Conditions: Cervical Cancer Endometrial Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 49
Healthy volunteers: no

Brief summary:
This is a phase II study of rucaparib, a small molecule inhibitor poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PARP), being tested in combination with bevacizumab in patients with recurrent cervical or endometrial cancer. The objective of this study is to determine the proportion of these patients who survive progression-free for at least 6 months while receiving this drug combination.

Detailed description:
Patients who consent to participate in this study will receive treatment with rucaparib and bevacizumab until unacceptable toxicity or tumor progression. Subjects will take one rucaparib pill will be taken twice daily, and bevacizumab will be adimistered via IV onDay 1 of each 21 day cycle. Subjects will receive tests and procedures that are part of regular cancer care as well as those required for the purposes of this study. If there is no cancer found in scans after 6 cycles of treatment, patients may continue with study treatment for 1 year. Follow up visits will occur every 3 months for the first 2 years after treatment is completed and every 6 months for 3 additional years.

Arms:
arm 1: None

Interventions: intervention 1: Rucaparib intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Rucaparib 600mg PO BID daily intervention 2: Bevacizumab 15mg/kg IV on day 1 of each cycle

Protocol document:
ICF_002.pdf: 
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Model Consent Form 
 
Protocol: A Phase II Trial of Bevacizumab and Rucaparib in Recurrent Carcinoma of the 
Cervix or Endometrium  
 
Study Sponsor:  University of Oklahoma Health Sciences Center (OUHSC) 
 
Funding Collaborator: Clovis Oncology 
 
This is a clinical trial (a type of research study). Your study doctor will explain the clinical trial to 
you. Clinical trials include only patients who choose to take part in them. Please take your time to 
make your decision. You may discuss this with your family, friends and doctors. If you have any 
questions, you can ask your study doctor for more information at any time. 
 
Clovis Oncology pharmaceutical company is providing the study medicine, rucaparib, free of 
charge and paying for certain study procedures.  
 
Why Have I Been Asked To Participate In This Study? 
You are being asked to take part in this trial/study because you have been diagnosed as having 
carcinoma of the cervix or endometrium. 
 
Why Is This Study Being Done? 
The purpose of this study is to find out what effects (good and bad) that combination treatment of 
rucaparib and bevacizumab has on you and others with persistent or recurrent cervical or 
endometrial cancer. This study is being done because currently there is no effective treatment for 
people with your condition. We will look to see if the medicine is helpful in shrinking cancers, 
keeping them from growing or spreading, or helping patients live longer. We will also collect 
information about any side effects and how you feel with the two medications. 
 
What is the Status of the Drugs (Devices or Procedures) Involved in this Study? 
Rucaparib is currently approved by the US Food and Drug Administration for treatment of patients 
with advanced ovarian cancer who have been treated with two or more chemotherapies; but is not 
approved for the disease in this study, so it is considered investigational in this study. 
 
Bevacizumab is currently approved by the US Food and Drug Administration for treatment of 
patients with various types of cancer, but the combination of bevacizumab and rucaparib is not 
approved for the disease in this study, so it is considered investigational in this study.  
 
How Many People Will Take Part In The Study? 
About 100 people will take part in this study within four medical centers nationwide. About XX 
of these individuals will participate at this medical center. 
 
What Is Involved In The Study? 
If you take part in this study, you will have the following tests and procedures: 
 


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Before you begin the study 
You will need to have the following exams, tests or procedures to find out if you can be treated in 
the study. These exams, tests or procedures are part of regular cancer 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 your study doctor. 
• Doctor’s visit with examination to include a pelvic examination 
• Blood work to measure blood counts, blood clot function, blood salt levels, and how well 
your liver and kidneys are working 
• A pregnancy test if you are capable of becoming pregnant 
• Urinalysis (examination of urine) 
• CT scan or MRI of the chest, abdomen and pelvis to measure your tumor 
 
You will need to have the following tests as part of the study. The following exams are not standard 
of care: 
• Research blood draws 
• Tumor biopsy 
• ECG (electrocardiogram)  
 
During the study  
If the exams, tests and procedures show that you can be treated in the study, and you choose to 
take part, then you will need the following tests and procedures. They are part of regular cancer 
care.  
• Doctor’s visit with examination to include a pelvic examination every treatment cycle 
(typically every 3 weeks) 
• Blood tests to measure blood counts, blood salt levels, and how well your liver and kidneys 
are working (as often as once 3 weekly, but may be weekly if you have blood cell counts 
decreased) 
• Urinalysis (examination of urine) done once every treatment cycle (typically every 3 
weeks) 
• Repeat CT scans every other cycle (typically every 8 weeks). 
 
You will receive treatment of rucaparib and bevacizumab until unacceptable toxicity or tumor 
progression. 
• You will take rucaparib twice a day by mouth with 8 oz. (240 mL) of room temperature 
water; tablets should be swallowed whole without chewing. You should take rucaparib 
doses as close to 12 hours apart as possible, preferably at the same times every day. If you 
miss a dose (i.e., did not take it within 4 hours of the scheduled time), you should skip the 
missed dose and resume taking rucaparib with the next scheduled dose. Missed or vomited 
doses should not be made up.  
o You will also need to fill out a pill diary when you take your pills. 
• You will receive bevacizumab by vein (IV) once each cycle on day 1 of the 21 day cycle. 
 
On day 22, if your oncologist feels you may safely continue treatment, you will begin a new 21 
day cycle. 
 
After your treatments are completed:   


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To monitor your well-being and the status of your cancer, you will have these tests and procedures 
that are part of regular cancer care: 
• Doctor’s visit with examination which may include pelvic examination  
o every 3 months for two years 
o then every 6 months for three years 
o then every year thereafter  
• Blood work if your physician feels they are necessary for monitoring 
• CT scan or MRI at the end of the study as indicated by your doctor 
• Urinalysis (examination of urine) 
 
You will need to have the following tests as part of the study. The following exams are not standard 
of care: 
• ECG (electrocardiogram) 
 
How Long Will I Be In The Study? 
You will be asked to take the study medicines as long as there is evidence that your tumor is not 
growing or spreading and you are not having any bad side effects.  If there is no cancer on your 
scans after 6 cycles of treatment, you may continue with the study treatment for one more year. 
 
After you have finished treatment, the study doctor will ask you to visit the office for follow-up 
exams at least every three months for the first two years and every six months for the next three 
years.  After this, we would like to keep track of your medical condition for the rest of your life 
by calling you once a year to see how you are doing. Keeping in touch with you and checking on 
you every year helps us look at the long-term effects of the study medicines.  
 
Can I Stop Being in the Study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping, so any risks from the 
study treatment can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what other care and testing could be most helpful for you. 
 
There may be anticipated circumstances under which your participation may be terminated by the 
investigator without regard to your consent. 
• The doctor feels that it is safest for you. 
• Your cancer or medical illnesses worsen. 
• New information becomes available that suggests another treatment would be better for 
you 
• You do not follow study requirements. 
• The study is stopped by the sponsor. 
 
What Are The Possible Side Effects, Risks and Discomforts of The Study?  
You may have side effects from taking rucaparib or from the procedures used in this study. You 
should discuss these with the researcher and/or your regular doctor. Other drugs may be given to 
make side effects less serious and uncomfortable. Many side effects go away shortly after the 


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rucaparib and/or bevacizumab are stopped, but in some cases side effects can be serious or long 
lasting and permanent. The treatment or procedure may involve risks that are currently 
unforeseeable.  
Side effects may vary from person to person, and can range from mild to very serious. If you have 
any side effects as a result of taking part in this study, tell your study doctor right away, even if 
you don’t think they are due to the rucaparib. 
Rucaparib Side Effects 
Oral rucaparib is an experimental drug that may have side effects that cannot be predicted at this 
time. Rare or unknown side effects could possibly occur, including life-threatening events or death. 
If you experience certain side effects, the study doctor may decide to stop or lower your dose of 
rucaparib until you recover from the side effects.  
The following is a list of reported side effects as well as other notable side effects considered to 
be possibly due to rucaparib, as reported by physicians about their patients who are taking 
rucaparib alone: 
Very common (Occurring in 10% or more of patients) 
• Nausea  
• Feeling tired (known as fatigue or lethargy) 
• Low blood counts, (red blood cells, white blood cells, and platelets).  Sometimes fever 
occurs with the low blood counts. These low blood count effects may be more likely to 
occur after multiple cycles of treatment. 
o A low red blood cell count may make you feel tired or dizzy. If you feel dizzy while 
taking rucaparib, you should avoid potentially hazardous tasks such as driving or 
operating machinery. 
o A low white blood cell count puts you at higher risk for bacterial or viral 
infections. Having a high temperature or fever while your white blood cell count is low 
is a medical emergency and you must proceed to the nearest emergency room as soon 
as possible.    
o A low platelet count affects the ability of your blood to clot and could lead to bleeding 
events. Symptoms include but are not limited to easy bruising, prolonged bleeding from 
cuts, blood in stools or urine, or nose bleeding. 
• A low phosphate level in your blood. Usually there are no symptoms, but if the levels are 
critically low, you may notice trouble breathing, confusion, muscle weakness, and/or 
irritability. 
• Increase in cholesterol. If your cholesterol increases significantly, your doctor may 
prescribe a medicine to lower your cholesterol level. 
• Changes in kidney and liver function blood tests. These changes will be evaluated by your 
study doctor along with any other side effects that you are experiencing as well as other 
test results.  
• Changes in your sense of taste 
• Stomach-related effects such as constipation, vomiting, diarrhea, decreased appetite, 
stomach pain (epigastric pain), and indigestion. 
• Difficulty breathing (dyspnea) 
• Dizziness 


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• Photosensitivity reaction 
o It is possible that rucaparib may make your skin and eyes more sensitive to sunlight. 
You should take all of the usual sun protection precautions when going outside. It is 
advised that you avoid excessive sun exposure, wear protective clothing (including 
wearing a hat and sunglasses), and use sunscreens regularly (sun protection factor 50 
or greater). 
• Fever sometimes can occur independent of a low blood count. If you experience an 
elevation of your temperature, please refer to your study doctor for fever management. 
• Difficulty sleeping  
Common (Occurring in 1% to less than 10% of patients)  
• Upper Airway Infection (like the common cold) 
o You may experience infections involving the nose, pharynx, larynx, and sinuses. 
Symptoms include a blocked (congested) nose, a runny nose, and sneezing. You may 
also have clear discharge (mucus) from the nose. You may feel generally unwell and 
may also be associated with fever. Treatment is usually supportive but if symptoms 
persist, please inform your doctor. 
Uncommon (Occurring in 0.1% up to less than 1% of patients) 
• Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) 
o Effects possibly related to rucaparib, but whose causal link has not been formally 
established, have been reported in a very small number of patients treated with 
rucaparib during the safety period (while on treatment with rucaparib and 28 days after 
last dose). MDS is a pre-cancerous condition where the bone marrow is not as good at 
producing blood cells (red and/or white blood cells and/or platelets). People with MDS 
need transfusions (red blood cells and/or platelets) and/or other treatments. In some 
cases, MDS will progress to AML, which is a cancer of the bone marrow where more 
abnormal and immature white blood cells (also called blasts) are made than normal 
white blood cells. People with AML need treatment with chemotherapy and/or a bone 
marrow transplant. Patients may develop AML without first being diagnosed with 
MDS.  
o Events of MDS and AML have also been reported with PARP inhibitors similar to 
rucaparib. At this time, it is not known whether rucaparib or other PARP inhibitors 
cause MDS or AML, or if these developed as a result of previous chemotherapy these 
patients received. Your study doctor will closely monitor your blood cell levels during 
treatment. If he/she has any concerns about your blood counts you may be asked to 
have a biopsy of your bone marrow. 
Allergic Reactions 
As with any drug, it is possible that you could have allergic reactions to rucaparib, such as itching, 
skin rash, facial swelling, and/or a severe or sudden drop in blood pressure. A sudden drop in blood 
pressure could lead to shock with loss of consciousness and/or possible seizures, including the 
possibility of death. If you have any of the above symptoms, seek medical attention right away. 
Possible Side Effects of Bevacizumab 
The following is a list of the most commonly-reported side effects and other notable side effects 
considered to be possibly due to bevacizumab, as reported by physicians about their patients who 
are taking bevacizumab alone: 


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Likely (Occurring in 20% or more of patients) 
• High blood pressure which may cause headache or blurred vision 
• Low appetite, nausea, vomiting, constipation or diarrhea 
 
Less Likely (Occurring in 4-20% of patients) 
• Anemia which may require blood transfusion 
• Low white cell count that may increase the risk of infection 
• Infection, including collection of pus in the belly or rectum 
• Abnormal heartbeat which may cause palpitations or fainting 
• Pain in the belly, rectum, chest, joints, muscles, or tumor 
• Internal bleeding (predominantly tumor-associated) which may cause black tarry stool, 
blood in vomit, coughing up of blood, or blood in urine 
• Bleeding from other sites, including the vagina, gingiva or nose 
• Blockage of internal organs which may cause vomiting or inability to pass stool 
• Sores in mouth 
• Allergic reaction during or after infusion of bevacizumab which may cause fever, chills, 
rash, itching, hives, low blood pressure, wheezing, shortness of breath, swelling of the face 
or throat 
• Delay in healing of wounds or spontaneous opening of wounds 
• Weight loss, tiredness, or dizziness or dehydration or muscle weakness 
• Damage to the jawbone which may cause loss of teeth or loss of motion 
• Headache, or excess tearing 
• Numbness, tingling, or pain in the fingers or toes 
• Hoarseness, stuffy nose, or cough 
• Dry skin, or swelling and redness of the skin 
• Blood clot in limbs or lungs which may cause swelling, pain, shortness of breath 
• Leakage of protein in the urine, which can rarely lead to damage to the kidney 
• Clots in the arteries, causing stroke (which may cause paralysis or weakness) or heart attack 
(which may cause chest pain or shortness of breath). This risk is significantly increased in 
patients who are elderly or with history of diabetes 
• Hypomagnesemia or hyponatremia (a low level of magnesium or sodium in the blood) 
 
Uncommon (Occurring in <3% of patients) 
• Heart failure which may cause shortness of breath, swelling of ankles, or tiredness 
• Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require surgery 
to repair 
• Gall-bladder perforation (a tear in gall-bladder) that can cause pain and require surgery to 
repair 
• A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, rectum, 
or vagina. These conditions may cause serious infections or bleeding and require surgery 
to repair 
• Sores in the throat 
• Flesh-eating bacteria syndrome, an infection in the deep layers of skin 


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• Bleeding in the tumor, brain, belly, or lungs which may cause confusion, blood in stool or 
coughing up blood 
• Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
• Kidney damage which may require dialysis 
• Redness, pain or peeling of palms and soles 
• Antibody development (anti-bevacizumab antibody) 
 
Rare but potentially serious (occur in less than 1% of patients taking bevacizumab alone or in 
combination with other anti-cancer drugs) 
• Anaphylaxis (a severe, potentially life-threatening allergic reaction)  
• Acute myocardial infarction (heart attack)  
• Cerebral infarction (stroke)  
• Hemolytic anemia (destruction of red blood cells causing anemia)  
• Hypertensive crisis, hypertensive encephalopathy,  
• Increased intraocular pressure, inflammation of eye, or permanent vision loss 
• Intestinal necrosis (bowel tissue death likely due to loss of blood flow to the intestines)  
• Pulmonary hypertension (high blood pressure in lung)  
• Tracheoesophageal fistula (abnormal connection between the esophagus and the trachea) 
 
Additional Notes on Possible Side Effects for Bevacizumab: 
• Risk in pre-menopausal women: more likely to develop menopause when taking 
bevacizumab. 
• Risk in children or adolescents: abnormal bone changes which may interfere with growth. 
Let your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time. 
Additional Risks or Discomforts 
Procedure to Collect A Tumor Tissue Sample: 
During the screening phase, if an archived tumor sample is not available, you will undergo a 
procedure to collect a sample of your tumor (called a biopsy), unless the biopsy procedure is 
considered unsafe by the study doctor or if the study doctor is unable to collect a sample, which 
will be used for biomarker research. You must indicate if you agree or do not agree to the 
biopsy procedures during screening by initialing at the end of this consent form. 
The risk and discomfort to you depends upon the site of the biopsy. Since a larger needle is being 
inserted into your body under local anesthesia, there is a risk of some pain or infection.  Bleeding, 
bruising or swelling could also occur. Ask the study doctor to tell you about more specific biopsy 
risks based on the site of your biopsy.   
Blood Sampling: 


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Having blood drawn from a vein in your body may cause some pain, redness, or bruising where 
the needle is inserted. An infection is also possible, but rare. If you feel faint while having your 
blood drawn, you should sit or lie down to avoid falling.   
Electrocardiogram (ECG): 
The ECG test is a recording of the electrical activity of your heart. The sticky pads used may be 
cold when applied and your skin may react to the sticky patches that attach the detectors 
(electrodes) to the chest for ECG. This skin irritation usually disappears when the patches are 
removed. If the hair under the patches needs to be shaved, irritation from shaving also could occur. 
 
