/login 
• 
Enroll the patient in the platform 
• 
Enter specific treatment dates for each cycle 
• 
Obtain IV vial numbers and pill bottle numbers at each time point. 
NOTE: pharmacy is unable to dispense medications/treatment without the 
vial and bottle numbers entered in the pharmacy column before investigator 
sign and release 


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If you have any questions, please contact the Tesaro help desk: 
• 
Phone: (855) 299-3496 or (781) 489-3200 
• 
Submit a ticket on Tesaro web page via “4G Clinical Help Center” 
7.2 
Self-administration statement 
Patients can be instructed in administration techniques and granted treatment 
independence with nursing staff approval. 
7.3 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days during treatment, 30 days after end of treatment (clinical follow-up), 
and every 3 months during survival follow-up (see Section 4.2). 
7.4 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
niraparib 
TSR-042 
1* 
200 mg once daily  
(two 100 mg capsules) 
500 mg q3w 
or 1000 mg q6w 
-1 
100 mg once daily  
(one 100 mg capsule) 
500 mg q3w 
or 1000 mg q6w 
*Dose level 1 refers to the starting dose. 
NOTE: If either of drug A or drug B is discontinued, the patient can continue on the other drug, 
unless specified otherwise in the dose modification tables. If both are discontinued, the patient 
will go to survival follow-up (Section 4.2). 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 5.0* 
unless otherwise specified   
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
 
 


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8.2 
Dose Modifications at the of new cycle of therapy (specific for TSR-042) 
Day 1 of Subsequent Cycles 
CTCAE 
System/ 
Organ/ Class 
Adverse Event 
Withhold 
Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Endocrine 
disorders 
Hypophysitis 
2 to 4 
For Grade 2 to 3 AEs, hold TSR-042 for a 
maximum of 6 weeks  
 
OR 
 
Hold TSR-042 until hormonal therapy results in 
return to adequate levels by laboratory values 
and restart dosing when AE resolves to 
Grade 0 to 1. For recurrence or worsening of 
Grade ≥2 hypophysitis after corticosteroid taper 
has been completed and patient is on adequate 
hormone replacement therapy, permanently 
discontinue. For Grade 4 AEs, permanently 
discontinue. 
 
Hyperthyroidism 
3 
Hold TSR-042 for a maximum of 6 weeks or 
until AE resolves to Grade 0 to 1 
 
4 
Permanently discontinue 
Gastrointestinal 
Diarrhea/colitis 
2 to 3 
Hold TSR-042 for a maximum of 6 weeks or 
until AE resolves to Grade 0 to 1 
disorders 
 
4 
Permanently discontinue 
Infections and 
infestations 
Encephalitis 
infection 
(immune-related) 
Any grade 
Permanently discontinue 
Injury, 
poisoning and 
Infusion-related 
reaction 
2a 
Hold TSR-042 for a maximum of 6 weeks or 
until AE resolves to Grade 0 to 1 
procedural 
complications 
3 or 4 
Permanently discontinue 
Investigations 
Alanine 
aminotransferase 
(ALT) increased  
or Aspartate 
aminotransferase  
2 
(AST or ALT >3 
and ≤5 × ULN or 
total bilirubin >1.5 
and ≤3 × ULN) 
Hold TSR-042 for a maximum of 6 weeks or 
until AE resolves to Grade 0 to 1 
 
(AST) increased 
or  
Blood bilirubin 
increased 
3 or 4 
(AST or ALT >5 × 
ULN or total 
bilirubin 
>3 × ULN) 
Permanently discontinue (see exception below)b 


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CTCAE 
System/ 
Organ/ Class 
Adverse Event 
Withhold 
Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Metabolism 
and nutrition 
disorders 
Glucose 
intolerance 
(T1DM) or 
Hyperglycemia 
3 or 4 
hyperglycemia or 
T1DM (associated 
with metabolic 
acidosis or 
ketonuria) 
Hold TSR-042 for a maximum of 6 weeks or 
until appropriately managed patients are 
clinically and metabolically stable per 
investigator’s discretion. 
 
OR 
 
Hold TSR-042 until AE resolves to Grade 0 to 1. 
Renal and 
urinary 
Acute kidney 
injury 
(Renal failure or 
nephritis) 
2 
Hold TSR-042 until AE resolves to Grade 0 to 1 
disorders 
3 or 4 
Permanently discontinue 
Respiratory, 
thoracic and 
Pneumonitis 
2 
Hold TSR-042 until toxicity resolves to Grade 0 
to 1. 
If Grade 2 recurs, permanently discontinue 
mediastinal 
disorders 
 
3 or 4 
Permanently discontinue 
Skin and 
subcutaneous 
Rash  
(acneiform or 
3 
Hold TSR-042until AE resolves to Grade 0 to 1 
tissue disorders maculopapular) 
4 
Permanently discontinue 
Any 
Recurrence of 
AEs after 
resolution to 
Grade ≤1 
3 or 4 
Permanently discontinue 
a Upon resolution within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 to 50 mL/h). Otherwise, TSR-042 will be withheld until symptoms 
resolve, and the patient should be pre-medicated for the next scheduled dose. 
b For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by ≥50% relative to baseline and lasts for at least 1 week, then study treatment should be 
discontinued. 
 
 


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8.3 
Dose Modifications Based on Interval Adverse Events (occurring within a cycle of 
treatment, specific for niraparib) 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
All 
Non-laboratory 
CTCAE* ≥Grade 3 
adverse reaction where 
prophylaxis is not 
considered feasible or 
adverse reaction persists 
despite treatment 
niraparib 
Hold niraparib for a maximum of 28 days 
or until resolution of adverse reaction 
Resume niraparib at a reduced dose per. 
Table 8.1 
 
Blood and lymphatic 
system disorders 
Anemia 
≥Grade 2 
niraparib 
Hold niraparib for a maximum of 28 days 
and monitor blood counts weekly until 
hemoglobin returns to ≥9 g/dL 
Resume niraparib at a reduced dose per 
Table 8.1 
Discontinue niraparib if hemoglobin has 
not returned to acceptable levels within 
28 days of the dose interruption period, or 
if the patient has already undergone dose 
reduction to 100 mg once daily* 
Investigations 
Neutrophil count 
decreased <1,000/μL or 
Hemoglobin<8 g/dL 
niraparib 
Hold niraparib for a maximum of 28 days 
and monitor blood counts weekly until 
neutrophil counts return to ≥1,500/μL or 
hemogloblin ≥9 g/dL. 
Resume niraparib at a reduced dose per 
Table 8.1 
Discontinue niraparib if neutrophil or 
hemoglobin levels have not returned to 
acceptable levels within 28 days of the 
dose interruption period, or if the patient 
has already undergone dose reduction to 
100 mg once daily.* 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count decreased 
Grade 1 <100,000/μL) 
niraparib 
First occurrence: 
• Hold niraparib for a maximum of 28 
days and monitor blood counts 
weekly until platelet counts return to 
≥100,000/μL 
• Resume niraparib at same dose per 
Table 8.1 
Second occurrence: 
• Hold niraparib for a maximum of 28 
days and monitor blood counts 
weekly until platelet counts return to 
≥100,000/μL. 
• Resume niraparib at a reduced dose 
per Table 8.1 
 
Discontinue niraparib if the platelet count 
has not returned to acceptable levels 
within 28 days of the dose interruption 
period, or if the patient has already 
undergone dose reduction to 100 mg once 
daily.* 
Investigations 
Platelet count decreased 
Grade 2 (<75,000/μL) 
niraparib 
First occurrence: 
• Hold niraparib for a maximum of 28 
days and monitor blood counts 
weekly until platelet counts return to 
≥100,000/μL 
• Resume niraparib at reduced dose per 
Table 8.1 
Second occurrence: 
• Hold niraparib for a maximum of 28 
days and monitor blood counts 
weekly until platelet counts return to 
≥100,000/μL. 
• Resume niraparib at a reduced dose 
per table 1 
• Discontinue niraparib if the platelet 
count has not returned to acceptable 
levels within 28 days of the dose 
interruption period, or if the patient 
has already undergone dose reduction 
to 100 mg once daily.* 


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CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Platelet count decreased  
(Grade 4) requiring 
transfusion 
niraparib 
For patients with platelet count 
≤10,000/μL, platelet transfusion should be 
considered. If there are other risk factors 
such as co-administration of 
anticoagulation or antiplatelet drugs, 
consider interrupting these drugs and/or 
transfusion at a higher platelet count. 
Resume niraparib at a reduced dose. 
Neoplasms 
AML/DS 
niraparib  Permanently discontinue niraparib.  
Nervous System 
Disorders 
Reversible posterior 
leukoencephalopathy 
syndrome / Posterior 
reversible 
encephalopathy 
syndrome (PRES) 
niraparib 
Treat symptoms, including control of 
hypertension. 
 
Permanently discontinue niraparib. 
Vascular 
Hypertension 
niraparib 
Manage with antihypertensive medicinal 
products. Resume niraparib at reduced 
dose per Table 8.1. 
 
For Grade 3 or higher: Hold niraparib 
until resolve to Grade 0. Resume niraparib 
at reduced dose per Table 8.1. 
 
Permanently discontinue niraparib in case 
of hypertensive crisis or if medically 
significant hypertension cannot be 
adequately controlled with 
antihypertensive therapy. 
**  Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start of the 
next cycle, then the dose will remain lowered for that entire subsequent cycle.  
It is not recommend to reduce niraparib below 100 mg daily.  
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.21 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia.  
9.22  
Anemia  
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications.  
9.23  
Thrombocytopenia  
Transfusion of platelets may be used if clinically indicated. ITP should be ruled 
out before initiation of platelet transfusion. 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
 


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9.5 
Immunotherapy-related Adverse Events 
Patients should be monitored for signs and symptoms of immunotherapy-related adverse 
events, which include but are not limited to the following:  
• 
Pneumonitis  
o For Grade 2 events, treat with systemic corticosteroids (1mg/kg daily 
prednisone equivalent). When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks.  
o For Grade 3-4 events, immediately treat with intravenous steroids (1-
2mg/kg prednisone equivalent). Administer additional anti-inflammatory 
measures, as needed.  
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• 
Diarrhea/colitis Patients should be carefully monitored for signs and 
symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus 
in stool, with or without fever) and of bowel perforation (such as peritoneal 
signs and ileus).  
o All patients who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion. For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis.  
o For Grade 2 diarrhea/colitis, administer oral corticosteroids (1mg/kg 
daily prednisone equivalent).  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed 
by high dose oral steroids (1-2mg/kg prednisone equivalent).  
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA)  
For T1DM or Grade 3-4 Hyperglycemia:  
o Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
o Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• 
Hypophysitis  
o For Grade 2 events, treat with corticosteroids (1mg/kg daily prednisone 
equivalent). When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.  
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids (1-
2mg/kg prednisone equivalent) followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.  


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• 
Hyperthyroidism or hypothyroidism Thyroid disorders can occur at any 
time during treatment. Monitor patients for changes in thyroid function (at 
the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders.  
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):  
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.  
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid (1-2mg/kg prednisone 
equivalent) followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.  
 
• 
Hepatic  
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).  
 
Treat with IV or oral corticosteroids  
 
For Grade 3-4 events, treat with intravenous corticosteroids (1-
2mg/kg prednisone equivalent) for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks.  
 
• 
Renal failure or nephritis  
o For Grade 2 events, treat with corticosteroids.  
o For Grade 3-4 events, treat with systemic corticosteroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
 
• 
Rash 
o Grade 2 - Treat symptomatically with topical steroid cream, as well as 
antihistamines (i.e., loratidine, diphenhydramine, etc.). For patients that 
do not respond, consider starting steroids at 0.5 mg/kg prednisone or 
equivalent.  
o Grade 3 - As above for Grade 2 and start steroids at 1 mg/kg prednisone 
or equivalent.  
o If any signs of Steven Johnson Syndrome (SJS) or Toxic Epidermal 
Necrolysis (TENS), immediately hospitalize patient and treat with high 
dose IV steroids (1 gram methylprednisolone) and consult dermatology. 
 
• 
 Management of Infusion Reactions:  
o Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion 
of infusion.  


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o Table 9.51 below shows treatment guidelines for subjects who 
experience an infusion reaction associated with administration of TSR-
042 
9.51 
Infusion reaction treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication 
at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 adverse 
events despite adequate premedication 
should be permanently discontinued from 
further trial treatment administration. 
Subject may be pre- 
medicated 1.5h (±30 
minutes) prior to infusion 
of TSR-042 with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine) 
Acetaminophen 1000 mg 
po (or equivalent dose of 
antipyretic) 
Grades 3 or 4 Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen Pressors 
Corticosteroids 
Epinephrine 
No subsequent dosing 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. Subject 
is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 


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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting  
Mayo Sites – attach to MCCC Electronic 
SAE Reporting Form 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo.edu 
and RSTP2CSAES@mayo.edu 
Send to GSK: 
OAX37649@gsk.com 
Fax Number:  
+44(0) 20 8754 7822 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form  
 
AND attach 
 
MedWatch 3500A 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo.edu 
and RSTP2CSAES@mayo.edu  
Send to GSK: 
OAX37649@gsk.com 
Fax Number:  
+44(0) 20 8754 7822 
 
 


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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware of 
the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but that 
for a specific protocol are being reported via expedited means in order to facilitate the review of 
safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: 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: 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 


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mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• 
An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for investigational agents/interventions.  
• 
An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent 
require an expedited report, unless hospitalization is required. Refer to Section 
10.4 for specific AE reporting requirements or exceptions. 
• 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent. Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity or specificity, 
expedited reporting is required. 
• 
An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from 
a drug overdose. 
• 
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch 3500A for Health Professionals (complete all three pages of the 
form).  
 


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10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Endocrine disorders 
Hypothyroidism 
≤Grade 3 
 
Hyperthyroidism 
≤Grade 3 
 
Hypophysitis 
≤Grade 3 
Gastrointestinal 
disorders 
Diarrhea 
≤Grade 3 
Investigations 
Alkaline phosphatase increased 
≤Grade 3 
 
Aspartate aminotransferase 
increased 
≤Grade 3 
 
Blood bilirubin in creased 
≤Grade 3 
 
Lymphocyte count decreased 
≤Grade 4 
 
Neutrophil count decreased 
≤Grade 4 
 
Platelet count decreased 
≤Grade 4 
 
White blood cell decreased 
≤Grade 4 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
≤Grade 3 
Skin and subcutaneous  Rash acneiform 
≤Grade 4 
tissue disorders 
Rash maculo-papular 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 


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● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
 
10.4 
Expedited Reporting Requirements for IND Agents  
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon 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. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 


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rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting  
10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report Form for investigational agents or 
commercial/investigational agents on the same arm.  
Submit MedWatch 3500A Form  
Mayo Clinic Cancer Center (MCCC) Institutions: 
Attach the MedWatch form to the electronic Mayo Clinic Cancer Center Safety 
Reporting Form, which will send a copy to the following email address: 
CANCERCROSAFETYIN@mayo.edu. This email will be managed by the SAE, 
IND and Safety Reporting Coordinators. 
Forward a copy to GSK: OAX37649@gsk.com 
Fax Number: +44(0) 20 8754 782210.43 
 
Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 


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Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report Form. The Mayo Clinic 
Compliance Unit will review and process the submission to the Mayo Clinic IRB 
and work with the IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported per SAE timelines. Three options are available to 
describe the event: 


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o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this Form. 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 


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10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v5.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic system 
disorders 
Anemia 
X 
X 
Endocrine disorders 
Hypothyroidism 
X 
X 
Gastrointestinal disorders 
Baseline number of stools 
X 
 
 
Diarrhea 
 
X 
General disorders 
Fatigue 
X 
X 
 
Fever 
X 
X 
 
Pain 
X 
X 
Immune system disorders 
Allergic reaction 
 
X 
Investigations 
Alanine aminotransferase increased 
X 
X 
 
Aspartate aminotransferase increased 
X 
X 
 
Blood bilirubin increased 
X 
X 
 
Creatinine increased 
X 
X 
 
Neutrophil count decreased 
X 
X 
 
Platelet count decreased 
X 
X 
Metabolism and nutrition 
disorders 
Hyperglycemia 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnea 
X 
X 
Skin and subcutaneous tissue  
Rash acneiform 
X 
X 
disorders 
Rash maculopapular 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 


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10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
GSK - Additional Event Reporting Instructions 
10.81    Pregnancy Reporting  
The Sponsor Institution must report all pregnancies associated with GSK product 
including follow up outcomes to GSK within 24 hours of awareness.  
Each pregnancy must be reported on a Pregnancy Notification Form within 24 
hours of becoming aware of the pregnancy. Pregnancy is not an AE, and 
therefore does not need to be reported as an AE unless there is a suspicion that 
the study drug may have interfered with the effectiveness of a contraceptive 
medication.  
An elective abortion without complications should not be regarded as an AE, 
however, it should be reported as the outcome to the pregnancy on the Pregnancy 
Follow-Up Form. Therapeutic abortions should be reported as a treatment 
procedure; the reason for the therapeutic abortion should be reported on the 
Pregnancy Follow-Up Form and as an AE. Hospitalization for normal delivery of 
a healthy newborn should not be considered an SAE. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy 
Follow-Up Form reported as an SAE on the SAE Report Form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported to the Sponsor 
Institution and GSK within 24 hours. Hospitalization for normal delivery of a 
healthy newborn should not be considered an SAE.  
10.82 Adverse Event of Special Interest (AESI)  
An Adverse Event of Special Interest is defined as any AE (serious or non-
serious) that is of scientific and medical concern specific to the study treatment, 
for which ongoing monitoring and rapid communication to the Sponsor 
Institution and to GSK is required.  
Adverse Events of Special Interest (AESI) for niraparib include the following:  
• Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
• Secondary cancers (new malignancies [other than MDS or AML]) 
• Pneumonitis 