CT and MRI Scans: 
Computed tomography (CT) scans use x-ray radiation. The amount of radiation you will receive 
during a CT scan is small, but the more radiation you receive over the course of your life, the more 
likely it is that the cells in your body may change or that you develop a new cancer. Some CT 
scans require you to take a “contrast solution” injected into a vein. It is possible that the contrast 
solution may cause you to have nausea, vomiting, itching, or skin rash. In rare cases, it may cause 
your throat to swell and make it hard to breathe. These may be signs of an allergic reaction so tell 
the study doctor right away if you have any of these side effects. You may have some discomfort 
from lying still in an enclosed space for a prolonged period of time. 
Sometimes a magnetic resonance imaging (MRI) scan is done in patients with allergies to the 
contrast solution used in a CT scan. An MRI does not use x-ray radiation, but it takes a little longer 
and patients sometimes have to lie in a more enclosed space than with a CT scan. A contrast 
solution may be injected into your vein before the scan is done to help the doctor see the tumor 
more clearly. 
Reproductive risks: 
Treatment with rucaparib may involve risks that are currently unforeseeable to a fetus, embryo, or 
unborn child. You cannot participate in this study if you are pregnant, or if you are thinking about 
becoming pregnant. You should not nurse (breast feed) a baby while in this study because the 
study drug may enter breast milk and possibly harm your child. 
If you are of childbearing potential, you must agree to undergo monthly serum pregnancy testing 
and use highly effective birth control while you are taking rucaparib and for 6 months afterward. 
Highly effective birth control is considered to be a method with a less than 1% per year failure rate 
and is defined in this study as established use of progesterone-only injectable or implantable 
contraceptives (e.g. Depo Provera, Implanon, Nexplanon), placement of an intrauterine device 
(IUD) or intrauterine system (IUS), surgical sterilization, or true, complete (as opposed to periodic) 
abstinence. If this applies to you, please discuss your plan for birth control with the investigator or 
study staff.  
If you become pregnant or suspect that you are pregnant during this study, you should immediately 
inform the study personnel. If you become pregnant or suspect that you are pregnant while on this 
study, tell the study doctor immediately; the study doctor will perform a pregnancy test. The study 
drug may be discontinued until the result of the pregnancy test is known. If pregnancy is confirmed, 
you may be withdrawn from the study. The study doctor will assist you in getting obstetrical care 
at your cost. Payment for all aspects of obstetrical, child, or related care will be your responsibility. 


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If you think you might want to have a child after taking part in this study, you should also talk with 
the study doctor about whether your eggs should be stored before you start study treatment.  The 
cost of storing your eggs is not covered by this study.  If you get pregnant at any time during this 
study or within 6 months after taking your last dose of study drug, tell the study doctor right away 
and you will need to stop taking rucaparib immediately (if you are taking rucaparib at the time). 
You may be asked for information about your health and the baby’s health to see how the 
pregnancy turned out. 
 
Are There Benefits to Taking Part in The Study?  
If you agree to take part in this study, there may or may not be direct medical benefit to you. We 
hope that the information learned from this study will benefit other patients with this disease in the 
future. 
 
What Other Options Are There?  
If you decide not to take part in this study, you have other choices for your care. For example:  
• You may choose to receive no therapy at this time and receive only care to help you 
feel more comfortable. 
• You may choose to take part in a different research study, if one is available 
Please talk to your regular doctor about these and other options. 
 
What about Confidentiality? 
Efforts will be made to keep your personal information confidential. You will not be identifiable 
by name or description in any reports or publications about this study. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law.  You will 
be asked to sign a separate authorization form for use or sharing of your protected health 
information. 
 
There are organizations outside the insert site name that may inspect and/or copy your research 
records for quality assurance and data analysis. These organizations include the study Sponsor and 
its representatives, the US Food & Drug Administration, and other regulatory agencies, and Clovis 
Oncology and its representatives.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required 
by U.S. Law.  However, this website will not include information that can identify you.  At most, 
the website will include a summary of the study and results.  You can search this website at any 
time. 
 
When the research results are published or discussed in conferences, no information will be 
included that reveals your identity. In a few rare situations, federal or state law requires disclosure 
of personal information.  
 
What Are the Costs? 
You and/or your health plan/insurance company will need to pay for some of the costs of treating 
your cancer in this study, including the cost of monitoring and managing the side effects of therapy.  


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Some health plans will not pay these costs for people taking part in studies.  Check with your 
health plan or insurance company to find out what they will pay for.  You will be responsible for 
paying any deductibles, co-insurance, and co-payments as required under the terms of your 
insurance plan(s). Taking part in this study may or may not cost your insurance company more 
than the cost of getting regular cancer treatment.  
 
Rucaparib is an investigational drug and will be provided free of charge by Clovis Oncology.  The 
tumor biopsy and related molecular assays which are specifically needed to check for the potential 
relationship with the effect of this medicine will be covered under the study. However, you or your 
insurance company will be required to pay for all expenses related to the administration of the drug 
and your other hospital care.  
 
Bevacizumab is currently commercially available for cancer therapy. You or your insurance 
company will be required to pay for bevacizumab and all expenses related to the administration of 
the drug and your other hospital care. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
Will I Be Paid For Participating in This Study? 
You will not be paid for taking part in this study.   
 
What if I am Injured or Become Ill While Participating in this Study? 
In the case of injury or illness resulting from this study, emergency medical treatment is available. 
No funds have been set aside by the Sponsor to compensate you in the event of injury.  
 
You will get medical treatment if you are injured as a result of taking part in this study.  The study 
will not pay for medical treatment. 
 
What Are My Rights As a Participant? 
Taking part in this study is voluntary. You may choose not to participate. Refusal to participate 
will involve no penalty or loss of benefits to which you are otherwise entitled. 
 
If you agree to participate and then decide against it, you can withdraw for any reason and leave 
the study at any time.  However, at certain times during the treatment, it may be harmful for you 
to withdraw, so please be sure to discuss leaving the study with the principal investigator or your 
regular physician.  You may discontinue your participation at any time without penalty or loss of 
benefits to which you are otherwise entitled. 
 
We will provide you with any significant new findings developed during the course of the research 
that may affect your health, welfare, or willingness to continue your participation in this study.   
 


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You have the right to access the medical information that has been collected about you as a part of 
this research study.  However, you may not have access to this medical information until the entire 
research study has completely finished. You consent to this temporary restriction. 
 
Where Can I Get More Information? 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form. If you want more information about this study, ask your study 
doctor. 
 
GENERAL INFORMATION ABOUT THE COLLECTION AND USE OF SPECIMENS 
FOR RESEARCH 
You are being asked to allow samples from your tumor and blood to be submitted and used in 
research.  Such bodily materials are referred to as specimens and are very important in helping 
doctors and scientists learn more about caring for and treating people with cancer and other 
diseases. The use of specimens in scientific research can also help doctors and scientists understand 
why some people develop cancer and others don’t, and why some people have cancers that respond 
or don’t respond well to current therapies, for example. 
The research that may be done with your specimens is not designed specifically to help you, but it 
may help others with cancer or other diseases in the future. Reports about research done with your 
specimens will not be given to you or your regular physicians, or be put in your health record. The 
research will not have an effect on your care.  
 
When research is performed on specimens connected with clinical information about the person, 
including the person’s disease and how the person responds to treatment, doctors and scientists 
can specifically study how to prevent, detect, treat and cure cancer and other diseases, or how to 
predict response to therapy, toxicities, recurrence and overall survival.  
 
The Sponsor uses procedures designed to protect your privacy and confidentiality. The chance that 
information from your health records would be incorrectly released is very small, but you should 
be aware of this risk.  To protect your privacy and confidentiality, the research investigators that 
study your specimens will never be given your name, address, phone number, Social Security 
number or any other personal information. In addition, your specimens will never be labeled with 
your name or other type of personal identifier. Your specimens will be labeled with a unique series 
of letters and numbers in order to keep track of the specimens.  Research investigators receive 
specimens labeled only with these codes. 
 
Your specimens will be used for research purposes and will not be sold.  However, the research 
may help to develop new products and therapies in the future that could be patented and licensed. 
In any event, there are no plans to provide you with any direct financial compensation.  


OU-SCC-Clovis-001  
 
 
 
Model ICF Version 3.1 19-Feb-2020 
Page 12 of 13 
 
 
If you agree now that your tumor specimen and/or blood specimens can be submitted and used for 
this research study and/or future research, you can change your mind at any time. At that time, 
please contact the staff at your treating institution, typically your doctor or nurse, and tell them 
that you have changed your mind about allowing your specimens to be used for research.  
  
SPECIFIC INFORMATION FOR THIS RESEARCH STUDY  
Requirements  
We would like to have your permission to have some of your tumor, if available, from a recent 
surgery. If you have not recently had surgery, we are requesting you undergo a biopsy to obtain a 
small piece of your tumor.  The reason for this is to study your tumor and the effect of this treatment 
on it. 
 
We are also asking participants to provide two teaspoons of blood one time to look at parts in the 
blood and how it relates to treatment response. This will be done when you enroll into the study. 
 
Risks of genetic testing:  
 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information.   
 
This law generally will protect you in the following ways:  
 
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.  
• Employers with 15 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting the 
terms of your employment.  
 
Be aware that this Federal law does not protect you or your family against genetic discrimination 
by companies that sell life insurance, disability insurance, or long-term care insurance.  Also, 
GINA does not prohibit discrimination of individuals with a genetic disorder that has been 
diagnosed.  However, in order to do everything possible to keep this from happening, the results 
of this test will NOT be given to anyone outside the study staff. This means that it will not be made 
available to you, your family members, your private physician, your employer, your insurance 
company or any other party as allowed by law.  
 
Whom Do I Call If I have Questions or Problems? 
If you have questions, concerns, or complaints about the study or have a research-related injury, 
contact insert PI name and phone number.  
 
If you cannot reach the Investigator or wish to speak to someone other than the investigator, contact 
the insert local IRB contact information. 


OU-SCC-Clovis-001  
 
 
 
Model ICF Version 3.1 19-Feb-2020 
Page 13 of 13 
 
Agreement for additional procedures and release of tumor samples 
When you agree to participate in this study, the study team will determine if the additional blood 
work or biopsy is needed. 
1. This patient has available tumor for research? 
Yes 
 
No 
 
 
 
 
2. Do you agree to allow your tumor that was already collected to be used for this study? 
Yes 
 
No 
 
N/A 
 
  
Initials of Patient 
3. This patient is being asked to complete a tumor biopsy? 
Yes 
 
No 
 
 
 
 
4. Do you agree to have a tumor biopsy completed prior to starting (if applicable) on 
this study? 
Yes 
 
No 
 
 
 
  
Initials of Patient 
 
Signature: 
By signing this form, you are agreeing to participate in this research study under the conditions 
described. You have not given up any of your legal rights or released any individual or entity from 
liability for negligence. You have been given an opportunity to ask questions. You will be given a 
copy of this consent document. 
 
I agree to participate in this study: 
 
_________________________ 
_______________________ _________ 
PARTICIPANT SIGNATURE  
Printed Name  
 
Date 
 
 
_________________________ 
_______________________ _________ 
SIGNATURE OF PERSON   
Printed Name  
 
Date  
OBTAINING CONSENT 

Prot_000.pdf: 
Version 5.0 (1-Apr-2020) 
1 
CLINICAL STUDY PROTCOL 
Study Title: A Phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the 
cervix or endometrium 
Sponsor Institute: 
Stephenson Cancer Center 
800 NE 10th Street, Oklahoma City, OK 73104 
 
Study Products: 
Rucaparib 
Bevacizumab 
IND Number: 
137278 
NCT Number: 
NCT03476798 
 
STUDY CHAIRS: 
Principal Investigator: 
Camille Gunderson, MD 
800 NE 10th Street,  
Oklahoma City, OK 73104  
E-mail: Camille-Gunderson@ouhsc.edu 
 
Co-Investigator: 
 
Kathleen Moore, MD 
 
Translational Scientist: 
Lurdes Queimado, MD, PhD 
 
Statistician:  
 
Kai Ding, PhD 
 
Funding Collaborator: 
Clovis Oncology 
 
Protocol Writer: 
 
Yuejin Wen, PhD, MD 
 
 
 


Version 5.0 (1-Apr-2020) 
2 
TABLE OF CONTENTS 
1 
INTRODUCTION AND RATIONALE .......................................................................................... 5 
1.1 
Study Hypothesis ............................................................................................................ 5 
1.2 
Rationale for Recurrent Cervical Cancer ........................................................................ 5 
1.3 
Rationale for Endometrial Cancer .................................................................................. 7 
1.4 
Summary of Investigational Product .............................................................................. 8 
1.5 
Summary of Bevacizumab Clinical Experience ............................................................. 17 
1.6 
Study Rationale ............................................................................................................ 18 
1.7 
Rationale for Correlative Studies ................................................................................. 19 
2 
STUDY OBJECTIVES .............................................................................................................. 20 
2.1 
Primary Objectives ....................................................................................................... 20 
2.2 
Secondary Objectives ................................................................................................... 20 
2.3 
Translational Objectives ............................................................................................... 20 
3 
PATIENT ELIGIBILITY AND EXCLUSIONS ............................................................................... 20 
3.1 
Inclusion Criteria .......................................................................................................... 20 
3.2 
Exclusion Criteria .......................................................................................................... 22 
3.3 
Patients with Reproductive Potential .......................................................................... 23 
4 
SUBJECT REGISTRATION AND ENROLLMENT ...................................................................... 24 
4.1 
Required Protocol Specific Regulatory Documents ..................................................... 24 
4.2 
Patients Registration and Enrollment .......................................................................... 24 
5 
STUDY MODALITIES ............................................................................................................. 25 
5.1 
Bevacizumab ................................................................................................................ 25 
5.2 
Rucaparib...................................................................................................................... 26 
6 
TREATMENT PLAN ............................................................................................................... 28 
6.1 
Treatment Schedule for Bevacizumab plus Rucaparib ................................................ 28 
6.2 
Method of Bevacizumab and Rucaparib Administration ............................................. 28 
6.3 
Dose Modifications....................................................................................................... 28 
6.4 
Precaution for Concomitant Medication during the Study ......................................... 33 


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6.5 
Supportive Care ............................................................................................................ 35 
6.6 
Duration of Therapy ..................................................................................................... 35 
6.7 
Duration of Follow-up .................................................................................................. 35 
7 
STUDY PARAMETERS ........................................................................................................... 35 
7.1 
Therapeutic Parameters ............................................................................................... 35 
7.2 
Study Calendar ............................................................................................................. 35 
7.3 
Biological Sample Collection for Correlative Studies ................................................... 38 
7.4 
Follow up Parameter .................................................................................................... 39 
8 
EVALUATION CRITERIA ........................................................................................................ 39 
8.1 
Parameters of Outcome –RECIST 1.1 Criteria .............................................................. 39 
8.2 
Subjective Parameters ................................................................................................. 40 
8.3 
Definition of Evaluable Patients ................................................................................... 40 
9 
STUDY MONITORING AND REPORTING PROCEDURES ........................................................ 41 
9.1 
Adverse Event Monitoring and Management .............................................................. 41 
9.2 
Reporting of Serious Adverse Events ........................................................................... 46 
9.3 
MED WATCH 3500A Reporting Guidelines .................................................................. 46 
9.4 
Safety Reporting Requirements for IND Holders ......................................................... 47 
10 STATISTICAL CONSIDERATIONS ........................................................................................... 48 
10.1 Sample Size ................................................................................................................... 48 
10.2 Data Analysis Plan ........................................................................................................ 49 
11 DATA AND SAFETY MONITORING PLAN .............................................................................. 51 
11.1 DSMC Auditing ............................................................................................................. 51 
12 DATA HANDLING AND RECORD KEEPING ............................................................................ 51 
12.1 Data Quality Assurance ................................................................................................ 51 
12.2 Electronic Case Report Forms ...................................................................................... 51 
12.3 Record Retention ......................................................................................................... 52 
13 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS .................................................... 52 
13.1 Investigators and Study Administrative Structure ....................................................... 52 


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13.2 Ethical Conduct of the Study ........................................................................................ 52 
13.3 Informed Consent ........................................................................................................ 52 
13.4 Institutional Review Board or Ethics Committee ......................................................... 52 
13.5 Confidentiality .............................................................................................................. 53 
13.6 Protocol Violations/Deviations .................................................................................... 53 
14 REFERENCES ......................................................................................................................... 54 
 
 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Study Hypothesis 
Deficiency in DNA repair process and sustained angiogenesis are critical for tumorigenesis and 
cancer progression [1]. Both poly (ADP-ribose) polymerase (PARP) inhibitors (sensing DNA 
damage) and vascular endothelial growth factor (VEGF) inhibitors (anti-angiogenesis) are 
currently under clinical evaluation in cancer treatment. Rucaparib, a PARP inhibitor, has been 
shown significant anti-cancer activity in BRCA mutant patients and BRCA wild-type patients with 
other defects in the homologous recombination repair pathway [2, 3]. The adverse events have 
been easily managed. Means to improve this clinical benefit for cancer patients are worthy of 
pursuit. Studies in pre-clinical setting suggested a potential synergistic effect of PARP inhibitors 
when combined with angiogenesis inhibitors [4-6]. We hypothesize that combination of rucaparib 
and bevacizumab will produce synergistic anti-cancer effect in patients with the carcinoma of the 
cervix or endometrium. 
1.2 
Rationale for Recurrent Cervical Cancer 
Treatment options for women with recurrent cervical cancer remain limited, and cisplatin 
chemotherapy remains the backbone in nearly all treatment regimens offered to women with 
recurrent disease. A phase 3 randomized trial by the Gynecologic Oncology Group (GOG) 
evaluating cisplatin with paclitaxel demonstrated some improvement in the risk for progression 
(32% reduction, p=0.003), but only modest non-statistically significant improvement in survival 
(GOG 169) [7]. In another attempt to improve upon single agent cisplatin’s therapeutic efficacy, 
cisplatin was combined with topotecan (GOG179). That resulted in a statistically significant 37% 
reduction in the risk of progression, and a significant 29% reduction in the risk of death. 
Despite these statistically significant improvements, the median survival for the 
cisplatin/topotecan combination was only 9.4 months (vs. 6.5 months for cisplatin/paclitaxel) [8]. 
With the advent of anti-VEGF therapy and with bevacizumab (Bev) showing efficacy as a single 
agent in recurrent cervical cancer, bevacizumab was tested in combination with the 
cisplatin/paclitaxel (CP) doublet and the topotecan/paclitaxel (TP) doublet in GOG240 [9]. Results 
for this prospective, randomized, phase 3 study demonstrated a statistically significant survival 
benefit in the cisplatin/paclitaxel/bevacizumab treated women. Patients receiving CP/Bev showed 
a median survival of 17 months, which was significantly better than the 13.3 months for women 
receiving CP alone. This significant benefit was also seen in PFS. The CP and TP treatment 
regimens were compared to each other and TP was determined to not be superior to CP. Toxicity 
associated with the addition of Bev to the chemotherapy doublet regimens was in-line with, and 
not higher than, previously published gastrointestinal toxicities. In light of these findings, CP-Bev 
appears to be the favored treatment for advanced and/or recurrent cervical cancer and received 
FDA approval for such in 2014. However, with an OS of only 17 months and with the median age 
of affected women in their 40s, much room remains to improve survival rates for women with 
recurrent cervical cancer. 
Although not a BRCA mutation mediated tumor, there is rationale for use of a PARP inhibitor in 


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cervical cancer. Expression of PARP has been demonstrated to be higher in cancer cells as 
compared to normal cells, and an overexpression of PARP correlates with drug resistance to 
chemotherapy [10]. Cervix cancer cells have shown two-fold elevated levels of PARP-1 
expression as compared to normal cells. Preclinical work in cervical cancer using the PARP 
inhibitor veliparib plus topotecan has demonstrated enhanced cancer cell death after exposure to 
the combination that was attributed to collapsed topotecan poisoned replication forks, formation 
of topotecan related single strand DNA nicks, and conversion of these nicks into double strand 
breaks [11]. This data was taken into a Phase I/II trial of topotecan + veliparib in women with 
recurrent adenocarcinoma or squamous cell carcinoma of the cervix [12]. Among 27 patients 
enrolled, two patients achieved partial responses (7.4%, 90% confidence interval 1–22%) after 
veliparib/topotecan treatment. One patient with squamous cell cancer had a partial response after 
four treatment cycles and then received three more cycles of therapy prior to disease progression 
and disease-attributed death. This patient had a response duration of four months. Another patient 
with adenosquamous cell cancer had 11 cycles of veliparib/topotecan therapy with a censored 
tumor response duration of 6.7 months. In addition, ten (37%) patients had stable disease. Three 
of these patients had a duration of stable disease of more than six months. Twelve (44%) patients 
had a best response of progression of disease. Two patients had an indeterminate response status. 
The median PFS was two months (90% confidence interval: 1–3 months), and median OS was 
eight months (90% confidence interval: 6–10 months) [12]. 
The topotecan + veliparib study had a correlative science component that evaluated primary tumors 
(pre-treatment archival) for PARP-1 nuclear staining intensity. Among 16 archived untreated 
primary cervical cancer samples, 12 (75%) had high (2–3+) PARP-1 nuclear staining intensity. By 
primary cervical cancer histology, four (67%) of six adenocarcinomas, one (50%) of two 
adenosquamous cancers, and seven (88%) of eight squamous cell cancers had high (2–3+) PARP-
1 nuclear staining intensity. Of the nine persistent/recurrent (n = 5) or metastatic (n = 4) cervical 
cancers representing disease treated by protocol veliparib/topotecan therapy, eight (89%) had high 
(2–3+) PARP-1 nuclear staining intensity. The median PARP-1 histological score (i.e., product of 
staining intensity and percent positive cells) was 168 (range: 0–299) in the 16 primary cervical 
cancers. Among those 16 primary cervical cancers, a low PARP-1 histological score correlated 
with a likelihood of veliparib/topotecan treatment response (Spearman correlation coefficient: 
−0.63, P = 0.011). A patient with a low PARP-1 histological score dichotomized by its median 
was more likely to have longer PFS (HR: 0.25, P = 0.023) and OS after protocol 
veliparib/topotecan therapy (HR: 0.12, P = 0.005) compared to a patient with a higher histological 
score. Too few persistent/recurrent or metastatic samples were obtained for PARP-1 correlative 
analyses [12]. 
In a second study, Thaker et al. added veliparib to cisplatin and paclitaxel for treatment of 
chemotherapy naïve patients with advanced or recurrent cervix cancer [13]. In this phase I study, 
the objective response rate among 29 patients with measurable disease was an encouraging 34%, 
with an additional 41% with stable disease. Median progression free survival was 6.2 months (95% 
CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). The results were more 


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7 
striking by the fact that patients had to have a history of chemo-radiation for their primary disease 
and then to have progressed (i.e., not primary Stage IVB disease). While the Kunos study was not 
as encouraging, there is a strong possibility this was due to sub-therapeutic doses of veliparib as 
compared to the Thaker study [13]. 
These two papers suggest a role for PARP inhibition in cervical cancer even though baseline 
homologous recombination deficiency is not as common as compared to ovarian cancer. Data 
would suggest that induction of hypoxia caused by radiation or therapeutic agents (such as 
bevacizumab) may impact DNA repair by various mechanisms that may be therapeutically 
exploited. These mechanisms include exploiting the “chronic” hypoxia induced by bevacizumab, 
which leads to translational downregulation of DNA repair and may lead to susceptibility in these 
hypoxic cells to DNA damaging agents or synthetically lethal agents such as a PARP inhibitor like 
rucaparib [14]. 
This current study aims to test the hypothesis of whether cervix cancer treated with the 
combination of bevacizumab and rucaparib demonstrates inhibition of DNA repair via pre- and 
post-treatment biopsies. 
1.3 
Rationale for Endometrial Cancer 
Endometrial cancer is the 4th most common cancer in women, affecting 60,050 women in the 
United States in 2016 and resulting in 10,470 deaths [15]. Although the vast majority of patients 
will have early stage disease, treatment options for advanced or recurrent endometrial cancer are 
limited. Numerous cytotoxic agents have been evaluated, but only a few drugs have been identified 
to have definitive cytotoxic activity: doxorubicin, cisplatin/or carboplatin and paclitaxel, which 
have been recommended for first line chemotherapy [16-19]. 
A recently published phase III trial evaluating ixabepilone as the experimental treatment arm 
versus standard therapy with adriamycin or every three weeks’ treatment with paclitaxel in 
recurrent or advanced (with one prior regimen) endometrial cancer demonstrated only 15% 
complete or partial response in the control arm. Median progression free survival (PFS) was 3.4 
vs 4 months (p=0.80), and median overall survival (OS) was superior in the control arm (11 vs 12 
months [p=0.0397]), calling for discontinuation of the study due to futility [20]. Clearly, better 
treatments are needed. The grim outcomes with cytotoxic therapies have prompted the 
Gynecologic Oncology Group (GOG) to evaluate biologic agents, including anti-angiogenic 
agents like bevacizumab [21, 22]. Single agent bevacizumab, a monoclonal antibody directed 
against VEGF-1, has been studied by the GOG in study 229E, which revealed a response rate (RR) 
of 13.5%, and 6-month progression-free rate of 40%. The overall median PFS was 4.2 months, 
and the median OS was 10.5 months [21]. 
Bevacizumab remains one of the most promising agents for endometrial cancer in the recurrent 
setting. The aforementioned data led to two studies that incorporated bevacizumab into primary 
treatment of endometrial cancer. GOG protocol 86P randomized chemotherapy naïve women with 
advanced or recurrent disease and no curative options in a 1:1:1 fashion to TC + bevacizumab x 6 
and bevacizumab maintenance until progression, TC + temsirolimus x 6 and temsirolimus 


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8 
maintenance until progression or ixabepilone/carboplatin + bevacizumab and bevacizumab 
maintenance until progression. PFS was the endpoint for this trial.  As compared to the historical 
control of TC, none of the arms had improved PFS, but the TC + bevacizumab arm did have a 
significantly improved OS, which warrants further exploration [23]. Similarly, the MITO-END-2 
trial randomized patients to either TC or TC + bevacizumab x 6-8 cycles and bevacizumab 
maintenance until progression. Here, the addition of bevacizumab significantly improved the PFS 
over TC alone (HR 0.57 (0.34, 0.96; p=0.036) [24]. This study further confirmed the activity of 
bevacizumab in endometrial cancer and justifies exploration of best practices for when to use 
bevacizumab and with which other agents to combine it. 
Although not a traditionally BRCA mutation-mediated tumor, there is rationale for use of a PARP 
inhibitor in endometrial cancer. Expression of PARP has been demonstrated to be higher in cancer 
cells as compared to normal cells, and overexpression of PARP correlates with drug resistance to 
chemotherapy [10]. Although the role of phosphatase and tensin homologue (PTEN) gene in 
controlling the signaling pathway of phosphoinositide 3 kinase (PI3K) is well established, a new 
functional role of PTEN in maintaining genomic stability has been elucidated [25]. It was observed 
that embryonic mouse cells who are deficient in PTEN exhibit genomic instability from defects in 
RAD51-mediated DNA double stranded break repair (DSBR) or defects in cell cycle checkpoints 
[26, 27]. Given that the exquisite sensitivity of BRCA mutated cells to PARP inhibitors is likely 
due to defects in RAD51-mediated DSBR by homologous recombination [28, 29], it is plausible 
that PTEN deficiency may also lead to HR defects and thus sensitivity to PARP inhibition. 
Mendes-Pereira et al demonstrated in vitro and in vivo (mice modeling) that PTEN induced HR 
deficiency can be exploited with use of olaparib.[30]. Therein, the authors first confirmed that 
PTEN mutant human cells had lower levels of RAD51 (as previously shown in mice), then 
translated that this deficient expression indeed significantly impaired DSBR by homologous 
recombination. PTEN deficient cells were 20-fold more sensitive to PARP inhibitor exposure 
(olaparib) than their wild type counterparts; they were also more sensitive to cisplatin (but only 5-
fold), but no difference was seen with paclitaxel, which does not target HR deficiency, thereby 
serving as a negative control. Similar results have been reported by other authors studying patients 
with endometrioid adenocarcinoma of the endometrium [31, 32]. 
Given that up to 80% of endometrioid endometrial cancers lack PTEN expression, there is good 
rationale for evaluation of targeted therapies. Previously, PTEN mutations have been exploited 
with use of mammalian target of rapamycin (mTOR) inhibitors or PI3K inhibitors. However, 
PTEN now seems to be an attractive target for PARP inhibitors. The aforementioned data 
demonstrates the utility of PARP inhibitors in non-BRCA mediated HR deficiency. Additionally, 
inhibition of angiogenesis is a promising avenue of targeted therapy in endometrial cancer. For 
advanced or recurrent endometrial cancer patients, for whom there are few, if any effective 
therapies beyond first line chemotherapy, the combination of bevacizumab and rucaparib 
represents an exciting opportunity to explore a novel approach with sound rationale. 
1.4 
Summary of Investigational Product 
Rucaparib is a small molecule inhibitor of PARP-1, PARP-2, and PARP-3 that has demonstrated 


Version 5.0 (1-Apr-2020) 
9 
clinical activity in a number of tumor types, especially those associated with a deleterious mutation 
in BRCA1/2 or other HRR gene, and/or high level of genomic loss of heterozygosity (LOH). 
Rucaparib is approved in the United States (US) for the treatment of adult patients with deleterious 
BRCA mutation (germline and/or somatic)-associated epithelial ovarian (EOC), fallopian tube 
(FTC), or primary peritoneal (PPC) cancer who have been treated with two or more prior 
chemotherapies, and for the maintenance treatment of adult patients with recurrent EOC, FTC, or 
PPC who are in a complete or partial response to platinum-based chemotherapy [33-35]. 
Prior Experience with Rucaparib 
An overview of data from nonclinical and clinical studies of rucaparib are provided below and 
described in detail in the rucaparib Investigator’s Brochure (IB). A summary of the benefit-to-risk 
ratio is also provided in the rucaparib IB. 
1.4.1 Non-clinical Experience with Rucaparib 
1.4.1.1 Pharmacology of Rucaparib 
The results from nonclinical studies are consistent with the anticipated mechanism of action and 
pharmacological effects of PARP inhibition. Pharmacological assessment demonstrated that 
rucaparib is a potent and selective inhibitor of PARP-1, PARP-2, and PARP-3 and has robust and 
durable in vitro and in vivo activity in multiple cell lines and patient-derived xenograft models 
with mutations in BRCA1, BRCA2, PALB2, RAD51C, and RAD51D. Rucaparib was also active 
in a BRCA wild-type model, consistent with in vitro data suggesting that rucaparib is active in 
cells with other defects in HRR through synthetic lethality. In vitro screens suggested that 
rucaparib has a limited potential for off-target effects. Safety pharmacology studies suggest that 
when given orally, rucaparib poses a low risk for causing neurobehavioral and cardiac effects in 
patients. 
1.4.1.2 Pharmacokinetics, Metabolism, and Drug-Drug Interaction Potential of Rucaparib 
In pharmacokinetic (PK) studies, rucaparib demonstrated species-dependent oral bioavailability, 
moderate plasma protein binding, and large volumes of distribution in nonclinical species. As a P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, rucaparib demonstrated 
minimal penetration of rucaparib-derived radioactivity through the blood-brain barrier. In vitro 
data suggested slow metabolism by cytochrome P450 (CYP) enzymes, with CYP2D6 and to a 
lesser extent CYP1A2 and CYP3A4 contributing to the metabolism of rucaparib. Rucaparib was 
mainly excreted in feces in rats and dogs after oral dosing. 
In vitro, rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to a lesser 
extent CYP2C8, CYP2D6, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 
(UGT1A1). Rucaparib induced CYP1A2, and down-regulated CYP2B6 and CYP3A4 in human 
hepatocytes at clinically relevant exposures. Rucaparib is a potent inhibitor of multidrug and toxin 
extrusion 1 (MATE1) and MATE2-K, a moderate inhibitor of organic cationic transporter 1 
(OCT1) and may inhibit P-gp and BCRP in the gut. 
1.4.1.3 Animal Toxicology of Rucaparib 
Oral dosing of rucaparib in single- and repeat-dose toxicity studies in rats and dogs resulted in 