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• Embryo-fetal toxicity 
AESIs should be reported on SAE Report Forms whether serious or not, as 
follows: 
• MDS and AML along with other secondary cancers should be reported to 
the Sponsor Institution and to GSK upon awareness for any patient who 
has received niraparib (regardless of the timeframe since the last dose). 
• Pneumonitis should be reported to the Sponsor Institution and to GSK 
through 90 days after the last dose of niraparib. 
• Embryo-fetal toxicity should be reported as outlined in the Pregnancy 
reporting section. 
10.83 Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental 
or Occupational Exposure  
• Abuse: is the persistent or sporadic, intentional excessive use of the study 
treatment which is accompanied by harmful physical or psychological effects.  
• Misuse: medicinal product is intentionally and inappropriately used not in 
accordance with the authorized/approved product information. 
• Medication error: is any preventable incident that may cause or lead to 
inappropriate study treatment use or patient harm while the study treatment is 
in the control of the health care professionals or patients. Such incident may be 
due to health care professional practice, product labeling, packaging and 
preparation, procedures for administration, and systems, including the 
following: prescribing, order communication, nomenclature, compounding, 
dispensing, distribution, administration, education, monitoring, and use. 
• Overdose: is a deliberate or accidental administration of study treatment to a 
study patient, at a dose greater than that which was assigned to that patient per 
the study protocol and under the direction of the Investigator. If an overdose 
with a GSK product, the Sponsor Institution and GSK should be notified 
immediately, and the patient should be observed closely for AEs. Associated 
AEs should be treated and monitored by the Investigator. The dosage of study 
drug administered, any associated AEs, and/or treatment provided to the 
patient because of the overdose, should be reported.  
• Accidental /Occupational exposure: is the unintentional exposure to a study 
treatment as a result of one’s professional or non-professional occupation, or 
accidental exposure to a non-professional to whom exposure was not intended 
(i.e., study product given to wrong patient).  
Reporting Special Situations: All occurrences of abuse, misuse, medication error, 
overdose, and accidental or occupational exposure associated with a GSK 
product must be reported on a GSK SAE Report Form with associated coversheet 
to the Sponsor Institution and to GSK within 5 business days of awareness 
regardless of whether or not an AE or SAE has occurred. If the abuse, misuse, 
medication error, overdose, or accidental / occupational exposure is associated 
with an AE, an SAE Report Form must also be submitted to the Sponsor 
Institution and to GSK within 24 hours of awareness.  
 
 


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10.84 Reporting to GSK 
The Sponsor Institution must report all SAEs and all follow up information to 
GSK on a GSK SAE Report Form, accompanied by the GSK coversheet within 
24 hours of becoming aware of the initial event or follow-up information.  
The Sponsor Institution must provide a causality assessment and must sign and 
date all SAE Report Forms. 
If supporting documentation is included in the submission to GSK (e.g., hospital 
reports, consultant reports, death certificates, autopsy reports, etc.), please redact 
any patient identifiers (including Medical Record number). 
GSK SAE, Pregnancy, and AESI Reporting Information 
OAX37649@gsk.com 
Fax Number: +44(0) 20 8754 7822 
On at least an annual basis, the Sponsor Institution will provide a copy of the 
safety reports submitted to applicable Regulatory Authorities or IECs. Annual 
reports should be provided to GSK within 3 business days of submission to the 
applicable regulatory body. 
10.85 Suspected Unexpected Serious Adverse Reactions (SUSARs)  
Per regulatory requirements, if an event is assessed by the Sponsor Institution as 
a Serious Unexpected Adverse Reaction (SUSAR), it is the responsibility of the 
Sponsor Institution to submit the SUSAR to Regulatory Authorities according to 
applicable regulations. 
In addition, the SUSAR will be distributed to the Investigators/sites utilizing a 
Council for International Organizations of Medical Sciences (CIOMS) report 
form, or the MedWatch 3500A form). The Investigator/site will submit a copy of 
the report to their respective Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) and GSK per the governing institutional requirements 
and in compliance with local laws and guidelines. 
10.86 Reporting Product Complaints for GSK Products 
Any written, electronic or oral communication that alleges dissatisfaction related 
to manufactured clinical drug product with regards to its manufacturing, testing, 
labeling, packaging, or shipping, must be reported by the Sponsor Institution or 
qualified designee to GSK within 1 working day of first becoming aware of the 
possible defect to GSKQA at tso.qa@gsk.com .   The product and packaging 
components in question, if available, must be stored in a secure area under 
specified storage conditions until it is determined whether the product is required 
to be returned for investigation of the defect.  If the product complaint is 
associated with an SAE, the SAE must be reported separately in accordance with 
the protocol, and the SAE report should mention the product quality complaint. 
 
 


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10.87 GSK Reporting Requirements for ALL Serious Adverse Events:  
The following must be reported: 
Any untoward medical occurrence that, at any dose; 
• 
Results in death;  
• 
Is life threatening (i.e., an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe);  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization;  
• 
Results in persistent or significant disability/incapacity;  
• 
Is a congenital anomaly/birth defect; or 
Is an important medical event (defined as follows: --Medical and scientific 
judgment should be exercised in determining whether situations or events 
should be considered serious adverse events:  an important medical event 
may not be immediately life-threatening or result in death or require 
hospitalization but may jeopardize the patient or require intervention to 
prevent one of the above outcomes.  Examples of such events are allergic 
bronchospasm, blood dyscrasias, or convulsions that may require intensive 
treatment in an emergency room or at home but do not result in 
hospitalization, development of drug) 
11.0 
Treatment Evaluation/Measurement of Effect  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1)17 and iRECIST criteria18 which is discussed further starting in Section 11.5 below. 
Since iRECIST still uses RECIST 1.1 principles, the RECIST 1.1 criteria is also in this section as 
well.  
Changes in the largest diameter (unidimensional measurement) of the tumors and the short axis 
measurements in the case of lymph nodes are used in the RECIST guideline. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 6 weeks.  
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.21 Measurable Disease 
• A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, 
CT component of a PET/CT, or MRI.  
• A superficial non-nodal lesion is measurable if its longest diameter is ≥1.0 cm 
in diameter as assessed using calipers (e.g. skin nodules) or imaging. In the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
• A malignant lymph node is considered measurable if its short axis is >1.5 cm 
when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  
• Tumor lesions in a previously irradiated area are considered measurable 
disease under the following conditions:  


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- If there is a soft tissue component that has grown since completion of 
radiation. 
- Bone metastases with a soft tissue component are considered measureable.  
11.22 Non-Measurable Disease 
• All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm). Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable as 
well. 
• Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. In addition, lymph nodes that have a 
short axis <1.0 cm are considered non-pathological (i.e., normal) and should 
not be recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods 
• All measurements should be recorded in metric notation (i.e., decimal fractions 
of centimeters) using a ruler or calipers. 
• The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.  
• Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
11.32 Acceptable Modalities for Measurable Disease 
• Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. 
o As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• PET-CT: If the site can document that the CT performed as part of a PET-CT is 
of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  


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• FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. 
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
o Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up:  
 If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  
 If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT at the same evaluation, additional follow-up CT scans (i.e., 
additional follow-up scans at least 4 weeks later) are needed to determine if 
there is truly progression occurring at that site. In this situation, the date of 
PD will be the date of the initial abnormal PDG-PET scan.  
 If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
it is not classified as PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance has been described 
in the protocol and supported by disease-specific medical literature for the 
indication  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
11.33 Measurement at Follow-up Evaluation:  
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
Cytologic and histologic techniques can be used to differentiate between PR and 
CR in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain.) 
11.4 
Measurement of Treatment/Intervention Effect 
11.41 Target Lesions & Target Lymph Nodes 
• The protocol defined irradiated tumor will not be considered for response in the 
primary endpoint. 
• The protocol defined irradiated tumor will be considered for secondary 
endpoint response. 
• Measurable lesions (as defined in Section 11.21) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” 


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and recorded and measured at baseline. These lesions can be non-nodal or 
nodal (as defined in Section 11.21), where no more than 2 lesions are from the 
same organ and no more than 2 malignant nodal lesions are selected.  
• Note: If fewer than 5 (for phase III trials replace with “3”) target lesions and 
target lymph nodes are identified (as there often will be), there is no reason to 
perform additional studies beyond those specified in the protocol to discover 
new lesions.  
• Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion (or malignant lymph node) does 
not lend itself to reproducible measurements in which circumstance the next 
largest lesion (or malignant lymph node) which can be measured reproducibly 
should be selected.  
• Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The BSD 
will be used as reference to further characterize any objective tumor response 
in the measurable dimension of the disease.  
• Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes 
will be calculated and reported as the post-baseline sum of dimensions (PBSD). 
If the radiologist is able to provide an actual measure for the target lesion (or 
target lymph node), that should be recorded, even if it is below 0.5 cm. If the 
target lesion (or target lymph node) is believed to be present and is faintly seen 
but too small to measure, a default value of 0.5 cm should be assigned. If it is 
the opinion of the radiologist that the target lesion or target lymph node has 
likely disappeared, the measurement should be recorded as 0 cm. 
• The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline. These 
lesions and lymph nodes should be followed in accord with 11.433. 
11.43 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray/physical examination must be measured on re-evaluation at evaluation times 
specified in Section 11.1. Specifically, a change in objective status to either a PR 
or CR cannot be done without re-measuring target lesions and target lymph 
nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. 
In selected circumstances, certain non-target organs may be evaluated less 
frequently. For example, bone scans may need to be repeated only when 
complete response is identified in target disease or when progression in bone is 
suspected. 