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10 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities were 
generally both reversible upon recovery and predictive of toxicities observed in patients. Rucaparib 
was shown to be clastogenic in an in vitro chromosomal aberration assay suggesting potential 
genotoxicity in humans.  
Reproductive and development toxicity studies in rat showed that rucaparib caused maternal 
toxicity and was embryotoxic. Although no rucaparib related effects on sperm total count, density, 
motility, or morphology were identified, based on published studies, PARP inhibitors have the 
potential to impair spermatogenesis and reduce fertility [36-39]. 
Complete information on the pre-clinical studies can be found in the Rucaparib Investigator’s 
Brochure (IB). 
1.4.2 Clinical Experience with Rucaparib 
Rucaparib, both as monotherapy and in combination with nivolumab, is being evaluated in Phase 
1, 2, and 3 clinical studies in patients with advanced cancer with and without evidence of HRD. 
Rucaparib clinical studies have evaluated/are evaluating patients with relapsed, high-grade ovarian 
cancer (OC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) in both the treatment 
and maintenance settings. 
Rucaparib is also being evaluated as treatment for patients with metastatic castration-resistant 
prostate cancer (mCRPC), both as monotherapy and in combination with nivolumab. 
Clinical pharmacology studies are ongoing in patients with advanced solid tumors to more fully 
characterize rucaparib drug-drug interactions (DDI), mass balance and drug metabolism, as well 
as PK and safety in patients with moderate hepatic impairment. 
Additional studies of rucaparib as monotherapy and in combination with other anticancer therapies 
are planned in ovarian and prostate cancer, as well as other tumor types. 
The rucaparib clinical studies and results are described in more detail in the rucaparib IB. 
1.4.2.1 Clinical Pharmacology, Pharmacokinetics, and Metabolism of Rucaparib 
Assessment of rucaparib PK in cancer patients showed an approximate dose-proportional exposure 
after once daily (QD) or BID dosing, rapid absorption with maximum plasma concentration (Cmax) 
achieved within 1.5 to 6 hours, and distribution into tissue. The oral bioavailability was 36% and 
terminal half-life (T1/2) ranged from 11 to 29.8 hours. 
Rucaparib was moderately bound to human plasma proteins in vitro 97(70%). The steady-state 
was achieved following one week of dosing with rucaparib BID, with approximately 4-fold 
accumulation. A high-fat meal increased the Cmax and area under the plasma concentration-time 
curve from 0 to 24 hours (AUC0-24h) of rucaparib by 20% and 38%, respectively, as compared with 
these parameters under fasted conditions. The effect of food on rucaparib PK is not considered to 
be clinically significant, thus rucaparib can be taken with or without food. 
Drug interactions with rucaparib as a substrate were assessed in a population PK analysis. CYP2D6 
phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, and ultra-rapid 
metabolizers) and CYP1A2 phenotypes (normal metabolizers and hyperinducers) did not 


Version 5.0 (1-Apr-2020) 
11 
significantly impact the steady-state exposure of rucaparib at 600 mg BID. Current smokers had 
overlapping rucaparib exposures as compared to nonsmokers and former smokers. Collectively, 
the results suggest that CYP1A2 and CYP2D6 play a limited role in rucaparib metabolism, and no 
rucaparib dose adjustment is needed when concomitantly administered with CYP inhibitors. 
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant effect 
on rucaparib PK. No dose modification of rucaparib is required for patients who are receiving 
concomitant treatment with a PPI. Results from Study CO-338-044 evaluating potential drug-drug 
interactions (DDI) with rucaparib, indicated that rucaparib, at 600 mg BID, moderately inhibited 
CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and showed no clinically significant 
effect on Pgp. Caution should be exercised in the concomitant use of drugs that are substrates of 
the above CYP enzymes. 
1.4.2.2 Overview of Efficacy 
Rucaparib has demonstrated clinical benefit in the treatment and maintenance settings in ovarian 
cancer patients [34, 35]. Based on these results, rucaparib was approved in the US for the treatment 
of patients with a deleterious BRCA mutation (germline and/or somatic) associated epithelial 
ovarian cancer (EOC), FTC, or PPC who have been treated with two or more chemotherapies, and 
for the maintenance treatment of adult patients with EOC, FTC or PPC (regardless of BRCA status) 
who are in a complete or partial response to platinum-based chemotherapy [33].  
In addition to BRCA1 and BRCA2, ovarian cancer patients with a deleterious RAD51C or 
RAD51D mutation also derived clinical benefit from rucaparib in the treatment 
(Study CO-338-017; ARIEL2) and maintenance (Study CO-338-014; ARIEL3) settings [3, 40]. 
While rucaparib has demonstrated significant clinical benefit in ovarian cancer in the treatment 
and maintenance settings, rucaparib clinical activity is not limited to ovarian cancer. Rucaparib 
recently received a Food and Drug Administration (FDA) Breakthrough Therapy Designation 
(BTD) based on preliminary clinical activity in 25 patients with mCRPC harboring a deleterious 
BRCA mutation and measurable disease at baseline enrolled in Study CO-338-052 (TRITON2) 
[41]. Clinical benefit from rucaparib treatment has also been observed in mCRPC patients with a 
deleterious PALB2 mutation [41]. 
Rucaparib clinical data further supports the hypothesis that patients with BRCA-mutated solid 
tumors from indications beyond ovarian and prostate cancers may likely benefit from rucaparib 
treatment. In a Phase 1 dose-escalation study (CO-338-010) of rucaparib in patients with an 
advanced solid tumor, four breast cancer patients and one pancreatic cancer patient, all harboring 
a deleterious BRCA mutation, achieved a Response Evaluation Criteria in Solid Tumors 
(RECIST)-confirmed partial response (PR) [42]. In RUCAPANC (CO-338-023), a Phase 2 study 
assessing the efficacy of rucaparib in BRCA-mutated pancreatic cancer, clinical benefit was 
observed (objective response rate [ORR] of 33.3% and disease control rate [DCR] of 44.4%) in 
the subgroup of patients who had received only one prior chemotherapy regimen for locally 
advanced/metastatic disease [43]. Similarly, clinical benefit (ORR of 36.8% and median 
progression-free survival [PFS] of 9.1 months) was also observed with maintenance treatment of 


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rucaparib in patients with platinum-sensitive BRCA mutated pancreatic cancer [44].  
1.4.2.3 Overview of Safety 
Results of a recent integrated safety analysis in over 1,000 patients with ovarian or prostate cancer 
who received 600 mg BID rucaparib in the treatment or maintenance setting showed that the most 
common treatment-emergent adverse events (TEAEs) reported were primarily mild to moderate 
(Common Terminology Criteria for Adverse Events [CTCAE] Grade 1-2) in severity and included 
gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and abdominal pain), 
asthenia/fatigue, anemia/decreased hemoglobin, alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) increased, decreased appetite, and dysgeusia. The most common TEAE 
≥ Grade 3 include anemia/decreased hemoglobin, ALT/AST increased, neutropenia/decreased 
absolute neutrophil count (ANC), and asthenia/fatigue. Section 6.6 of the rucaparib Investigator’s 
Brochure (IB) serves as guidance to the investigator on adverse drug reactions (ADRs) for 
rucaparib, based on incidence of TEAEs by all CTCAE grades and by CTCAE ≥ Grade 3. 
The laboratory abnormalities were consistent with the TEAEs, with decreased hemoglobin (and 
associated increase in mean corpuscular volume [MCV] and mean corpuscular hemoglobin 
[MCH]), increased ALT, increased AST, and increased serum creatinine, most commonly 
occurring. Decreased platelets, neutrophils, leukocytes, lymphocytes and increased cholesterol 
were observed to a lesser extent. The transient elevations in ALT/AST with rucaparib treatment 
were not associated with abnormal increases in bilirubin or other criteria for drug-induced 
hepatotoxicity and generally resolved over time. Furthermore, no cases met Hy’s law criteria for 
drug-induced liver injury (DILI) [45, 46], and few patients discontinued rucaparib due to 
ALT/AST elevations [34, 35]. Similarly, elevations in creatinine were self-limiting and generally 
stabilized over time. The majority of creatinine elevations were Grade 1 or Grade 2. Elevated 
serum creatinine levels resolved upon interruption or discontinuation of rucaparib were not 
accompanied by changes in blood urea nitrogen (BUN) and did not lead to discontinuation of 
rucaparib treatment. Increased creatinine with rucaparib treatment is likely due to the potent 
inhibition by rucaparib of MATE1 and MATE2-K renal transporters. 
An updated analysis of safety presented in the United States (US) prescribing information (USPI) 
[33] and the EU Summary of Product Characteristics (SmPC) [47] demonstrate that safety results 
in ovarian cancer patients treated with rucaparib have remained consistent with those previously 
reported, and that the safety profile across both the treatment and maintenance indications is 
consistent.  
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk of 
cardiac effects by rucaparib. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered adverse 
events of special interest (AESIs), as these events have been observed in patients exposed to 
cytotoxic chemotherapy (e.g., platinum and anthracyclines) used for treatment of ovarian cancer 
as well as with PARP inhibitors, including rucaparib. Patients in rucaparib clinical studies 


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13 
diagnosed with MDS or AML had significant confounding risk factors including prior cytotoxic 
chemotherapy, as well as a deleterious BRCA mutation [48, 49]. Based on these confounding 
factors, there is insufficient scientific evidence to conclude that MDS and AML are causally related 
to rucaparib.  Clovis has added these potential risks to all Informed Consent Forms (ICFs) / Patient 
Information Sheets (PISs). AESI’s (both serious and non-serious) will be reported to Clovis within 
24 hours of awareness and will continue to be reported to Clovis under SAE reporting 
requirements. 
More information on AESIs for rucaparib is provided in the rucaparib IB. 
1.4.2.4 Completed Studies 
A4991002 was a Phase 1 open-label, dose-escalation study of IV rucaparib in combination with 
temozolimide (TMZ) in 32 patients with advanced solid tumors or malignant melanoma. 
A4991005 was a Phase 2, open-label study of IV rucaparib in combination with TMZ in 46 patients 
with metastatic melanoma. The results from these studies are available in manuscript form [50, 
51]. Clinical data indicate that rucaparib exposures were similar between extensive metabolizers 
and poor metabolizers of CYP2D6. 
A4991014 was a Phase 1, open-label, dose-escalation study of IV and oral rucaparib administered 
with different chemotherapeutic agents in 85 patients (33 patients dosed orally) with advanced 
solid tumors. Rucaparib PK parameters following a single 30 minute IV infusion (12 to 40 mg) 
and oral dose (12 to 360 mg) showed dose-proportional increases in exposure and dose-
independent half-life (T1/2) of approximately 17 hours after IV or oral dosing. Oral bioavailability 
was 36%. 
In addition, a phase II study (NCT00664781) was carried out in patients with advanced breast and 
or ovarian cancer with proven BRCA-1/2 mutation [2]. The investigators reported that Rucaparib 
was well tolerated in patients up to doses of 480 mg per day; because dose levels at 480 mg twice 
a day or 600 mg twice a day resulted in DLTs (CTCAE grade 3 fatigue) and drug discontinuation 
because of persistent fatigue in two patients. The treatment with intermittent dosing of intravenous 
rucaparib resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) 
patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilization for 
>52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 
81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed 
continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease 
(SD) ⩾12 weeks, with a median duration of response of 179 days (range 84-567 days) [2]. 
1.4.2.5 Preliminary Data from On-going Clinical Studies 
Study CO-338-010 (NCT01482715) 
Study CO-338-010 is a 3-part, open-label, Phase 1/2 study of oral rucaparib monotherapy 
administered daily in continuous 21-day cycles. Part 1 (Phase 1) evaluated PK and safety of 
escalating doses of rucaparib in patients with solid tumors dose (N = 56; enrollment complete) and 
identified 600 mg BID as the recommended starting for Phase 2 based on safety, PK, and the 
clinical activity profile [42]. Part 2 (Phase 2) is evaluating the efficacy and safety of rucaparib in 


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patients with relapsed, high-grade ovarian cancer associated with a BRCA mutation. Part 2A 
enrolled platinum-sensitive patients (i.e., disease progression occurred at least 6 months after last 
dose of platinum was administered) with a gBRCA1/2 mutation who had received two to four prior 
treatment regimens (N = 42, enrollment complete). Part 2B is enrolling patients with a gBRCA1/2 
or sBRCA1/2 mutation who received at least three prior chemotherapy regimens (N = 40 planned). 
Part 3 enrolled patients with relapsed solid tumor and a BRCA mutation to characterize the PK, 
food-effect, and safety of a higher dose strength tablet (enrollment completed). 
Dose levels of 40 to 500 mg QD and 240 to 840 mg BID rucaparib were evaluated in the 56 patients 
enrolled in Part 1. A dose-limiting toxicity (DLT) of National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE) Version 4.0 (v4.03 ) [52] Grade 3 nausea was 
observed in 1 of the 6 patients at 360 mg BID rucaparib in Cycle 1. No DLTs were observed at 
any other dose level in Cycle 1. However, similar to other PARP inhibitors, non-DLT 
myelosuppression was observed beyond Cycle 1. 
Dose proportional PK were observed up to 600 mg BID. The mean Tmax and mean T1/2 were 
approximately four hours and 17 hours, respectively. Oral administration of 600 mg rucaparib with 
a high-fat meal resulted in a moderate increase of Cmax and AUC of rucaparib compared with that 
under fasted conditions. The increases in rucaparib exposures were not considered clinically 
significant, thus rucaparib can be taken with or without food. In pooled plasma samples from three 
patients who received 600 mg rucaparib BID, rucaparib, an oxidation and deamination product 
(M324), and a subsequent N- methylated metabolite (M338) were tentatively identified as major 
circulating moieties. M324 was a major metabolite in rats and dogs, but M338 was not observed 
in animals. This is to be further evaluated in a [14C] rucaparib study in patients. 
Efficacy data from Part 1 showed Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 responses in patients with gBRCA mutant ovarian cancer, breast cancer, and pancreatic 
cancer. The disease control rate (complete response [CR], partial response [PR], or stable disease 
[SD] > 12 weeks) at doses ≥ 360 mg BID in evaluable ovarian cancer patients was 92% (11/12). 
Responses were durable across tumor types. 
In Part 2A, the latest efficacy data indicate that rucaparib provides significant clinical benefit to 
patients with a gBRCA1/2 mutation. Of the 42 patients treated, 25 patients (60%) achieved a 
confirmed complete or partial response according to RECIST Version 1.1 and the median duration 
of response (DOR) was 7.8 months (95% Confidence Interval [CI] 5.6, 10.5) [42]. 
Treatment-related adverse events (AEs; all grades) reported in ≥15% of patients treated with 600 
mg BID rucaparib include gastrointestinal and related symptoms (nausea, vomiting, dysgeusia, 
and abdominal pain), anemia, asthenia/fatigue, neutropenia, thrombocytopenia, and headache. 
Elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels were 
also reported. Elevations of ALT/AST occurred early (within first 2-4 weeks of treatment), were 
generally mild to moderate (Grades 1-2), not accompanied by any significant changes in bilirubin 
levels, often transient, and resolved to within normal ranges or stabilized. As has been observed 
with rucaparib and other PARP inhibitors, myelosuppression may be delayed and observed after a 