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11.431 Evaluation of Target Lesions 
o Complete Response (CR): All of the following must be true: 
 
Disappearance of all target lesions. 
 
Each target lymph node must have reduction in short axis to < 
1.0 cm. 
o Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis 
of all the target lymph nodes at current evaluation) taking as 
reference the BSD (see Section 11.41). 
o Progression (PD): At least one of the following must be true: 
 
At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis during follow-up.  
 
At least a 20% increase in PBSD (sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the 
target lymph nodes at current evaluation) taking as reference the 
MSD (Section 11.41). In addition, the PBSD must also 
demonstrate an absolute increase of at least 0.5 cm from the 
MSD.  
 
See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, 
nor sufficient increase to qualify for PD taking as reference the 
MSD. 
11.432 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
o Complete Response (CR): All of the following must be true: 
 
Disappearance of all non-target lesions.  
 
Each non-target lymph node must have a reduction in short axis 
to <1.0 cm. 
o Non-CR/Non-PD: Persistence of one or more non-target lesions or 
non-target lymph nodes. 
o Progression (PD): At least one of the following must be true: 
 
At least one new malignant lesion, which also includes any 
lymph node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up.  
 
Unequivocal progression of existing non-target lesions and non-
target lymph nodes. (NOTE: Unequivocal progression should not 
normally trump target lesion and target lymph node status. It 
must be representative of overall disease status change.)  
 
See Section 11.32 for details in regards to the requirements for 
PD via FDG-PET imaging. 
 
 


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11.44 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-
target lymph nodes, and new disease as defined in the following tables:  
For Patients with Measurable Disease  
Target Lesions & 
Target Lymph 
Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of 
Disease 
Overall 
Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not 
Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not 
all Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not 
all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* See Section 11.431 
11.45 Symptomatic Deterioration  
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported 
as PD due to “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. 
11.5 
Immune-Related Response Assessment (iRECIST) 
All study endpoints requiring measurement data will be assessed per RECIST criteria 
(defined above). Patients will not be required to end study participation at the first 
evidence of progression since Immunotherapeutics may result in infiltration of immune 
cells leading to transient increase in the size of malignant lesions, or undetectable lesions 
becoming detectable. For this reason, iRECIST18 will be utilized in order to help to make 
the decision to remove a patient from the study after first evidence of progression. The 
criteria are identical to those of RECIST 1.1 in many respects but have been adapted to 
account for instances where an increase in tumor burden, or the appearance of new 
lesions, does not reflect true tumor progression. Key differences are described below. All 
responses defined using iRECIST criteria are designated with a prefix. 


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11.51 Confirming Progression  
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses 
the terms iUPD (unconfirmed progression) and iCPD (confirmed progression). 
Confirmatory scans should be performed at least 4 weeks, but not longer than 9 
weeks after iUPD. 
For patients that had an iUPD in the previous assessment, iCPD is confirmed in 
two ways: 
1) Existing iUPD gets worse in any lesion type (target, non-target, or new 
lesions) which contributed to the current iUPD status (a patient can have 
more than one of the following sources of iUPD). 
If iUPD was at least 
partially based on… 
Then iCPD is confirmed if… 
Target lesions 
A cumulative increase (can occur over multiple 
assessments) of at least 5 mm in the absolute 
value of the sum from the first occurrence of the 
current iUPD 
Non-target lesions 
Any increase in the non-target lesion burden 
from the first occurrence of the current iUPD 
New lesions 
A cumulative increase (can occur over multiple 
assessments) of at least 5 mm in the absolute 
value of the sum of those considered to be target 
new lesions or any new lesions (from the first 
occurrence of the current iUPD) 
2) RECIST 1.1 criteria are met in lesion types (target, non-target, or new 
lesions) which did not contribute to current iUPD status, including the 
appearance of new lesions. 
If a patient meets either (or both) of these criteria, they are considered to have 
confirmed progression (iCPD). See Appendix III for examples of confirming 
progression. 
11.52 New Lesions  
New lesions should be assessed and measured as they appear using RECIST 1.1 
criteria, and recorded as New Lesion-Target (NLT) and New Lesion-Non-Target 
(NLNT) to allow clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or 
iCPD). However, the measurements of NLT should NOT be included in the sum 
of measures of original target lesions identified at baseline. 
Progression is confirmed in the New Lesion category if the next imaging 
assessment, conducted at least 4 weeks (but not more than 9 weeks) after iUPD 
confirms further progression from iUPD with either an increase of at least 5 mm 
in the absolute value of the sum of NLT OR and increase (but not necessarily 
unequivocal increase) in the size of NLNT lesions OR the appearance of new 
lesions. 
 
 


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The following table summarizes how to use iRECIST in a number of different 
scenarios. 
 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5 mm in SOM for 
NLT or any increase for NLNT) or number. If no 
change in NLs (size or number) from last TP, 
remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in 
further increase in size of NT disease (need not 
meet RECIST 1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
- further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD SOM ≥5 
mm and / or 
- NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD ≥5 mm and 
/ or 
- previously identified NT lesion iUPD (need not 
be unequivocal) and /or 
- size or number of new lesions previously 
identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
- increase in size or number of new lesions 
previously identified 
*  
Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. 
** In any lesion category. 
*** Previously identified in assessment immediately prior to this TP. 
11.6 
Definitions of Analysis Variables 
Formal definitions of variables used in analyses can be found in the Statistical 
Considerations section of the protocol. 
 
 


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12.0 
Descriptive Factors  
12.1 
Prior treatment: 1 vs 2 vs 3+ 
12.2  
Mismatch repair status: proficient vs deficient 
12.3 
Deleterious mutation: BRCA 1 vs BRCA 2 vs PALB2 
12.4 
Exposed to platinum treatment: yes vs no 
12.5 
Refractory to cancer treatment: yes vs no 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who are iCR, iPR, or iSD will continue treatment per protocol. 
13.2 
Progressive disease (iCPD) 
Patients who develop iCPD while receiving therapy will have an end of treatment visit, 
then a clinical follow-up visit then go to the survival follow-up phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than iPD will have an end of 
treatment visit, then a clinical follow-up visit 30 days post-treatment, then go to the 
survival follow-up phase per Section 4.0. 
13.4 
Duration of therapy for iCR 
Patients who achieve a iCR will receive treatment until confirmed progressive disease 
according to iRECIST, clinical progression, intolerable adverse effects, or 
patient/investigators decision. They will have an end of treatment visit, then a clinical 
follow-up visit 30 days post-treatment, then go to survival follow-up.  
13.5 
Duration of therapy for iPR or iSD 
Patients who are in iPR, iSD or iUPD will continue on treatment until confirmed 
progressive disease according to iRECIST, clinical progression, intolerable adverse 
effects, or patient/investigators decision. They will have an end of treatment visit, then a 
clinical follow-up visit 30 days post-treatment, then go to survival follow-up.  Subsequent 
treatment is at the discretion of their attending physician. 
13.6 
Non-CNS iCPD  
Patients who develop non-CNS iCPD at any time should have an end of treatment visit, 
then a clinical follow-up visit 30 days post-treatment, then go to the survival follow-up 
phase. These patients should be treated with alternative chemotherapy if their clinical 
status is good enough to allow further therapy.  
13.7 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. If 
the patient received treatment, the patient may continue treatment at the discretion of the 
physician as long as there are not safety concerns. The patient will continue in the Active 
Monitoring/Treatment phase of the study, as per Section 4.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Survival 
Follow-up will be required per Section 4.0 of the protocol.  