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period of continuous dosing. All treatment-related AEs were successfully managed with 
concomitant medication and treatment interruption and/or dose reduction, or supportive care (in 
the case of myelosuppression AEs). 
Extensive centrally reviewed electrocardiogram (ECG) monitoring was conducted in the Phase 1 
portion of Study CO-338-010 and results are available for 55 of 56 treated patients. No patient had 
a QTcF measurement ≥ 500 msec and only one patient had a QTcF measurement ≥ 480 msec. This 
measurement occurred in a patient receiving 480 mg BID rucaparib and concomitant 
administration of citalopram, a medication with known potential to cause QT prolongation. This 
patient continued to receive rucaparib monotherapy at a dose of 480 mg BID with no further QTcF 
measurement ≥ 480 msec. Only one patient had a QTc increase from baseline > 60 msec. This 
patient had a history of QT prolongation prior to study entry and received one dose of rucaparib 
before discontinuing from the study due to eligibility violation. Overall, rucaparib in doses up to 
840 mg BID exhibited a mean change of QTcF from baseline of 11.3 msec at the maximum 
concentration (5565 ng/mL) observed in the study. At a dose of 600 mg BID, the mean values for 
change of QTcF in Cycle 1 ranged from 5.0 to 14.0 msec. Overall, the alteration of the mechanism 
of repolarization was minimal. There were no AEs suggestive of cardiac arrhythmia (e.g., 
presyncope, syncope, sudden death) in any patient. 
Study CO-338-017 (ARIEL2) (NCT01891344) 
ARIEL2 is a 2-part, single-arm, open-label Phase 2 study in patients with relapsed, high-grade 
ovarian, fallopian tube, or primary peritoneal cancer. The primary purpose of this study is to define 
a tumor-based molecular signature of HRD in ovarian cancer that correlates with response to 
rucaparib and enables selection of appropriate ovarian cancer patients for treatment with rucaparib 
[3]. Tumor HRD status is assessed using next generation sequencing, with an algorithm for HRD 
status based on the presence of a BRCA1/2 mutation (germline or somatic) and/or degree of tumor 
genome-wide loss of heterozygosity (genomic LOH), a phenotypic consequence of HRD. Patients 
are prospectively classified into one of three subgroups: tumor BRCA mutant (tBRCAmut), tumor 
BRCA wild-type with high genomic LOH (BRCAwt/LOHhigh; also referred to as BRCA- like), and 
tumor BRCAwt with low genomic LOH (BRCAwt/LOHlow; also referred to as biomarker negative). 
Part 1 enrolled ovarian cancer patients with relapsed, platinum-sensitive disease who had received 
≥1 prior platinum-based regimen (N = 204; enrollment complete). Enrollment of patients known 
to harbor a gBRCA1/2 mutation was capped in order to maximize the ability to assess rucaparib 
activity in the BRCAwt patient population. A total of 17 patients known to harbor a germline 
BRCA1/2 mutation were enrolled. Another 23 patients were identified as having a BRCA1/2 
mutation (three germline, 20 somatic) based on analysis of their tumor. 
Efficacy data indicate a RECIST ORR in BRCA1/2mut tumor-evaluable patients of 80.0% (32/40 
patients), median DOR of 11.2 months (95% CI: 7.4, 13.7), and median PFS of 12.8 months (95% 
CI: 9.0, 14.7). The objective response rate was similar in patients with a germline (85.0%; 17/20) 
or somatic BRCA1/2 mutations (75.0%; 14/19). Clinical activity was also observed in patients with 
a BRCA-like molecular signature as assessed by genome-wide loss of heterozygosity (genomic 


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LOH). A RECIST ORR of 29.0% (24/82 patients), median DOR of 11.0 months (95% CI: 7.6, 
20.6), and median PFS of 5.7 months (95% CI: 5.3, 7.6) was observed in patients with a BRCA-
like tumor (BRCAwt with high genomic LOH) versus a RECIST ORR of 10.0% (7/70 patients), 
median DOR of 5.8 months (95% CI: 4.6, 8.5), and median PFS of 5.2 months (95% CI: 3.6, 5.5) 
in patients with a BRCAwt/low genomic LOH tumor [3]. 
A BRCA-like molecular signature was observed in approximately 55% of patients with a BRCAwt 
tumor, indicating there is a significant population of ovarian cancer patients beyond those who 
have a BRCA1/2 mutation who may benefit from rucaparib treatment. Importantly, approximately 
30% of BRCAwt patients noted as having low genomic LOH in an archival tumor sample had high 
genomic LOH in their pre-treatment screening biopsy, indicating that a recent tumor sample is 
preferred to assess BRCA-like status in order to identify patients most likely to benefit from 
rucaparib treatment. 
An exploratory objective in ARIEL2 was to assess rucaparib efficacy in tumors with an alteration 
in a HR gene other than BRCA1/2. The overall frequency of non-BRCA1/2 HR gene mutations 
was low (11%, 22/204 tumor samples) and the presence of a mutation did not always correlate 
with LOH, with the exception of tumors with a RAD51C or RAD51D mutation, which consistently 
exhibited high genomic LOH. RECIST and/or cancer antigen-125 (CA-125) responses were 
observed in patients with a RAD51C (75%, 3/4), ATM (50%, 1/2), ATR (100%, 1/1), BRIP1 
(50%, 1/2), NBN (100%, 2/2), and RAD51D (50%, 1/2) mutation. (Clovis, data on file) ARIEL2 
Part 2 is currently enrolling advanced ovarian cancer patients (N=300 planned) who have received 
at least three prior chemotherapy regimens (N = 300 planned) in order to refine the BRCA-like 
molecular signature (i.e., genomic LOH) and assess its predictive utility in a more heavily pre-
treated patient population. 
Similar to the safety profile in Study CO-338-010 Part 2A, the most frequent (reported in ≥ 15% 
of patients) treatment-related AEs (all grades) included gastrointestinal-related toxicities (nausea, 
constipation, vomiting, and diarrhea), asthenia/fatigue, elevations in ALT/AST, anemia/decreased 
hemoglobin, dysgeusia, and decreased appetite. The most common grade 3 or worse treatment-
emergent adverse events were anaemia or decreased haemoglobin (22%), and elevations in ALT 
or AST (12%) [3]. 
Study CO-338-014 (ARIEL3) (NCT01968213) 
ARIEL3 is a double-blind, placebo-controlled, Phase 3 study of rucaparib as switch maintenance 
treatment in patients with relapsed, platinum-sensitive, high-grade ovarian, fallopian tube or 
primary peritoneal cancer who achieve a response to platinum-based chemotherapy (N = 540 
planned; enrollment completed). The primary endpoint is PFS in HRD within subgroups as 
determined by next generation sequencing analysis of archival tumor tissue using an optimized 
algorithm from Study CO-338-017 (ARIEL2). 
Study CO-338-023 (RUCAPANC) (NCT02042378) 
Study CO-338-023 (RUCAPANC) is a single-arm, open-label Phase 2 study of rucaparib treatment 
in patients with previously treated locally advanced or metastatic pancreatic ductal 


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adenocarcinoma and a known deleterious BRCA mutation. The primary endpoint is efficacy as 
measured by objective response rate (ORR). Of the 19 patients evaluable for response, two 
achieved a confirmed PR and one achieved a confirmed CR. These patients all received only one 
prior line of therapy. The overall safety profile was similar to that observed in ovarian cancer 
patients. 
1.5 
Summary of Bevacizumab Clinical Experience 
1.5.1 Bevacizumab for Cancer Treatment 
Bevacizumab is a monoclonal antibody that exerts anti-cancer effects by inhibiting VEGF and 
slowing the growth of new blood vessels. Bevacizumab has been studied in Phase I, II, and III 
clinical trials in more than 5000 patients and in multiple tumor types. In a large phase III study 
(NCT00109070), the efficacy and safety of bevacizumab added to the standard first-line 
chemotherapy were evaluated in patients with metastatic colorectal cancer. The addition of 
bevacizumab to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically 
and statistically significant increase in duration of survival and progression-free survival [53]. 
Bevacizumab was then approved by the FDA on 26 February 2004 for first-line treatment in 
combination with IV 5-FU-based chemotherapy for subjects with metastatic colorectal cancer. 
Based on anti-cancer advantage demonstrated in many clinical studies, the FDA has approved 
bevacizumab in combination with chemotherapy for various types of metastatic or advanced 
cancer, including colorectal cancer, lung cancer, breast cancer, brain cancer, kidney cancer, 
cervical cancer, and recently, ovarian cancer. 
Pharmacokinetic data with 5 mg/kg every two weeks shows comparability with 7.5 mg every three 
weeks and 10 mg/kg every 2 weeks is comparable to 15 mg/kg every three weeks. 
1.5.2 Safety Profile for Bevacizumab 
Bevacizumab-associated adverse events identified in clinical trials include hypertension, wound 
healing complications and increased risk of bleeding [54, 55]. Gastrointestinal perforation and 
thromboembolic events have been reported although the incidence is rare [56, 57]. These and other 
safety signals are described in further detail as follows. Additional information is provided in the 
bevacizumab Investigator’s Brochure. 
Hypertension: Hypertension is one of the most frequently described adverse effects of 
bevacizumab based therapy and oral medications have been used to manage the hypertension when 
indicated. The frequency of all grades of hypertension associated with bevacizumab is 20–30%. 
Hypertension is often asymptomatic. However, patients can develop seizures and impaired vision. 
Clinical sequelae of hypertension are rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) [54]. The 
management should include control of hypertension, management of specific symptoms, and 
discontinuation of bevacizumab. 
Wound healing complications: Wound healing complications have been reported in patients 
receiving bevacizumab. However in an analysis of pooled data from two trials in metastatic 
colorectal cancer, with cancer surgery 28-60 days before study treatment, wound healing 


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complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control 
patients [58]. Surgery in patients currently receiving bevacizumab is not recommended. No 
definitive data are available to define a safe interval after bevacizumab exposure with respect to 
wound healing risk in patients receiving elective surgery; however, the estimated half-life of 
bevacizumab is 20 days. Bevacizumab should be discontinued in patients with severe wound 
healing complications. 
Hemorrhage: Overall, grade 3–4 bleeding events with bevacizumab occur at a rate of 1.2%– 4.6% 
in a pooled database from six clinical trials in multiple tumor types [54]. The hemorrhagic events 
that have been observed in bevacizumab clinical studies were predominantly tumor-associated 
hemorrhage and minor mucocutaneous hemorrhage. The tumor-associated hemorrhage tends to 
occur in patients with lung and GI cancers; but may also occur in patients with central nervous 
system metastases. Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been 
seen in 20-40% of patients treated with bevacizumab. These were most commonly grade 1 
epistaxis that lasted less than five minutes, resolved without medical intervention and did not 
require any changes in bevacizumab treatment regimen. There have also been less common events 
of minor mucocutaneous hemorrhage in other locations, such as gingival bleeding and vaginal 
bleeding. 
Thromboembolic Events: Bevacizumab is a VEGF inhibitor and can increase the risk for both 
venous and arterial thromboembolic events (VTE or ATE). A meta-analysis of 1,745 patients with 
various tumor types demonstrated a two-fold higher ATE incidence in patients receiving 
bevacizumab and chemotherapy than in those receiving chemotherapy alone (3.8% versus 1.7%; 
p =0.031) [54]. In the phase III pivotal trial in metastatic CRC, there was a slightly higher rate of 
VTE that was not statistically significant in patients treated with bevacizumab plus chemotherapy 
compared with chemotherapy alone (19% vs. 16%). Furthermore, subjects with certain baseline 
characteristics (age ≥ 65 years and/or a history of a prior arterial TE event) may be at higher risk 
of experiencing such an event. See the bevacizumab Investigator Brochure for additional 
information on risk factors. Aspirin may be used as a prophylaxis of ATE in patients at high risk of such 
events; and the use of aspirin ≤ 325 mg daily was allowed in the several randomized studies. 
Gastrointestinal perforation Patients with metastatic carcinoma may be at increased risk for the 
development of gastrointestinal perforation when treated with bevacizumab and chemotherapy 
[56]. Bevacizumab should be permanently discontinued in patients who develop gastrointestinal 
perforation. A causal association of intra-abdominal inflammatory process and gastrointestinal 
perforation to bevacizumab has not been established. Nevertheless, caution should be exercised 
when treating patients with intra-abdominal inflammatory processes with bevacizumab. 
1.6 
Study Rationale 
Both rucaparib and bevacizumab have shown anti-cancer effects for patients with advanced or 
metastatic cancer [2, 3, 9, 21]. Both drugs have been approved by the FDA for treatment of patients 
with ovarian cancer. A phase II trial has demonstrated that treatment with bevacizumab as a single 
agent at 15 mg/kg intravenously every 21 days was well tolerated and active in patients with 
recurrent cervical cancer; approximately 24% patients survived progression free for at least six 


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months, and 11% of patients had a partial response [59]. Another phase II trial of bevacizumab as 
single agent treatment in recurrent or persistent endometrial cancer revealed a response rate (RR) 
of 13.5%, and 40% progression-free at six months [21]. Further, clinical studies have demonstrated 
that the use of bevacizumab in combination with other chemotherapies is safe and effective with a 
significant improvement in overall survival of patients with advanced cervical cancer or 
endometrial cancer [21, 60]. As discussed in sections 1.2 and 1.3, although not a traditionally 
BRCA mutation-mediated tumor, there is rationale for use of a PARP inhibitor in cervical cancer 
and endometrial cancer. More important, studies in a pre-clinical setting suggested a potential 
synergistic effect of PARP inhibitors when combined with angiogenesis inhibitors [4-6]. To better 
define the potential benefit of adding bevacizumab to rucaparib in patients with recurrent cervical 
or endometrial cancer, we plan to perform a prospective phase II trial. We anticipate that 
combination of rucaparib and bevacizumab will produce a synergistic anti-cancer effect in patients 
with the carcinoma of the cervix or endometrium who have progressed disease after the first line 
chemotherapy. 
1.6.1 Rationale for Multi-center Study 
In order to have a faster enrollment and data readout, up to four study sites are planned to 
participate in this study. 
1.7 
Rationale for Correlative Studies 
We will assess microsatellite instability in the biopsies of patients with recurrent endometrial 
cancer. Additionally, biopsies will be assessed for DNA damage via a proprietary assay (PADDA) 
as well as RAD51C assay [61]. Furthermore, we will assess circulating tumor DNA and other 
biomarkers in blood samples. 
DNA damage is constantly generated in living cells. Additional insults to the DNA result from 
exposure to genotoxic substances. DNA damage is the main initiator of cancer and plays a key role 
in the pathogenesis of aging and neurodegenerative diseases [62-64]. Available data indicate that 
variations in DNA damage and DNA repair capacity influence patients' risk to develop cancer and 
patient’s response to chemo- and radio-therapy [65]. However, no predictive markers of cancer 
risk or response to treatment have yet been established. 
There are no assays with sufficient sensitivity to quantify or map endogenous DNA damage. 
Currently, the most reliable strategies to detect induced DNA damage are PCR-based assays [66-
69]. However, existing assays have two major limitations: they require high doses of damaging 
agent to generate detectable levels of lesions [70], and they are not practically feasible for 
population screening. Therefore, due to technical limitations, the precise levels of DNA damage, 
and how those levels impact cell fate and human health, are largely unknown. 
Recently, we developed a novel and highly sensitive primer-anchored DNA damage detection 
assay (PADDA). In contrast with available assays, PADDA is able to map and quantify 
endogenous and induced DNA damage [71, 72]. PADDA reliably discriminates in vivo levels of 
persistent endogenous DNA damage in yeast and mice [71, 72] and demonstrated a strong 
correlation between persistent nucleotide damage and the later establishment of mutations 


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precisely in those nucleotides [71]. PADDA does not require hazardous reagents, sophisticated 
equipment or specialized skills [72] and can be used on a real-time PCR system to ease population 
screenings. Additionally, we validated PADDA for the study of human samples, established a 
tissue bank of head and neck squamous cell carcinoma patients and teamed with physicians to 
move this novel assay to clinical application. 
Furthermore, RAD51 plays an important role in DNA double-strand break repair. Cytoplasmic 
expression (RAD51C(+)) was associated with poor prognosis and aggressive behavior in various 
cancer [73, 74]. RAD51 foci has been shown to predict tumor response to cancer therapy in diverse 
contexts [75, 76]. The higher expression of RAD51 gene could mediate cancer stem cells 
resistance to PARP inhibitors in both BRCA1-mutant and BRCA1-wild-type Triple-Negative 
breast cancer [75]. In this study, we plan to study RAD51 nuclear foci by immunostaining as 
described in a published paper [75]. 
2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
• To estimate the proportion of patients with persistent or recurrent cervical or endometrial 
cancer, who survive progression-free for at least six months, treated with combination 
bevacizumab and rucaparib. 
2.2 
Secondary Objectives 
• To estimate the proportion of patients with persistent or recurrent cervical or endometrial 
cancer, who have objective tumor response (complete or partial), treated with combination 
bevacizumab and rucaparib. 
• To determine the nature and degree of toxicity of combination rucaparib and bevacizumab 
in this cohort of patients. 
• To estimate the progression-free survival (PFS) of patients with persistent or recurrent 
cervical or endometrial cancer treated with combination rucaparib and bevacizumab 
• To estimate the overall survival (OS) of patients with persistent or recurrent cervical or 
endometrial cancer treated with combination rucaparib and bevacizumab 
2.3 
Translational Objectives 
• To obtain the fresh tumor biopsies after consent and prior to study treatment in eligible 
patients to determine MSI, HRD status, and degree of DNA damage via a novel DNA 
damage assay (PADDA) as well as RAD51C assay 
• To determine whether these marker expression levels alone or in combination are 
associated with response, PFS, and/or overall survival. 
3 PATIENT ELIGIBILITY AND EXCLUSIONS 
3.1 
Inclusion Criteria 
1. Patients with histologically-documented carcinoma of the cervix or endometrium; 


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2. Patients with measurable and/or evaluable lesions as defined by RECIST 1.1 
3. Women at least 18 years of age 
4. Patient with persistent or recurrent squamous cell or adenocarcinoma of the cervix, or any 
carcinoma or carcinosarcoma of the endometrium who has undergone at least one prior 
line of systemic therapy. Prior bevacizumab is allowed. (Note: previous cisplatin during 
radiation therapy should NOT count as a prior line of systemic therapy) 
5. ECOG performance status of 0, 1, or 2; 
6. Patient should agree to have tumor biopsy and baseline blood draw for correlative studies. 
If unable to be safely biopsied and patient desires enrollment, may be enrolled per principal 
investigator discretion. 
7. Adequate organ function should be confirmed by the following laboratory values obtained 
≤ 14 days prior to first dose of rucaparib. Suggested criteria for adequate organ function 
include: 
a. Bone Marrow Function 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
ii. 
Platelets > 100 x 109/L 
iii. 
Hemoglobin ≥ 9 g/dL independent of transfusion ≤ 14 days prior to screening 
hemoglobin assessment 
b. Hepatic Function 
i. 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x 
upper limit of normal (ULN); if liver metastases, then ≤ 5 x ULN 
ii. 
Bilirubin ≤ 1.5 x ULN; < 2 x ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome; and 
iii. 
Serum albumin ≥ 30 g/L (3.0 g/dL) 
c. Renal Function  
i. 
Serum creatinine ≤ 1.5 x ULN; or 
ii. 
Measured or calculated creatinine clearance (CrCL) ≥ 30 ml/min. For calculated 
CrCL, the Cockcroft Gault formula or institutional standard formula can be 
used. 
8. Patients must have a life expectancy of at least three months (to be able to complete one 
cycle of study treatment) 
9. Patients should have no major existing co-morbidities or medical conditions that will 
preclude therapy in the view of the principal investigator 
10. Prior bevacizumab is allowed if off drug ≥ 28 days prior to study enrollment 
11. Ability to understand and the willingness to sign a written informed consent document. 
12. Women of childbearing potential must not be considering getting pregnant and must avoid 
pregnancy during the study and for at least six months after the last dose of rucaparib or 
longer if requested by local authorities. See Section 3.3 for more information. 


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22 
3.2 
Exclusion Criteria 
1. Have active second malignancy, i.e., patient known to have potentially fatal cancer present 
for which she may be (but not necessarily) currently receiving treatment; However patients 
with a history of malignancy that has been completely treated, with no evidence of that 
cancer currently, are permitted to enroll in the trial provided all chemotherapy was 
completed >6 months prior and/or bone marrow transplant (BMT) >2 years prior to first 
dose of rucaparib; 
2. Prior treatment with any PARP inhibitor. 
3. Untreated or symptomatic central nervous system (CNS) metastases. Patients with 
asymptomatic CNS metastases are eligible provided they have been clinically stable for at 
least 4 weeks. 
4. Received treatment with chemotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C); or radiation, biologic/targeted agents, experimental drugs within 3 weeks 
prior to first dose of rucaparib; and/or ongoing adverse effects from such treatment > NCI 
CTCAE V4.0 Grade 1 (Grade 2 non-hematologic toxicity to most recent treatment may be 
permitted with prior advanced approval from Sponsor). 
5. Hospitalization for bowel obstruction within 3 months prior to enrollment. 
6. Patients must have no history of gross hemoptysis (defined as bright red blood of a ½ 
teaspoon or more) or coagulopathy. Patients with history of major tumor-related bleeding 
that is not controlled despite locoregional treatment or at high risk of recurrent tumor-
related bleeding will be excluded. 
7. Patients with history of hypertension must be well-controlled (≤150/100) on a stable 
regimen of anti-hypertensive therapy. 
8. Patients with tumors that invaded major vessels (e.g. the carotid) as shown unequivocally 
by imaging studies will be excluded due to the possibility of increased risk for tumor 
bleeding with bevacizumab therapy. 
9. Patients should not have a major surgical procedure, open biopsy, or significant traumatic 
injury within 28 days prior to study enrollment, or anticipation of need for major surgical 
procedure during the course of the study. No history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscess within 28 days prior to registration. No serious non-
healing wound, ulcer, or bone fracture. 
10. Patients should not have unstable angina or myocardial infarction within the previous 6 
months; no uncontrolled hypertension; no symptomatic congestive heart failure; no serious 
cardiac arrhythmia requiring medication; no clinically significant peripheral vascular 
disease; no history of any CNS cerebrovascular ischemia or stroke within the last 6 months; 
no active serious infection. 
11. Patients should not have other coexisting medical condition that would preclude full 
compliance with the study. 


Version 5.0 (1-Apr-2020) 
23 
12. Patients may not be receiving any other investigational agents. 
13. Patients should not have a history of prior severe infusion reaction to a monoclonal 
antibody. Patients with known hypersensitivity of Chinese hamster ovary cell products or 
other recombinant human antibodies. 
14. Pregnant women are excluded from this study because rucaparib and bevacizumab have 
the potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with rucaparib and bevacizumab, breastfeeding should be discontinued if the mother is 
treated with rucaparib and bevacizumab. Should a woman become pregnant or suspect she 
is pregnant while in this study, she should inform her treating physician immediately. See 
3.3 for more information. 
15. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the 
study because of possible drug interactions with rucaparib and bevacizumab. 
3.3 
Patients with Reproductive Potential 
Pregnancy is an exclusion criterion. Women of childbearing potential must not be considering 
getting pregnant and must avoid pregnancy during the study and for at least 6 months after the last 
dose of rucaparib or longer if requested by local authorities.  
Female patients of childbearing potential must have a negative serum pregnancy test result ≤ 3 
days prior to administration of the first dose of rucaparib. In addition, a serum pregnancy test must 
be performed ≤ 3 days prior to Day 1 of every cycle during the Treatment Phase and at the time of 
treatment discontinuation. Treatment should be discontinued immediately in any woman found to 
have a positive pregnancy test while taking rucaparib.  
Female patients are considered to be of childbearing potential unless 1 of the following applies: 
• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy, or 
• Is postmenopausal, defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal 
range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy; however, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm 
a postmenopausal state. 
Female patients of reproductive potential must practice highly effective methods (failure rate < 
1% per year) of contraception with their partners, if of reproductive potential, during treatment 
and for 6 months following the last dose of rucaparib or longer if requested by local authorities. 
Highly effective contraception includes: 
• Ongoing use of progesterone only injectable or implantable contraceptives;  
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• Bilateral tubal occlusion; 


Version 5.0 (1-Apr-2020) 
24 
• Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the 
usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods) is not acceptable; or 
• Male sterilization, with appropriate post-vasectomy documentation of absence of sperm in 
ejaculate. 
Patients should be instructed to notify the investigator if pregnancy is discovered either during or 
within 6 months of completing treatment with rucaparib. 
4 SUBJECT REGISTRATION AND ENROLLMENT 
4.1 
Required Protocol Specific Regulatory Documents 
This protocol, the Informed Consent document, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB by the Principal Investigator and 
reviewed and approved by the IRB before the study is initiated. 
The Sponsor must pre-approve the informed consent document prior to submission to the IRB. All 
regulatory documents must be available to the Sponsor prior to site activation. Before the study 
can be initiated at any site, the following documentation must be provided to the Clinical Trials 
Office (CTO) at SCC-IIT-Office@ouhsc.edu: 
• A copy of the IRB approval letter for the protocol and informed consent 
• CVs and medical licensure for the principal investigator 
• Form FDA 1572 appropriately completed and signed with appropriate documentation.  
• CAP and CLIA Laboratory certification and institution lab normal values 
• Delegation of Authority Log 
• Executed clinical trial agreement (e.g., contract) 
4.2 
Patients Registration and Enrollment 
Patients must have signed and dated all applicable consents and authorization forms to be 
registered in Velos eResearch database system, which is sponsored by The University of 
Oklahoma Stephenson Cancer Center (OU-SCC). 
First, the study site should send the required documentation to SCC-IIT-Office@ouhsc.edu to 
begin the registration process. A Screening identification (Screening ID) number will be provided 
by OU-SCC research staff. After all screening procedures and assessments have been completed 
and eligibility has been established, the subject Study ID number will be generated by OU-SCC. 
Once the patient has been provided a Study ID number, only the Study ID number should be used. 
Both patient ID numbers should be documented in Velos. 
Patients must not start protocol treatment prior to registration. Patients will start protocol treatment 
only after pre-treatment evaluation is complete and eligibility criteria have been met. 
NOTE: Per the Institutional Review Board (IRB) reporting, a patient is considered accrued 
once he or she signs a consent form for the study. A patient is considered enrolled once the 
patient begins treatment. Evaluable patients are defined in protocol Section 8.3. 


Version 5.0 (1-Apr-2020) 
25 
5 STUDY MODALITIES 
5.1 
Bevacizumab 
Bevacizumab is currently commercially available for cancer therapy, including treatment for 
cervix 
cancer. 
Please 
refer 
to 
the 
package 
insert 
for 
bevacizumab, 
see 
https://www.gene.com/download/pdf/avastin_prescribing.pdf 
and 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf for the most 
complete and current information on the following: 
5.1.1 Formulation 
Bevacizumab (brand name: Avastin) is a recombinant humanized anti-VEGF monoclonal antibody 
composed of human IgG1 framework regions and antigen-binding complementarity-determining 
regions from a murine monoclonal antibody (muMAb VEGF A.4.6.1). 
Generic Name 
Bevacizumab 
Code Number 
rhuMAb VEGF, RO4876646 
Trade Name 
Avastin® 
Chemical Structure 
human IgG1 framework regions and antigen-binding 
complementarity-determining regions from a murine 
monoclonal antibody 
Molecular Weight 
~149 000 daltons 
Description 
Clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion 
 
Bevacizumab is manufactured by recombinant DNA technology, using a genetically engineered 
Chinese hamster ovary (CHO) cell line. The protein is purified from the cell culture medium by 
routine methods of column chromatography and filtration. The final product is tested for quality, 
identity, safety, purity, potency, strength, and excipient/ chemical composition according to 
International Conference on Harmonisation (ICH) guidelines. The purity of bevacizumab is > 
95%. 
Bevacizumab may be supplied in 6-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL 
or 16 mL of bevacizumab, respectively (all at 25 mg/mL). Vials contain bevacizumab with 
phosphate, trehalose, polysorbate 20, and sterile water for injection (SWFI). Vials contain no 
preservative and are suitable for single use only. 
5.1.2 Storage 
Bevacizumab vials should be stored in a refrigerator at 2°C-8°C. Keep vial in the outer carton due 
to light sensitivity. DO NOT FREEZE. DO NOT SHAKE. 
5.1.3 Preparation 
Bevacizumab does not contain any antimicrobial preservative; therefore, care must be taken to 


Version 5.0 (1-Apr-2020) 
26 
ensure the sterility of the prepared solution. Chemical and physical in-use stability has been 
demonstrated for 48 hours at 2°C-30°C in 0.9% sodium chloride solution. From a microbiological 
point of view, the product should be used immediately. If not used immediately, in-use storage 
times and conditions are the responsibility of the user and would normally not be longer than 24 
hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions. 
Bevacizumab should be prepared by a healthcare professional using aseptic technique. Withdraw 
the necessary amount of bevacizumab and dilute to the required administration volume with 0.9% 
sodium chloride solution. The concentration of the final bevacizumab solution should be kept 
within the range of 1.4 - 16.5 mg/ml. Discard any unused portion left in a vial, as the product 
contains no preservatives. Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration. 
5.1.4 Adverse Effects 
Consult the package insert for the most current and complete information. 
5.1.5 Suppliers 
Commercially available from: Genentech, Inc. South San Francisco, CA 94080-4990, USA. 
Consult the prescription information and/or package insert for additional information. 
5.2 
Rucaparib 
5.2.1 Formulation and Supplier 
Rucaparib camsylate (also known as CO-338; formerly known as PF-01367338-BW and AG-
014447) is an oral formulation. Rucaparib tablets for oral administration will be supplied to the 
study sites by Clovis. A brief description of the investigational product is provided below. 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation 
(strengths 
expressed as free base): 
Tablet; film coated; 200 mg (blue, round, debossed with C2),
250 mg (white, rounded diamond shape, debossed with C25,
300 mg (yellow, oval, debossed with C3) 
How Supplied: 
200, 250, and 300 mg (as free base) strength tablets in HDPE
equivalent with child-resistant caps. Patients may receive one
or more strengths.  
Storage Conditions: 
15 to 30°C (59-86°F) 
 
5.2.2 Rucaparib Ordering, Dispensing, Stability and Destruction 
Order instructions: The institutional pharmacy is responsible for managing the inventory of 
rucaparib. Sites will be required to register users in WebEZ system to place orders for study 
provided rucaparib. 
Dispensing: All tablets are provided in high-density polyethylene (HDPE) bottles (or equivalent) 


Version 5.0 (1-Apr-2020) 
27 
with child-resistant caps and should be stored in the provided containers between 15° to 30° C 
(59° to 86° F). Patients may be dispensed one or more strengths depending on their current dose 
of rucaparib. The number of bottles of each strength dispensed will be sufficient to supply 28 days 
of treatment, including a small overage until the next rucaparib dispensation visit. Bottles 
containing rucaparib tablets will be labeled according to national regulations for investigational 
products. 
Sites are to dispense enough rucaparib to patients to last until their next scheduled visit. 
Stability: Unopened bottles of rucaparib tablets are stable to the date indicated on the package and 
can be stored at room temperature with no special storage requirements. 
Destruction: prior to dispensing the next bottles of study medications, old study supplied 
medications are to be collected and logged on to the Drug Accountability Record. It is expected 
that returned, unused by assigned patient, damaged, expired or otherwise out of specification study 
drug will be destroyed by the site, using internal site procedures for the safe disposal of cytotoxic 
materials. 
5.2.3 Adverse Effects: 
Safety information from completed studies assessing oral rucaparib is summarized in rucaparib 
Investigator’s Brochure and detailed safety data are included in the clinical study reports. Based 
on rucaparib’s mechanism of action and data from completed studies, the following rucaparib 
associated toxicities could be expected: 
• Nausea 
• Asthenia / Fatigue 
• Anemia / decreased hemoglobin 
• ALT/AST elevations 
• Vomiting 
• Decreased appetite 
• Constipation 
• Dysgeusia 
• Thrombocytopenia 
• Diarrhea 
• Blood creatinine increased 
• Abdominal pain 
• Dyspnea 
• neutropenia/decreased ANC 
• Increased cholesterol 
• Decreased lymphocytes 
• Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatments with 
rucaparib. When outdoors, patients should use typical precautions such as applying 


Version 5.0 (1-Apr-2020) 
28 
sunscreen (sun protection factor 50 or greater) and/or covering exposed skin with clothing 
and wearing a hat and sunglasses. 
6 TREATMENT PLAN 
An original, informed consent form, indicating prior approval by the institution’s Human Rights 
or Clinical Trials Committee for participation in this study, must be forwarded to the SCC CTO 
Office. 
6.1 
Treatment Schedule for Bevacizumab plus Rucaparib 
• Rucaparib 600mg, PO, BID on days 1 to 21. Cycle = 21 days 
• Bevacizumab 15mg/kg, IV, on day 1 of every 21-day cycle. The total dose must be 
calculated using the most recent subject actual weight (obtained within 3 days of the dosing 
visit, and prior to the infusion). The dose will not be recalculated unless the patient has 
±10% weight change. 
Patients will receive bevacizumab and rucaparib until unacceptable toxicity or tumor progression. 
6.2 
Method of Bevacizumab and Rucaparib Administration 
6.2.1 Rucaparib Administration 
Each patient will receive oral rucaparib daily at 600 mg BID with 8 oz (240 mL) of room 
temperature water, taken on an empty stomach or with food. Tablets should be swallowed whole, 
without crushing or chewing. Patients should take rucaparib doses as close to 12 hours apart as 
possible, preferably at the same times every day. If a patient misses a dose (i.e., does not take it 
within 4 hours of the scheduled time), the patient should skip the missed dose and resume taking 
rucaparib with the next scheduled dose. Missed or vomited doses should not be made up. Patients 
will be instructed to record daily doses taken or not taken in a patient diary. Treatment with 
rucaparib is continuous and each cycle will comprise 21 days. 
6.2.2 Bevacizumab Administration 
Each patient will receive bevacizumab 15 mg/kg IV per institutional standard. 
Bevacizumab infusions should not be given bolus or IV push. Pre-medications may be given prior 
to bevacizumab according to institutional standards. 
6.3 
Dose Modifications 
Toxicity and grades will be classified using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE V4.0). A copy of the CTCAE V4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
6.3.1 Rucaparib Dose Modification and Toxicity Management 
Patients may develop study drug-related toxicities that may require dose reduction, dose delay, 
skipping doses or dose discontinuation. Treatment modifications will be made based on specified 
safety criteria. The following criteria will be used to determine dosing delay, restarting doses, dose 
reduction or discontinuing rucaparib. 
If rucaparib is held, bevacizumab should also be held to maintain concurrent administration. 