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13.8 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. If the patient received treatment, the patient may continue treatment at 
the discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, as per Section 4.0 of the 
protocol. 
13.9 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 


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14.0 
Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Research 
(Section for 
more 
information) 
Specimen 
Purpose  
(check all that 
apply) 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline Cycle 1 
Day 15 
End of 
Cycle 1 
End of 
Cycle 2 
End of 
Cycle 4 EOT Process at site? 
(Yes or No) 
Temperature 
Conditions for 
Storage /Shipping 
Circulating 
Tumor DNA  
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Blood 
Cell-Free 
DNA BCT 
Streck 
10mL 
(3 tubes) 
X 
X 
X 
X 
X 
X 
No 
Ambient 
Shipping 
Evaluation of 
Serum 
Cytokine 
Profile by 
ELISA 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Blood 
Red Top 
Tube 
10 mL 
(1 tube) 
X 
X 
X 
X 
X 
X 
No 
Refrigerate 
Shipping 
Circulating 
biomarker  
work, 
including DNA 
and Proteomic 
based studies 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Blood 
EDTA 
10 mL 
(2 tube) 
X 
X 
X 
X 
X 
X 
No 
Refrigerate 
Shipping 
RNA 
Extraction 
based studies 
☐ Correlative 
☐ Eligibility 
Confirmation 
☒ Banking 
Blood 
PaxGene 
RNA 
2.5 mL 
(1 tube) 
O 
O 
O 
O 
O 
O 
No 
Ship Frozen (dry 
ice)  
X = Mandatory, O = Optional 


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14.2 
Collection and Processing  
14.21 Kits will be used for this study. Kits to be ordered through Biospecimens 
Collection and Processing (BAP) in Rochester. All specimens must be collected 
Monday - Friday. 
14.22 Label specimen tube(s) with protocol number, patient study ID number, and time 
and date blood is drawn. Samples when processed at Mayo Biorepositories 
Florida will be labeled with RLIMS label containing subject ID, study name, 
specimen type and volume. 
14.23 Collect and process all blood/blood products according to the instructions below. 
All samples will be shipped to MCR Rochester for processing and storage.  
Samples will be processed in Rochester as indicated below. 
14.231 The cell free DNA Streck tube for circulating tumor DNA should be 
collected at room temperature. Centrifuge the Streck tube within 2 hours 
of collection at 1600g for 10 minutes at 10°C. Carefully pipette up to 
5mL of plasma into a 15mL specimen tube. Centrifuge sample at 3,220g 
for 10 minutes at 10°C. Transfer the platelet poor plasma into (2) 5mL 
cryovials and freeze cryovials at -80°C and store.  
14.232 The Red Top tube should be incubated at room temperature for 30 
minutes to allow the clotting process to complete. Centrifuge the Red 
Top Tube at lab standards (2000g x 10min at 4°C). Carefully transfer 
serum into (4) 2mL cryovials and freeze cryovials at -80°C and store.  
14.233 The 10mL EDTA tubes for circulating biomarker work is to be 
centrifuged at lab standards (2000g x 10min at 4°C). Carefully transfer 
the plasma into (4) 2mL cryovials per 10mL EDTA tube and the white 
blood cells (buffy coat layer) into (1) 2mL cryovial. Freeze all cryovials 
at -80°C and store.  
14.234 The PAXgene RNA tube for RNA bases studies is to be accessioned into 
BAP and follow a step down freezing process based on manufacturer’s 
recommendation (see Appendix IV). 
14.3 
Shipping and Handling 
14.31 Kits will be used for this study. 
14.311 
Kits will be supplied by the Rochester Biospecimen Accessioning and 
Processing (BAP).  
14.312 
The kit contains collection supplies for specimens. 
14.32 Shipping Specimens 
Specimens must be shipped on the day they are collected. 
Specimens will be shipped in a dual-temperature shipping container.  Place the 
refrigerated EDTA and No Additive tubes with a properly prepared cold pack in 
one compartment.  See kit instructions for specific details for cold pack 
preparation (i.e., frozen or refrigerated) and proper packing of blood and cold 
pack to avoid freezing of specimen. Place the Streck tubes in the ambient 
compartment of the dual-temperature shipping container. 


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Ship the frozen PaxGene RNA tube with dry ice in the properly labeled frozen 
shipping container. 
14.33 Handling Specimens 
Verify that ALL sections of the BAP Requisition form and specimen collection 
labels are completed and filled in correctly. BAP will retain residual whole 
blood, plasma, white blood cells, DNA, and serum for future research studies 
according to patient consent information.  
 
15.0 
Drug Information 
15.1 
TSR-042 (dostarlimab) 
15.11  Background 
TSR-042 is a humanized monoclonal antibody (mAb) of the immunoglobulin G4 
(IgG4) isotype that binds with high affinity to PD-1, resulting in inhibition of 
binding to PD-L1 and PD-L2. TSR-042 is produced by recombinant DNA 
technology in a mammalian expression system using a stable Chinse hamster 
ovary (CHO) cell line. 
15.12 Formulation 
TSR-042 50 mg/mL drug product is a single use sterile liquid formulation that 
can readily be diluted in an IV solution for intravenous administration. It is a pH 
6.0 formulation containing 50 mg/ml TSR-042, 25 mM sodium citrate, 100 mM 
arginine, 31 mM sodium chloride, and 0.02% polysorbate 80. The deliverable 
volume in each vial is 10 mL.15.13 
 
15.13 Preparation and storage 
The product should be stored between 2°C and 8°C, and in accordance with the 
Pharmacy Manual or protocol as provided by the Sponsor. 
15.14 Administration 
TSR-042 is administered as an intravenous infusion in accordance with the 
Storage and Handling Guidelines provided by GSK.  
15.15 Pharmacokinetic information 
Absorption: TSR-042 is administered IV, thus absorption is not 
applicable. 
Distribution: The Vss of TSR-042 was determined in subjects participating in 
Part 1 of Study 4010-01-001 following a 30-minute IV infusion. The mean Vss 
was 74.2, 71.7, and 60.7 mL/kg following the administration of 1, 3, and 10 
mg/kg, respectively. These results suggest a limited distribution outside the 
vascular space, which is consistent with the behavior of endogenous IgG.  
 
Metabolism: TSR-042 is a therapeutic mAb IgG4, which is expected to be 
catabolized into small peptides, amino acids, and small carbohydrates by 
lysosome through fluid-phase or receptor-mediated endocytosis.  
Elimination: The clearance of TSR-042 was determined in subjects participating 
in Part 1 of Study 4010-01-001 following single IV infusion. The mean 
clearances were 0.201, 0.117, and 


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0.152 mL/h/kg for the 1, 3, and 10 mg/kg dose groups, respectively. Body weight 
(range 45.6 to 145.6 kg) was not a significant covariant for TSR-042 clearance. 
The estimated terminal t½ was approximately 13 to 18 days.  
15.16 Potential Drug Interactions 
No drug-drug interaction studies have been conducted. Monoclonal antibodies 
such as TSR-042 are not substrates for cytochrome P450 or drug transporters, 
and are unlikely to be cytokine modulators. Additionally, pharmacokinetic drug-
drug interactions of TSR-042 with small molecule drugs are not expected. There 
is no evidence of drug-drug interactions mediated by non-specific clearance of 
lysosome degradation for antibodies. 
15.17 Known potential adverse events 
Common potential adverse events (>10%): 
Central nervous system: Fatigue 
Dermatologic: Pruritus, rash, maculopapular rash 
Endocrine & metabolic: immune-mediate endocrinopathy – especially thyroid, 
pituitary and adrenal  
Gastrointestinal: Nausea, diarrhea, vomiting, decreased appetite 
Hematologic: Anemia 
Neuromuscular & skeletal: arthralgia  
Less common potential adverse events, 1% - 10%: 
Hepatic: increased AST, increased ALT 
Respiratory: immune-mediated pneumonitis—dyspnea, chest pain, cough 
Rare potential adverse events, <1%: 
Gastrointestinal: immune-mediated colitis 
15.18 Drug procurement 
Investigational TSR-042 will be supplied free of charge by GSK. 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
15.2 
Niraparib (Zejula®, formerly MK-4827) 
15.21 Background 
Niraparib is an orally available, potent, highly selective poly (adenosine 
diphosphate [ADP]-ribose) polymerase (PARP)1 and PARP2 inhibitor being 
developed as a monotherapy agent for tumors with defects in the homologous 
recombination (HR) DNA repair pathway and as a sensitizing agent in 
combination with cytotoxic agents and radiotherapy as well as in combination 
with immune-oncology biologics. 
15.22 Formulation 
Investigational Niraparib is available for clinical trials as 100 mg capsules filled 
with a dry blend of niraparib tosylate monohydrate, lactose monohydrate, and 
magnesium stearate in a hard gelatin capsule.  
15.23 Preparation and storage 
Niraparib 100 mg capsules are packaged in high density polyethylene (HDPE) 
bottles fitted with child-resistant plastic closures. Niraparib 100-mg capsules 