Version 5.0 (1-Apr-2020) 
29 
6.3.1.1 Criteria for Rucaparib Dose Modification 
Treatment with rucaparib should be held if any of the following are observed and a dose reduction 
should be considered or implemented. 
• Grade 3 or 4 hematologic toxicity. Anemia should be managed as described below. 
• Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or diarrhea 
adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to the study center routines).  
• Grade 3 or 4 ALT/AST elevations should be managed as described below. 
• In addition, and at the discretion of the investigator, the dose of rucaparib may be held 
and/or reduced for Grade 2 toxicity not adequately controlled by concomitant medications 
and/or supportive care. 
• For patients who meet treatment interruption guidelines above, treatment with rucaparib 
should be held until the toxicity improves to ≤ CTCAE Grade 2. Twice daily dosing may 
then be resumed at either the same dose or a lower dose, per investigator discretion. If 
treatment is resumed at the same dose, and the patient experiences the same toxicity, 
treatment should be interrupted, then resumed at a reduced dose following resolution of the 
event to ≤ CTCAE Grade 2. If the patient continues to experience toxicity, additional dose 
reduction steps are permitted; however, the investigator should consult with the sponsor’s 
medical monitor before reducing to 300 mg BID. If a patient continues to experience 
toxicity despite dose reduction steps to 300 mg BID, or if dosing with rucaparib is 
interrupted for > 21 consecutive days due to toxicity, treatment should be discontinued, 
unless otherwise agreed and documented between the investigator and the sponsor. 
Dose reduction steps are presented in Table 1. 
Management of Anemia including Evaluation for MDS/AML and Follow-up of Patients who 
Discontinue Treatment with Ongoing Anemia: 
• If the patient develops anemia CTCAE Grade ≥ 3, rucaparib treatment should be held until 
the anemia improves to CTCAE Grade ≤ 2 whereupon daily dosing may then be resumed 
at either the same dose or a lower dose, per investigator discretion. 
• If the duration of dosing is interrupted for > 14 consecutive days due to anemia CTCAE 
Grade ≥ 3, treatment should be permanently discontinued, unless otherwise agreed and 
documented between the investigator and the sponsor or designee. 
• In addition, if anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a 
dependence upon blood transfusion occurs, then weekly complete blood counts should be 
performed until resolution of the event. 
• If, after 42 days of interruption of rucaparib, the anemia has not improved to CTCAE Grade 
≤ 1 then the patient should be referred to a hematologist and analysis of the bone marrow 
with cytogenetic studies are recommended according to standard hematologic practice. 
• The bone marrow analysis should include a bone marrow aspirate (for cellular morphology, 


Version 5.0 (1-Apr-2020) 
30 
cytogenetic analysis, and flow cytometry) and a core biopsy (for bone marrow cellularity). 
Management of Rucaparib Treatment-Emergent ALT/AST Elevations: 
• Grade 4 ALT/AST elevations 
o Hold rucaparib until values have returned to Grade 2 or better, then resume rucaparib 
with a dose reduction.  
o Monitor liver function tests weekly for 3 weeks after rucaparib has been restarted 
• Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, should be 
managed as follows: 
o Monitor liver function tests weekly until resolution to ≤ Grade 2. 
o Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is permitted 
provided bilirubin is < ULN, alkaline phosphatase is < 3 x ULN, and there are no other 
signs of liver dysfunction. 
o If patient has Grade 3 ALT/AST and continues on rucaparib, and levels do not decline 
within 2 weeks or they continue to rise, treatment interruption and resolution to ≤ Grade 
2 will be required before rucaparib can be resumed, either at the current dose or at a 
reduced dose. 
Drug-induced liver injury (DILI) is described in the US FDA Guidance for Industry, Drug- 
Induced Liver Injury: Premarketing Clinical Evaluation [45] and should be referenced when 
managing treatment-emergent ALT/AST elevations. 
Rucaparib treatment must be interrupted if biochemical criteria for suspected DILI are met, 
according to presence of the following laboratory abnormalities: 
ALT or AST > 3 x ULN 
and 
Bilirubin > 2 x ULN 
While treatment is interrupted, the patient should be evaluated for the presence of confounding 
factors including malignant disease in the liver, co-administration of other suspect drugs, 
cholestasis, and viral or autoimmune hepatitis that could have caused the laboratory abnormalities. 
Other laboratory investigations of liver function such as international normalized ratio (INR) 
should be implemented as indicated. If no alternative cause is identified, rucaparib must be 
permanently discontinued. 
All cases of possible DILI should be followed until all abnormalities have returned to normal, 
returned to baseline levels, or an alternative cause is found to explain the combination of the 
increased transaminases and total bilirubin. 
Table 1 Rucaparib Dose Reduction Steps 
Starting Dose 
600 mg BID 
Dose Level -1 
500 mg BID 


Version 5.0 (1-Apr-2020) 
31 
Dose Level -2 
400 mg BID 
Dose Level -3* 
300 mg BID 
*Consult with the sponsor before reducing to Dose Level – 3. Further 
dose reduction may be possible but requires consultation with the 
sponsor’s medical monitor. 
 
6.3.1.2 Criteria for Rucaparib Re-treatment 
Treatment may resume if: 
• ANC ≥ 1.0 x 109/L 
• Platelet count ≥ 100 x 109/L 
• Non-hematologic toxicities have returned to baseline or ≤ CTCAE V4.0 Grade 1 severity 
(or, at the investigator’s discretion, ≤ CTCAE V4.0 Grade 2 severity if not considered a 
safety risk for the patient). Grade 3 or Grade 4 ALT/AST elevations should be managed as 
described above. 
6.3.2 Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that require holding 
bevacizumab, the dose will remain the same once treatment resumes. 
Any toxicities associated or possibly associated with bevacizumab treatment should be managed 
according to standard medical practice. Bevacizumab has a terminal half-life of 2 to 3 weeks; 
therefore, its discontinuation results in slow elimination over several months. There is no available 
antidote for bevacizumab. 
Subjects should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity occurs because of bevacizumab at any time during the study, treatment with 
bevacizumab should be discontinued. 
If bevacizumab is to be discontinued due to adverse effects determined related to bevacizumab, 
rucaparib may be continued if at the discretion of the treating physician, it can be safely done so 
knowing the possible side effect profile of rucaparib. This may be done if the side effects of 
bevacizumab have resolved to ≤ grade 1 and all other treatment parameters have been met. Once 
bevacizumab is held, it cannot start until the next cycle of rucaparib starts. 
If bevacizumab is interrupted for ANY reasons for >4 weeks (unless otherwise specified), the 
patient should discontinue bevacizumab therapy on protocol. 
Based on the safety profile of bevacizumab, the management for potential toxicity is summarized 
as below. 
Infusion Reaction: 
Infusion of bevacizumab should be interrupted for subjects who develop dyspnea or clinically 
significant hypotension. Subjects who experience a NCI CTCAE V4.0 Grade 3 or 4 allergic 


Version 5.0 (1-Apr-2020) 
32 
reaction/hypersensitivity, adult respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from bevacizumab treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who experience any 
infusion-associated symptoms not specified above. When the subject’s symptoms have completely 
resolved, the infusion may be continued at no more than 50% of the rate prior to the reaction and 
increased in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the 
full rate during the next cycle. 
Thromboembolic Event: 
• Arterial thromboembolic event ≥ Grade 2: Bevacizumab should be discontinued 
• Venous thromboembolic event ≥ grade 4: Bevacizumab should be discontinued 
• Venous thromboembolic event ≤ grade 3: 
1. Hold bevacizumab treatment. If the planned duration of full-dose anticoagulation is < 
2 weeks, bevacizumab should be held until the full-dose anticoagulation period is over. 
2. If the planned duration of full-dose anticoagulation is > 2 weeks, bevacizumab may be 
resumed during full-dose anticoagulation if all of the criteria below are met: 
- 
The subject must not have pathological conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels or other conditions) 
- 
The subject must not have had hemorrhagic events while on study 
- 
The subject must be on stable dose of heparin or have an in-range INR (usually 2-
3) on a stable dose of warfarin prior to restarting bevacizumab. 
3. If thromboembolism worsen/recur upon resumption of study therapy, discontinue 
bevacizumab 
Hypertension: 
Subjects with baseline hypertension should be treated with anti-hypertensive medication as 
needed. The goal of blood pressure (BP) control should be consistent with general medical 
practice. 
• Grade 3 (SBP≥160 mmHg or DBP ≥100 mmHg): 
o Start or adjust anti-hypertensive medication 
o Hold bevacizumab until BP < 160/90mmHg 
o For hypertension that is refractory requiring delay of bevacizumab for > 4 weeks, 
discontinue bevacizumab 
• Grade 4 (Hypertensive crisis or malignant hypertension): Discontinue bevacizumab 
Hemorrhage: 
• Grade 2-4 intracranial or pulmonary bleeding: Discontinue bevacizumab 
• Grade 3 other hemorrhage not from CNS or pulmonary: 
o Patients receiving full-dose anticoagulation should discontinue bevacizumab. 
o For patients not on full-dose anticoagulation, hold bevacizumab until ALL of the 
following criteria are met: 
 the bleeding has resolved and hemoglobin is stable 


Version 5.0 (1-Apr-2020) 
33 
 there is no bleeding diathesis that would increase the risk of therapy 
 there is no anatomic or pathologic condition that could increase the risk of 
hemorrhage recurrence. 
o Patients who experience recurrence of grade 3 hemorrhage should discontinue study 
therapy. 
• Grade 4 other hemorrhage not from CNS or pulmonary: Discontinue bevacizumab 
Wound healing complications: 
• Grade 2: Hold bevacizumab until healing 
• Grade 3-4: Discontinue bevacizumab 
Proteinuria 
• Grade 1 (urine dipstick 1+ or urine collection 0.15 to 1.0 g/24 hr): No bevacizumab 
modifications 
• Grade 2 (urine dipstick 2+ to 3+ or urine collection > 1.0 to 3.5 g/24 hr): 
o For 2+ dipstick, may administer bevacizumab and obtain 24-hour urine prior to next 
dose. 
o For 3+ dipstick, obtain 24-hour urine prior to administration of bevacizumab. 
o Withhold bevacizumab for proteinuria >2 g/24 hr and resume when proteinuria is 
o ≤ 2 g/24 hr. 
• Grade 3 (urine dipstick 4 + or urine collection > 3.5 g/24 hr): Withhold bevacizumab. 
• Resume when proteinuria is ≤ 2 g/24 hr. 
• Grade 4 (nephrotic syndrome): Discontinue bevacizumab. 
Perforation of GI or any other organ: 
• Any grade: Discontinue bevacizumab 
Other Unspecified AEs related to bevacizumab: 
• Grade 3: Hold bevacizumab until symptoms resolve to<Grade 1 
• Grade 4 : Discontinue bevacizumab; However upon consultation with the study chair, 
resumption of bevacizumab may be considered if a patient is benefiting from therapy, and 
the Grade 4 toxicity is transient, has recovered to ≤ Grade 1 and unlikely to recur with 
retreatment. 
6.4 
Precaution for Concomitant Medication during the Study 
6.4.1 Non-study Anti-cancer Agent 
Patients may not use any non-study anti-cancer agent (investigational or non- investigational) 
during the study. 
6.4.2 Hematopoietic Growth Factors and Blood Products 
Hematopoietic Growth Factors and Blood Products will be allowed as concomitant therapy. 
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment of 
cytopenias should be administered according to institutional guidelines. Transfusion thresholds for 


Version 5.0 (1-Apr-2020) 
34 
blood product support will be in accordance with institutional guidelines. 
6.4.3 Pre-caution for CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the in vivo CYP interaction study (CO-338-044), rucaparib is a moderate 
inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. Caution should 
be used in patients on rucaparib taking concomitant medicines that are substrates of CYP1A2, 
CYP2C9, and/or CYP3A. (see IB, Appendix B). Although in vitro rucaparib metabolism mediated 
by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo cannot be excluded. Caution 
should be used for concomitant use of strong CYP3A4 inhibitors or inducers.  
Table 2 Examples of CYP Substrates with Narrow Therapeutic Range 
CYP Enzyme 
Substrates with Narrow Therapeutic Range a 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine 
 
The table is based on the Draft FDA Guidance on Drug Interaction Studies–Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations, 2012. 
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of CYP 
inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
6.4.4 Precaution for Anticoagulants 
Rucaparib is a weak inhibitor of CYP2C9 in vivo. Caution should be exercised in patients receiving 
rucaparib and concomitant warfarin (Coumadin). Patients taking warfarin should have INR 
monitored regularly per standard clinical practice. 
6.4.5 Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator and should be documented on the eCRF. Other concomitant medications, except for 
analgesics, chronic treatments for concomitant medical conditions, or agents required for life-
threatening medical problems, should be avoided. Herbal and complementary therapies should not 
be encouraged because of unknown side effects and potential drug interactions, but any taken by 
the patient should be documented appropriately on the eCRF.  
Rucaparib marginally increased digoxin area under the plasma concentration-time curve (AUC) 
by 20%. Caution should be exercised for patients receiving rucaparib and requiring concomitant 
medication with digoxin. Patients taking digoxin should have their digoxin levels monitored after 
starting rucaparib and then regularly per standard clinical practice. In vitro, rucaparib is a potent 


Version 5.0 (1-Apr-2020) 
35 
inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. 
As inhibition of these transporters could increase metformin renal elimination and decrease liver 
uptake of metformin, caution is advised when metformin is co-administered with rucaparib. In 
addition, rucaparib is an inhibitor of the BCRP with 50% inhibitory concentration (IC50) value 
suggesting potential BCRP inhibition and increased exposures of medicinal products that are 
BCRP substrate (e.g., rosuvastatin). 
6.5 
Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the study. 
6.6 
Duration of Therapy 
Patients will be treated until disease progression or toxicity unless patient withdraws consent. If 
the patient is showing clinical benefit with disease progression, the patient may continue treatment 
after consulting with the Principal Investigator and Medical Monitor. 
6.7 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy early, will be 
followed for response until progression, and for survival for up to 2 years from the date of 
registration. All patients must also be followed through completion of all protocol therapy. 
7 STUDY PARAMETERS 
7.1 
Therapeutic Parameters 
1. Pre-study scans should be performed within 4 weeks prior to registration. 
2. All patients must have a pre-dosing weight taken at every visit, as appropriate. 
3. All required pretreatment laboratory studies should be done as outlined in the study 
calendars in Sections 7.2. 
4. Initial H&P and laboratory tests can be used for C1D1 if done within 72 hours 
7.2 
Study Calendarl 
 
Parameter 
Prior to 
Study 
within 28 
days of 
enrollment 
Prior to 
Study 
within 14 
days of 
enrollment 
Day 1 or 
Prior to 
each cycle 
(+/- 3 
days) 
Day 15 
of 
Cycle 1 
Every 2 
cycles 
(+/- 7 
days) 
End of 
treatment 
(within 30 
days post 
last dose) 
Every 3 
months 
for 2 
years e 
Informed 
consent 
X 
 
 
 
 
 
 
Inclusion 
/exclusion 
X 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 


Version 5.0 (1-Apr-2020) 
36 
Parameter 
Prior to 
Study 
within 28 
days of 
enrollment 
Prior to 
Study 
within 14 
days of 
enrollment 
Day 1 or 
Prior to 
each cycle 
(+/- 3 
days) 
Day 15 
of 
Cycle 1 
Every 2 
cycles 
(+/- 7 
days) 
End of 
treatment 
(within 30 
days post 
last dose) 
Every 3 
months 
for 2 
years e 
History & 
Physical f 
X 
 
X 
 
 
X 
 
ECOG PS k 
X 
 
X 
 
 
X 
 
Vital signs/ 
weight i 
X 
 
X 
 
 
X 
 
CT CAP or 
MRI 
X 
 
 
 
X 
X 
 
Hematology g 
 
X 
X 
X 
 
X 
 
Serum 
Chemistries a 
 
X 
X 
X 
 
X 
 
PT/PTT/INR 
 
X 
If clinically indicated 
 
Urinalysis h 
 
X 
X 
 
 
X 
 
Toxicity 
assessment c 
 
 
X 
 
 
X 
 
Serum 
Pregnancy 
Test d 
X 
 
X 
 
 
X 
 
ECG j 
X 
 
 
 