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have a proposed shelf-life of up to 36 months when stored in the intended 
container closure system and under the conditions specified in the Storage and 
Handling Guidelines. 
15.24 Administration 
Capsules should be administered once daily at approximately the same time each 
day.  
Food does not significantly affect the absorption of niraparib; therefore, niraparib 
may be taken without regard to meals. 
If a patient vomits or misses (greater than 12 hours from normal dosing time) a 
dose of niraparib, an additional dose should not be taken. The next dose should 
be taken at the regularly scheduled time.  
15.25 Pharmacokinetic information 
Niraparib exhibits linear pharmacokinetics (PK), and exposure is dose 
proportional. Absorption and clearance are dose-independent (range: 30 to 400 
mg). 
Absorption: Following a single-dose administration of 300-mg niraparib under 
fasting conditions, niraparib was measurable in plasma within 30 minutes, and 
the mean Cmax for niraparib was reached in about 3 hours. Following multiple-
oral doses of niraparib from 30 mg to 400 mg QD, accumulation of niraparib was 
approximately 2-fold. 
The systemic exposures (Cmax and AUC) to niraparib increased in a dose-
proportional manner when the dose of niraparib increased from 30 mg to 400 mg. 
The absolute bioavailability of niraparib is approximately 73%, indicating 
minimal first-pass effect. 
Concomitant intake of a high-fat meal did not significantly affect the PK of 
niraparib after administration of 300 mg of niraparib. 
Distribution: Niraparib was moderately bound to human plasma proteins 
(approximately 83.0%). The apparent Vd/F was 1220 L, indicating extensive 
tissue distribution of niraparib. In a population PK analysis, the Vd/F of niraparib 
was 1074 L in patients with cancer. 
Metabolism: Niraparib is metabolized primarily by CEs to form a major inactive 
metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed 
M1 glucuronides) were the major circulating metabolites. The mean t½ of M1 
was 88 hours. The exposure ratio of M1 to niraparib was approximately 1.3- to 
2.2- fold in plasma. 
Elimination: Following a single oral 300-mg dose of niraparib, the mean t½ of 
niraparib ranged from 48 to 51 hours (approximately 2 days). In a population PK 
analysis, the CL/F of niraparib was 16.2 L/h in patients with cancer. Niraparib is 
eliminated primarily through the hepatobiliary and renal routes. Following 
administration of a single oral 300-mg dose of [14C]-niraparib, on average, 
86.2% (range: 71% to 91%) of the dose was recovered in urine and feces over 21 
days. Radioactive recovery in urine accounted for 47.5% (range: 33.4% to 
60.2%) and in feces for 38.8% (range: 28.3% to 47.0%) of the dose. In pooled 
samples collected over 6 days, 40.0% of the dose was recovered in the urine 
primarily as metabolites, and 31.6% of the dose was recovered in the feces 
primarily as unchanged niraparib. 


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15.26 Potential Drug Interactions 
No formal drug interaction studies have been performed with niraparib. Neither 
niraparib nor the major metabolite M1 is an inhibitor of any drug-metabolizing 
CYP enzymes. A clinically meaningful drug interaction via inhibition of CYPs is 
highly unlikely. 
Niraparib weakly induces CYP1A2 in vitro; therefore, investigators should be 
advised to use caution with drugs that are sensitive substrates for CYP1A2 with a 
narrow therapeutic range, i.e., theophylline and tizanidine. M1 is not a CYP1A2 
inducer.  
15.27 Potential adverse events  
Common potential adverse events (>10%):  
Cardiac: Hypertension, palpitations   
Central nervous system: Fatigue, headache, insomnia, dizziness  
Gastrointestinal: Nausea, vomiting, diarrhea, constipation,  abdominal pain, 
dyspepsia, dysgeusia   
Genitourinary: Urinary Tract Infection  
Hematologic: Anemia, neutropenia, thrombocytopenia 
Neuromuscular & skeletal: back pain, arthralgia  
Respiratory: Cough, Dyspnea, nasopharyngitis 
Less common potential adverse events, 1% - 10%: 
Cardiac: Tachycardia, peripheral edema,  
Central nervous system: Depression, anxiety 
Endocrine & metabolic: Hypokalemia, increased gamma-glutamyl transferase  
Gastrointestinal: mucositis, stomatitis, dry mouth   
General: decrease in weight 
Hematologic: leukopenia, 
Hepatic: increased AST, increased ALT 
Ophthalmic: Conjunctivitis  
Neuromuscular: myalgia,  
Renal: Increased serum creatinine 
Respiratory: epistaxis 
Rare potential adverse events <1%: 
Acute myelocytic leukemia, hypertensive crisis, myelodysplastic syndrome 
15.28 Drug procurement 
Investigational Niraparib will be supplied free of charge by GSK. 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution.  
15.29 Nursing Guidelines 
15.291 
QTc prolongation can be seen. Monitor patient’s concomitant 
medications for potential overlap of other medications that prolong the 
QTc interval. 
15.292  
Fatigue was common. Instruct patient in energy conserving lifestyle. 
15.293 
Gastrointestinal side effects, included diarrhea, anorexia, and nausea. 
Instruct patients to report these side effects and treat symptomatically. 
Monitor for effectiveness of intervention. 


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15.294 
Dyspnea and cough have been seen. In addition isolated cases of 
pneumonitis have been seen. Instruct patient to report any shortness of 
breath to the study team. 
15.295 
Pain including headache, back and extremity pain have been reported. 
Administer analgesics as needed and assess for their effectiveness. 
15.296 
Monitor CBC w/differential as anemia, thrombocytopenia, and 
neutropenia are common. Instruct patients to report any unusual 
bruising or bleeding and/or sign/symptoms of infection to the health 
care team. 
15.297 
Electrolyte abnormalities have been seen with agent. Monitor closely.  
15.298 
Hypertension should be medically managed with antihypertensive 
medicinal products as well as adjustment of the niraparib dose, if 
necessary. Niraparib should be discontinued in case of hypertensive 
crisis or if medically significant hypertension cannot be adequately 
controlled with antihypertensive therapy. 
15.299 
Posterior revsersible encephalopathy syndrome (PRES) is a rare 
neurologic disorder that can present with the following signs and 
symptoms including seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated 
hypertension. In patients developing PRES, treatment of specific 
symptoms including control of hypertension is recommended, along 
with discontinuation of niraparib. 
16.0 
Statistical Considerations and Methodology  
16.1 
Primary Endpoint and Analysis:  
This is a single arm Phase II study designed to determine as primary endpoint the disease 
control rate at 12 weeks (DCR12), using the standard iRECIST criteria of patients 
receiving the combination of niraparib and TSR-042. Because the study features a 
heterogeneous population featuring 3 different genetic/somatic mutations, there will be 
no interim analysis. The study will stay remain open, unless a higher than expected 
toxicity issue is identified.  
DCR12 definition and determination: 
For this protocol, the patients must undergo response scanning according to the iRECIST 
criteria. The DCR12 is defined as the percentage of patients who have either iCR, iPR or 
iSD at 12 weeks. Patients who have developed a iUPD at 6 weeks will only be considered 
to have achieved disease control at 12 weeks, if at 12 weeks there is no confirmation of 
disease progression (iCPD) and the patient regresses to either iCR, iPR or iSD. DCR will 
be analyzed descriptively as a point estimate with a 95% confidence interval. 
The primary endpoint will assess the disease control rate at 12 weeks (DCR12), using the 
standard iRECIST criteria (see Section 11.0, where 11.5 specifically discusses iRECIST). 
All eligible patients who are registered and start treatment will be evaluable for the 
DCR12. A 1-stage design will be utilized (see below). This design has 80% power to 
detect an improvement in DCR12 from 25% to 50%, with a significance level of 0.10. 
See 1-stage design details below: 
Final analysis: We will enroll 19 eligible patients total. As various different types of 
mutations are to be included, various response patterns are possible; therefore the result 


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(expressed as the DCR12) might indicate but will not definitively be able to conclude that 
the treatment is worthwhile. If at least 8 patients are a success for DCR12 in the first 19 
eligible patients (41%), the treatment will be considered worthy of further investigation. 
Otherwise, depending upon per mutations results, the study might continue or the 
treatment is considered unworthwhile and can be permanently closed due to lack of 
efficacy.  
16.2 
Secondary Endpoints and Analysis:  
The following endpoints will be assessed as well: objective response rate (ORR), 
duration of confirmed stable disease according to iRECIST, time to next treatment 
(TTNT), overall survival , time to and duration of confirmed response, progression-free 
survival, and adverse events.  
Response rate: The confirmed response rate (by iRECIST ) will be assessed. Any 
confirmed response that occurs during the first 8 cycles of treatment will count as a 
success (24 weeks). Per iRECIST, responses need to be confirmed (2 consecutive 
responses at least 4 weeks apart) to count as a response. We will also assess the duration 
of confirmed stable disease according to iRECIST. All eligible patients who are 
registered and start treatment will be evaluable for response.  
Time to next treatment (TTNT): The TTNT is defined as the time from the end of study 
treatment to receiving the next treatment. TTNT will be estimated using the Kaplan-
Meier method.  
Overall Survival: Overall Survival (OS) is defined as the time from study entry to death 
from any cause. OS will be estimated using the Kaplan-Meier method.  
Time to and Duration of Confirmed Response: The time to response and duration of 
confirmed responses will be assessed using the Kaplan-Meier method, where the time to 
response will be the time from registration to confirmed response and the duration of 
confirmed response will be defined as the time from the first documented date of 
confirmed response (CR or PR) to the date at which progression is first documented.  
Progression-Free Survival: Progression-free survival (PFS) is defined as the time from 
study entry to the first of either disease progression or death from any cause, where 
disease progression will be determined based on iRECIST criteria. PFS will be estimated 
using the Kaplan-Meier method.  
Adverse events: The maximum grade for each type of adverse event will be summarized 
using CTCAE version 5.0. The frequency and percentage of grade 3+ adverse events will 
be estimated. We’ll also assess AEs at least possibly related to treatment as well.  
16.3 
Translational endpoints 
The goals of the translational studies are to assess germline DNA and serum markers of 
immune response, to determine changes in circulating tumor DNA (ctDNA) profile after 
therapy with a PARPi and a PD-1 inhibitor, to study mechanisms of resistance in ctDNA 
profile after therapy with a PARPi and a PD-1 inhibitor, to assess the tumor 
microenvironment for immune related changes (immune infiltration, PD-L1 and PD-1 
expression, tumor-infiltrating lymphocytes [TIL]), to assess genetic profile of the tumor 
pre- and post-treatment, and to determine changes in the cytokine profile pre- and post-
treatment. 
Due to the limited sample size, these analyses will be hypothesis generating and 
descriptive in nature. Descriptive statistics will be summarized and the blood and tissue 
marker data will be correlated with clinical endpoints (response, DCR12, duration of 


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response, OS, PFS, advere events, etc.). For time-to-event data, the Kaplan-Meier method 
will be used. For categorical data, we’ll use the Fisher’s exact test. For marker data used 
to predict binary outcomes (i.e. response vs. no response), we’ll use Logistic regression 
models.  
16.4 
Total sample size and study duration 
To account for possible drop-outs, cancellations, etc. we plan to accrue 20 total patients. 
We plan to accrue around 2 patients per month, so the study accrual phase should be 
around 10 months total. The final analysis can be done around 24 months after the study 
begins, which includes time for data entry, clean-up, and analysis.  
16.5 
Data & Safety Review 
16.51 Reviews 
The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.52 Adverse Event Stopping Rule: The stopping rule specified below is based on the 
knowledge available at study development. We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. Accrual may be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (ie, an 
adverse event with attribute specified as “possible”, “probable”, or “definite”) 
that satisfy the following: 
• 
If 3 or more of the first 10 patients (or 30% or more of all patients after 
10 are accrued) experience a Grade 4 AE. With exceptions: cytopenia, 
fatigue,  
• 
If 2 or more experience a Grade 5 AE at any time. 
After consideration by the study team (study chair, statistician, etc.), a decision 
will be made as to whether accrual can be resumed. 
16.6 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or ethnic 
group.  
16.61 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
 
 


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16.62 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 10% minorities. Expected sizes of racial by gender subsets are 
shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
9 
9 
18 
Ethnic Category: Total of all subjects* 
10 
10 
20 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
9 
9 
18 
Racial Category: Total of all subjects 
10 
10 
20 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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17.0  
Pathology Considerations/Tissue Biospecimens 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Research Study 
(Section for more 
information) 
Specimen 
Purpose 
(check all 
that apply) 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Baseline 
End of 
Cycle 4 
End of 
Treatment 
(any 
reason) 
Process at 
site? (Yes 
or No) 
Temperature 
conditions for 
storage/ 
shipping 
Sample 
Storage 
Location 
Tumor Collection 
(For xenograft 
and/or organoid) 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Fresh Tissue 
Core (1 core 
each) 
(1) 50mL Conical 
with MEM 
X 
X 
 
Yes in 
Rochester 
MCA, 
MCF ship 
on ice 
Wet Ice 
Dr. 
Couch’s 
Lab 
Identification/ 
Characterization of 
Intratumoral 
Immune Cells and 
BRCAness by IHC 
and CyTOF 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Archive 
FFPE Tissue 
or Fresh 
Tissue Cores 
FFPE blocks 
(preferred) or 
7 unstained glass 
slides with 
4 micron-thick 
sections 
 
X 
O 
Yes  
Ambient 
Dr. 
Couch’s 
Lab 
Large Panel 
Sequencing with low 
pass genome for copy 
number, tumor 
mutation burden 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
Archive 
FFPE Tissue 
or Fresh 
Tissue Cores 
Ten (10) unstained 
glass slides with 
5 micron thick 
sections & One (1) 
H&E stained Slides 
 
X 
 
Yes 
Ambient 
Dr. 
Couch’s 
Lab 
Tumor Collection for 
DNA and RNA future 
studies 
☐ Correlative 
☐ Eligibility 
Confirmation 
☒ Banking 
Fresh Tissue 
Cores (up to 
2 cores) 
(2) Snap Frozen 
Cores 
O 
 
 
Yes 
Frozen / Liquid 
Nitrogen 
MCR BAP 
Tumor Collection for 
DNA and RNA future 
studies 
☐ Correlative 
☐ Eligibility 
Confirmation 
☒ Banking 
Fresh Tissue 
Cores (up to 
2 cores) 
(1) FFPE Block 
O 
 
 
Yes 
Ambient 
Dr. 
Couch’s 
Lab 
Tumor Collection for 
DNA and RNA future 
studies 
☐ Correlative 
☐ Eligibility 
Confirmation 
☒ Banking 
Fresh Tissue 
Core (1 core) 
(1) RNA Later 
O 
 
 
Yes 
Frozen / Dry Ice MCR BAP 
X = Mandatory, O = Optional


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17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
Along with original diagnostic slides, include pathology reporting form, surgical 
pathology report and operative report. 
17.3 
Correlative Tissue Collection  
17.31 For Research Biopsy:  
• Image guided biopsies are recommended where feasible.  
• Frozen tissue will be handled and processed for specific processes through 
BAP. 
• FFPE Core shall be created from fresh tissue biopsy procedures.  
• Tissue Kits will not be provided for this protocol 
• Ship frozen samples to MCR BAP for storage. 
• Lab contact for fresh tissue samples (on ice): 
Dr. Fergus Couch 
Stabile Building, 2-43, 200 1st Street SW 
Rochester, MN 55905  
(contact is Anil Belur Nagaraj 507-284-7904 – pager) 
17.32 Paraffin Embedded Tissue 
Paraffin embedding procedure will follow standard practices. Tissue will be 
placed in formalin cassette, processed and embedded. Afterwards, tissue will be 
sectioned based on Table 17.1.  
If samples will not be tested shortly after collection, they will be stored as FFPE 
Blocks at Dr. Couch’s lab until sectioned for testing: 
Dr. Fergus Couch 
Stabile Building, 2-43, 200 1st Street SW 
Rochester, MN 55905  
(contact is Anil Belur Nagaraj 507-284-7904 – pager) 
17.33 Frozen Tissue 
BAP MCR will collect fresh tissue cores and store at -80°C for extraction of 
DNA and RNA. Any remaining tissue is to be stored in BAP MCR, until 
investigator requests for further studies.  
Tissue must be snap frozen in liquid nitrogen and remain frozen at -80°C in 
storage.  
17.34 Fresh Tissue for xenograft 
For core biopsies from locally recurrent or metastatic biopsy prior to initiation of 
therapy, will be placed into a labeled specimen container of MEM with protocol 
number, study patient ID number, and date and time sample is obtained. 
Specimens are to be delivered to Dr. Fergus Couch’s laboratory detailed below. 
Dr. Couch’s Laboratory 
Stabile Building, 2-43, 200 1st st SW 
Rochester, MN 55905  
(contact is Anil Belur Nagaraj 507-284-7904 – pager) 
 
 


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17.4 
Background and Methodology 
17.41 For tissue biopsies before, during and post treatment, goal is to study changes in 
tumor microenvironment and mutational status post-exposure to PARP inhibition 
and immunotherapy. The biopsy samples will be biobanked for these analyses in 
the future. These would include assessment of PD-L1 expression and assessment 
of mutational status pre- and post-exposure to immunotherapy. PD-L1 expression 
and changes in microenvironment would be assessed by immunohistochemistry 
using standard approved antibodies. 
17.42 For assessment of mutational status, comprehensive tumor based genetic testing 
will be performed to study changes in mutational load to exposure of PARP 
inhibition and immunotherapy over time. 
17.43 If feasible, samples would also be collected for xenograft development for 
potential future studies looking into drug based studies and to study uptake of 
grafts from these patients. 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up 
See Section 4.2.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis, progression, and genetic 
sequencing prior to study entry as well as for evidence of response to study therapy and 
progression after study therapy. These documents should be submitted within 14 days of 
registration (for prior to study entry materials) or within 14 days after the visit at which 
response or progression is determined. 
 
If a bone marrow aspirate collection is conducted (as indicated in the test schedule for 
subjects diagnosed with MDS/AML), the biopsy report will be required as supporting 
documentation. 
 
 


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18.6 
Labeling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded 
• 
Research testing on blood and tissue specimens. 
• 
Research biopsies at Baseline, Cycle 4 and optional EOT  
19.3 
Other budget concerns: 
GSK will provide Mayo Clinic with niraparib and TSR-042 and funding to support the 
costs of running this study. 
20.0 
References 
1. Ang, Y. L. E. and D. S. P. Tan (2017). "Development of PARP inhibitors in gynecological 
malignancies." Curr Probl Cancer 41(4): 273-286. 
2. Brown, J. S., R. Sundar and J. Lopez (2018). "Combining DNA damaging therapeutics with 
immunotherapy: more haste, less speed." Br J Cancer 118(3): 312-324. 
3. Connor AA, Denroche RE, Jang GH, et al, Association of Distinct Mutational Signatures 
with Correlation of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. JAMA 
Oncology, 2017; 3(6), pp774-783. 
4. Drean, A., C. J. Lord and A. Ashworth (2016). "PARP inhibitor combination therapy." Crit 
Rev Oncol Hematol 108: 73-85. 
5. Golan, T. and M. Javle (2017). "DNA Repair Dysfunction in Pancreatic Cancer: A Clinically 
Relevant Subtype for Drug Development." J Natl Compr Canc Netw 15(8): 1063-1069. 
6. Higuchi, T., D. B. Flies, N. A. Marjon, G. Mantia-Smaldone, L. Ronner, P. A. Gimotty and S. 
F. Adams (2015). "CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in 
BRCA1-Deficient Ovarian Cancer." Cancer Immunol Res 3(11): 1257-1268. 
7. Javle, M., T. Golan and A. Maitra (2016). "Changing the course of pancreatic cancer--Focus 
on recent translational advances." Cancer Treat Rev 44: 17-25. 
8. Jiao, S., W. Xia, H. Yamaguchi, Y. Wei, M. K. Chen, J. M. Hsu, J. L. Hsu, W. H. Yu, Y. Du, 
H. H. Lee, C. W. Li, C. K. Chou, S. O. Lim, S. S. Chang, J. Litton, B. Arun, G. N. 
Hortobagyi and M. C. Hung (2017). "PARP Inhibitor Upregulates PD-L1 Expression and 
Enhances Cancer-Associated Immunosuppression." Clin Cancer Res 23(14): 3711-3720. 
9. Konstantinopoulos PA, Sachdev JC, Schwtrzberg L, et al, Dose-finding combination study of 
niraparib and pembrolizumab in patients with metastatic triple-negative breast cancer or 
recurrent platinum-resistant epithelial ovarian cancer. Annals of Oncology, Sept 2017, Vol 
28. 
10. Kraya A, Maxwell KN, Wenz BM, et al. Aanlaysis of tumor Immunogenicity in germline 
BRCA1/2 mutation associated breast and ovarian cancers. Cancer Immunology Research, 
2017 (abstract) 


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11. Matsuo, K., S. E. Spragg, M. A. Ciccone, E. A. Blake, C. Ricker, H. Q. Pham and L. D. 
Roman (2018). "Nivolumab use for BRCA gene mutation carriers with recurrent epithelial 
ovarian cancer: A case series." Gynecol Oncol Rep 25: 98-101. 
12. Papa, A., D. Caruso, M. Strudel, S. Tomao and F. Tomao (2016). "Update on Poly-ADP-
ribose polymerase inhibition for ovarian cancer treatment." J Transl Med 14: 267. 
13. Ramakrishnan Geethakumari, P., M. J. Schiewer, K. E. Knudsen and W. K. Kelly (2017). 
"PARP Inhibitors in Prostate Cancer." Curr Treat Options Oncol 18(6): 37. 
14. Schaefer, N. G., E. James and R. L. Wahl (2011). "Poly(ADP-ribose) polymerase inhibitors 
combined with external beam and radioimmunotherapy to treat aggressive lymphoma." Nucl 
Med Commun 32(11): 1046-1051. 
15. Turk, A. A. and K. B. Wisinski (2018). "PARP inhibitors in breast cancer: Bringing synthetic 
lethality to the bedside." Cancer 124(12): 2498-2506. 
16. Waddell N, Pajic M, Patch AM, et al, Whole genomes redefine the mutational landscape of 
pancreatic cancer. Nature, 518, Feb 2015, pp 495-501. 
17. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47 
18. Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. The Lancet Oncology, 2017. 18(3): p. e143-e152. 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 
 


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Appendix II Patient Medication Diary 
Name _ 
 
Study ID Number  
 
Please complete this diary on a daily basis. Write in the amount of the dose of niraparib that you 
took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
If you experience any health/medical complaints or take any medication other than niraparib, 
please record this information. 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Niraparib 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Niraparib 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Niraparib 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ 
Comments: 
 
 
 
Use a separate sheet of paper if more space is needed. 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________ 
Study Coordinator Use Only 
Number of pills returned ______ 
Number of vials returned: _______ 
 
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________ 


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Appendix III Examples of confirmed progression  
The following examples show how a patient that is currently an iUPD can become an iCPD (confirmed 
progression). These examples all use target lesion growth as the source of the first progression (iUPD) 
and show how additional information in future assessments can lead to iCPD. The examples are not 
exhaustive, but are meant to be illustrative of how iCPD can occur. Similar examples can be created 
where non-target lesions and/or new lesions led to the initial iUPD. 
1) iUPD due to target lesion growth from baseline followed by iCPD due to continued growth of 
target lesions (by at least 5 mm). 
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
132 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
None 
TP response (R) 
 
PD 
PD 
TP response (iR) 
 
iUPD 
iCPD 
2) iUPD due to target lesion growth from baseline followed by iCPD due to gradual continued 
growth (over 2 assessments) of target lesions (by at least 5 mm from time of first iUPD). 
 
Baseline 
TP1 
TP2 
TP3 
T lesions (sum) 
100 
125 
128 
132 
NT lesions 
Pres 
No change 
No change 
No change 
New lesions 
 
None 
None 
None 
TP response (R) 
 
PD 
PD 
PD 
TP response (iR) 
 
iUPD 
iUPD 
iCPD 
3) iUPD due to target lesion growth from baseline followed by iCPD due to new lesion appearing 
after start of iUPD. This iCPD is based on criteria #2 outlined in Section 11.5.1.  
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
125 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
1 new lesion 
TP response (R) 
 
PD 
PD 
TP response (iR) 
 
iUPD 
iCPD 
4) iUPD due to target lesion growth from baseline followed by iCPD due to additional target lesion 
growth as well as a new lesion. 
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
132 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
1 new lesion 
TP response (R) 
 
PD 
PD 
 
 
 


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Appendix IV PAXgene Manufacturer’s Recommendations 
Information below is from manufacturer’s website: https://www.qiagen.com/us/resources/  
Document: “PAXgene Blood RNA System Brochure” 
 


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Appendix V 
Patient Blood Pressure and Heart Rate Monitoring Diary 
Name _ 
 
Study ID Number  
 
Please complete this diary on the dates specified below. You will be asked to the record the 
requested information once a week for the first 2 months of therapy while on this study. 
If you are in the clinic for any of the visits listed below for this study, please leave the space 
blank as the study staff will record your blood pressure and heart rate during your visit. 
 
Cycle / Day 
Date  
(dd/mmm/yyyy)  
Blood Pressure  
Systolic/Diastolic  
(top/bottom number)  
Heart Rate (beats per 
minute) 
Cycle 1 Day 1 
 
 
 
Cycle 1 Day 8 
 
 
 
Cycle 1 Day 15  
 
 
Cycle 2 Day 1 
 
 
 
Cycle 2 Day 8 
 
 
 
Cycle 2 Day 15  
 
 
Cycle 3 Day 1 
 
 
 
Cycle 3 Day 8 
 
 
 
Cycle 3 Day 15  
 
 
Patient signature: ___________________________________________ 
Comments: 
 
 
 
Use a separate sheet of paper if more space is needed. 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________