 
X 
 
Concomitant 
Medications 
X 
 
X 
 
 
X 
 
Blood sample 
for correlative 
study 
 
X 
 
 
 
 
 


Version 5.0 (1-Apr-2020) 
37 
Parameter 
Prior to 
Study 
within 28 
days of 
enrollment 
Prior to 
Study 
within 14 
days of 
enrollment 
Day 1 or 
Prior to 
each cycle 
(+/- 3 
days) 
Day 15 
of 
Cycle 1 
Every 2 
cycles 
(+/- 7 
days) 
End of 
treatment 
(within 30 
days post 
last dose) 
Every 3 
months 
for 2 
years e 
Tumor tissue 
Xb 
 
 
 
 
 
 
Rucaparib 
dispensed/ 
collected 
 
 
X 
 
 
X 
 
Bevacizumab 
infusion 
 
 
X 
 
 
 
 
Survival 
 
 
 
 
 
X 
X 
 
a. Total protein, albumin, creatinine or estimated glomerular filtration rate (GFR) using the 
Cockcroft-Gault formula or institutional standard formula, blood urea nitrogen (BUN) or 
urea, total bilirubin, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase 
(LDH), glucose, sodium, potassium, magnesium, chloride, CO2, calcium, phosphorus, at 
screening, during treatment at each study visit and at the End of Treatment Visit for all 
patients. Fasting is not required before blood sampling. Serum chemistry results must be 
reviewed by the investigator before the start of treatment with rucaparib and ongoing at 
times testing occurs. Additional and more frequent tests may be performed at the 
investigator’s discretion. 
b. Patients must agree for pre-treatment biopsy. If fresh pre-treatment biopsy cannot be safely 
obtained, archival tumor tissue is acceptable. 
c. Any SAEs, AESIs, and treatment related Grade 3/4 AEs must be followed until resolution 
or stabilization, or until lost to follow-up. 
d. For women of childbearing potential only. A serum pregnancy test must be performed ≤ 3 
days prior to first dose of rucaparib (a negative result is required before dosing can begin) 
and at the End of Treatment Visit. A serum pregnancy test must be performed ≤ 3 days 
prior to Day 1 of every cycle during the Treatment Phase. A positive serum pregnancy test 
during study participation must be reported to the sponsor. 
e. Long-term follow up started 3 months post EOT with a window of +/- 2 weeks. 
f. Focused physical exam, including a pelvic exam. Physical examinations will also include 
an assessment of all the major body systems. Complete physical examination, along with 
body weight, will be performed during screening, at study visits during the Treatment 
Phase and at treatment discontinuation. 


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38 
g. Red blood cell (RBC) count and parameters (hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin 
concentration (MCHC)) and reticulocyte count, white blood cell (WBC) count and 
differential (with ANC), and platelet count will be assessed at screening, during treatment 
at each study visit and at the End of Treatment Visit for all patients. Hematology results 
must be reviewed by the investigator before the start of treatment with rucaparib and 
ongoing at times testing occurs. Additional and more frequent tests may be performed at 
the investigator’s discretion. 
h. Performed locally on a freshly voided clean sample by dipstick for protein, glucose, blood, 
pH, and ketones. If dipstick findings are abnormal based on the investigator’s judgment, 
then a microscopic evaluation will be performed to assess the abnormal findings. Urinalysis 
will be performed at screening, during treatment at each study visit and at the End of 
Treatment Visit for all patients, but may be conducted at other times as clinically indicated. 
i. Vital signs will include blood pressure, pulse, and body temperature and will be taken after 
the patient has been resting for at least 5 minutes during screening, at study visits during 
the Treatment Phase and at the End of Treatment Visit. Height will be measured during the 
screening visit only. Weight will be measured per institutional guidelines during screening, 
during treatment at each study visit and at the End of Treatment Visit. 
j. For all patients, 12-lead ECGs will be performed at screening (within 28 days prior to 
enrollment) and at the End of Treatment Visit. The following will be measured or 
calculated: heart rate, PR, QRS, QT, and rhythm. The investigator or qualified designee 
will review the ECGs locally and assess the results as normal or abnormal (clinically 
significant or not clinically significant). If it is clinically indicated, ECGs can be performed 
at other times during the study. 
k. ECOG performance status will be assessed during screening, at study visits during the 
Treatment Phase and at the End of Treatment Visit. The ECOG performance status should 
be assessed by the same study personnel at each visit, if possible. For eligibility purposes, 
patients with borderline ECOG performance status should be considered carefully to avoid 
enrolling patients who may have significant impairment. 
l. During the COVID-19 crisis, protocol mandated visits may be performed via telemedicine 
or visits may be combined in order to prevent imminent safety risks to patients. All such 
changes to the visit schedule must be clearly documented in the subject’s chart. Changes 
in study visit schedules or missed visits must be explained in the final clinical study report. 
7.3 
Biological Sample Collection for Correlative Studies 
We will assess microsatellite instability in the biopsies of patients with recurrent endometrial 
cancer. Additionally, response rates will be correlated with Foundation Medicine somatic testing 
(obtained as part of standard of care). Fresh biopsies will be assessed for DNA damage via a 
proprietary assay (PADDA) as well as RAD51C foci assay [61, 75]. Additional correlative studies 
such as HRD may be performed if sufficient tissue is available.  
• Patients must agree to have a fresh tumor biopsy, after a written consent and prior to study 


Version 5.0 (1-Apr-2020) 
39 
treatment. Archival tumor tissue is only acceptable for pre-treatment sample if the fresh 
tumor biopsy cannot be safely obtained. However, if fresh frozen samples cannot be 
collected, PADDA assay will not be performed. 
• Peripheral Blood should be collected prior to treatment. 
Please see lab manual for more detailed information of sample collection and shipping. 
7.4 
Follow up Parameter 
Follow-up is required as outlined in Sections 6.7 and 7.2. In brief, patients will be seen every 21 
days (prior to each cycle of therapy) while receiving study treatment. CT scans to assess response 
will be performed prior to every odd cycle. Patients will also be seen 30 days after last study 
medication is issued as the end of treatment (EOT) visit for safety and efficacy assessment, with a 
window of +/- 7 days. For EOT visit, CT scan should be repeated if the previous CT scan done 
over 4 weeks. Required study procedures are based on the presence or absence of bevacizumab or 
rucaparib related cardiovascular or other toxicities. At the EOT, information collected for 
subsequent treatments and AESI will require appropriate documentation (i.e., laboratory and/or 
pathology reports) and should be reported. Additionally, birth control must continue for 6 months 
after discontinuation of rucaparib. 
A patient is considered off study therapy when the patient has progressed or died prior to 
completion of study therapy, a non-protocol drug or therapy (directed at the disease) is initiated or 
all study therapy is totally discontinued. Survival and progression data will continue to be collected 
for up to 2 years. 
8 EVALUATION CRITERIA 
8.1 
Parameters of Outcome –RECIST 1.1 Criteria 
8.1.1 Definition of Measurable Lesions 
Measurable disease is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when measured by 
conventional techniques, including palpation, plain x-ray, CT, and MRI, or ≥ 10 mm when 
measured by spiral CT. 
8.1.2 Baseline Documentation of “Target” and “Non-Target” lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest dimension) and their suitability for accurate repetitive measurements by one consistent 
method of assessment (either by imaging techniques or clinically). A sum of the longest dimension 
(LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as reference to further characterize the progression of the measurable 
dimension of the disease. Tumor within a previously irradiated field will be designated as “non-
target” lesions unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy. 


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40 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and each of these lesions should be followed 
as stable (the persistence of a non-target lesion), complete response (the disappearance of a non-
target lesion) or progressive disease (the unequivocal progression of a non-target lesion). 
All baseline evaluations of disease status should be performed as close as possible to the start of 
treatment and never more than 4 weeks before the beginning of treatment. 
Measurement of the longest dimension of each target lesion size is required for follow- up. Change 
in the sum of these dimensions affords some estimate of change in tumor size and hence therapeutic 
efficacy. All disease must be assessed using the same technique as baseline. 
8.1.3 Definition of Disease Progression 
Progression for patients with measurable disease at baseline is defined as ANY of the following: 
• At least a 20% increase in the sum of LD target lesions taking as reference the smallest 
sum LD recorded since study entry 
• In the case where the ONLY target lesion is a solitary pelvic mass measured by physical 
exam which is not radiographically measurable, a 50% increase in the LD is required taking 
as reference the smallest LD recorded since study entry 
• The appearance of one or more new lesions 
• Death due to disease without prior objective documentation of progression 
• Global deterioration in health status attributable to the disease requiring a change in therapy 
without objective evidence of progression 
• Unequivocal progression of existing non-target lesions, other than pleural effusions 
without cytological proof of neoplastic origin, in the opinion of the treating physician (in 
this circumstance an explanation must be provided) 
Progression for patients with non-measurable disease at baseline is defined as increasing clinical, 
radiological, or histological evidence of disease since study entry. 
8.1.4 Survival 
Survival is the observed length of life from the date of study entry to death or the date of last 
contact. 
8.1.5 Progression-Free Survival 
Progression free survival is defined as the period from the date of study entry until disease 
progression or death (whichever occurs first). Cases who have not had an event will be censored 
at the date of last disease assessment documenting the patient was free of progression. Progression 
will be evaluated by RECIST v1.1. 
8.2 
Subjective Parameters 
The performance status, specific symptoms, and side effects are graded according to the CTCAE 
V4.0. 
8.3 
Definition of Evaluable Patients 


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41 
Evaluable patients will be defined as patients with measurable and/or evaluable lesions who 
receive at least cycle 1 doses of study treatment (one dose of IV bevacizumab and 21 days of 
rucaparib, PO, BID) and complete the first post-treatment CT or MRI for tumor assessment. 
Patients who discontinued study treatment due to toxicity incurred by previous therapy will still 
be evaluated but will be replaced by additional patients for the efficacy analysis. 
Patients removed from study for early withdraw or hypersensitivity reactions will be replaced if 
they have received less than one cycle of study treatments during cycle 1, but will be included in 
the safety analysis. 
Patients who do not receive at least one cycle doses of study treatment will be considered 
unevaluable for efficacy analysis and will be replaced unless the missed doses were due to 
development of grade 3-4 adverse events related to study treatment. Patient who missed doses but 
have more than 80% total drug accountability will still be considered evaluable. The dose 
adjustment of rucaparib will follow after adjustment of SOC per protocol as described in Section 
6.3. 
9 STUDY MONITORING AND REPORTING PROCEDURES 
9.1 
Adverse Event Monitoring and Management 
9.1.1 Definition of an Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not related to the investigational medicinal product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction, or the significant worsening of the 
indication under investigation that is not recorded elsewhere on the eCRF. Anticipated fluctuations 
of pre-existing conditions, including the disease under study, that do not represent a clinically 
significant exacerbation or worsening are not considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the patient a non-leading question (e.g., “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). The existence of an AE may 
be concluded from a spontaneous report of the patient; from the physical examination; or from 
special tests such as the ECG, laboratory assessments, or other study-specified procedure (source 
of AE). Symptoms reported spontaneously by the patient during the physical examination would 
also qualify as an AE (and hence documented on the AE eCRF, not on the physical examination 
eCRF, which is reserved for physical signs or findings). 
9.1.2 Definition of a Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after informed 
consent is given and prior to dosing if the SAE is related to a study procedure) that: 
• Results in death. Any event resulting in death during the reporting period (from date of first 


Version 5.0 (1-Apr-2020) 
42 
dose of rucaparib through 30 days after last dose) must be treated as an SAE and reported 
as such. An event related to a study procedure that occurs after informed consent, but prior 
to dosing, that results in death must also be reported as an SAE. 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly or birth defect 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home or 
the development of drug dependency or drug abuse. 
9.1.3 Definition of an Adverse Events of Special Interest (AESIs) 
AESIs (serious or non-serious) are defined as AEs of scientific and medical concern specific to 
the sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (e.g., regulators) might also be warranted. 
Details on Clovis’ currently agreed list of AESIs for rucaparib can be found in the current rucaparib 
IB. These AESIs are to be reported to Clovis within 24 hours of knowledge of the event.  
9.1.4 Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• Pre-planned or elective hospitalization including social and/or convenience situations (e.g., 
respite care) 
• Hospital visits of less than 24 hours duration (e.g., patient presents to the emergency room, 
but is not admitted to a ward) 
• Overdose of either rucaparib, bevacizumab or concomitant medication unless the event 
meets SAE criteria (e.g., hospitalization). However, the event should still be captured as a 
non-serious AE on the appropriate eCRF page. 
• Events of progression of the patient’s underlying cancer as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as an AE/SAE; and 
• Events that meet the SAE criteria and occur after informed consent, but before the first 
dose of rucaparib, which are considered unrelated to screening procedures.  
9.1.5 Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 


Version 5.0 (1-Apr-2020) 
43 
changes in lab values within the normal range will require similar judgment. An abnormal 
laboratory value that is not already associated with an AE is to be recorded as an AE only if any 
one of the following criteria is met: 
• an action on rucaparib treatment is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically significant 
9.1.6 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the course of the study, rucaparib dosing should be held 
immediately. 
A pregnancy is not considered to be an AE or SAE; however, all pregnancies occurring during 
study participation or within 6 months of last dosing must be reported to Clovis using the Clinical 
Pregnancy Report Form within the same timelines as for an SAE. 
All pregnancies should be followed through to outcome whenever possible. Once the outcome of 
the pregnancy is known, the Clinical Pregnancy Outcome Report Form should be completed and 
submitted to the sponsor and Clovis. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according to the 
AE or SAE/AESI processes using the appropriate AE or SAE/AESI forms. 
9.1.7 Recording of Adverse Events, Serious Adverse Events, and Adverse Events of Special 
Interest 
Events that occur after signing of informed consent, but prior to initiation of rucaparib, unless 
serious and due to a protocol-mandated procedure, should be recorded. Any serious event related 
to a protocol-mandated procedure should be reported as an SAE during the screening period. Any 
AE that occurs after first dose of rucaparib through 30 days after receiving the last dose of 
rucaparib will be recorded on the AE eCRF. 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of breath 
may be reported as pneumonia, if that is a reasonable diagnosis.  
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded.  
SAEs and AESIs that occur during the study or within 30 days after receiving the last dose of 
rucaparib, whether or not related to rucaparib, must be reported immediately (i.e., within 24 hours 
of knowledge of the event) to the sponsor/ SAE designee. The contact information for reporting 
of SAEs/AESIs can be found on the SAE/AESI Reporting Form. After the 30-day reporting 
window after discontinuation of rucaparib treatment, only SAEs assessed as related to rucaparib 
and all AESIs, irrespective of causality, need to be reported. Information on the follow-up of AEs, 
SAEs, and AESIs is provided below. 


Version 5.0 (1-Apr-2020) 
44 
The contact information for reporting of SAEs/AESIs to Clovis include email: 
drugsafety@clovisoncology.com or Fax: 1-303-261-8319, which can be found on the SAE/AESI 
Reporting Form. 
The contact information for reporting of SAEs/AESIs to Sponsor: 
E-mail: SCCIITreporting@ouhsc.edu or via fax at 1-405-271-1416. 
Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE V4.0 grading scale 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf). 
Severity is not the same as Serious. 
For AEs not covered by NCI CTCAE V4.0, the severity will be characterized as mild, moderate, 
severe, life-threatening, or fatal according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and may 
interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or 
prolongation of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
• Fatal events are those events that led to the patient’s death 
Causal Relationship of Adverse Events to Rucaparib 
Medical judgment should be used to determine the cause of the AE considering all relevant factors 
such as, but not limited to, the underlying study indication, coexisting disease, concomitant 
medication, relevant history, pattern of the AE, temporal relationship to the study medication, de-
challenge or re-challenge with rucaparib. 
 
Not 
Related To 
Rucaparib 
• An AE that is clearly due to extraneous causes (e.g., concurrent disease, 
concomitant medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of 
rucabarib 
• It does not follow a known pattern of response to rucaparib 
• It does not reappear or worsen when rucaparib is restarted 
• An alternative explanation is likely, but not clearly identifiable 


Version 5.0 (1-Apr-2020) 
45 
Related to 
Rucaparib 
• An AE that is difficult to assign to alternative causes 
• It follows a strong or reasonable temporal sequence from administration of 
rucaparib 
• It could not be reasonably explained by the patient’s clinical state, concurrent 
disease, or other concomitant therapy administered to the patient 
• It follows a known response pattern to rucaparib 
• It is confirmed with a positive re-challenge or supporting laboratory data 
 
Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the following 
criteria: 
Action Taken with Study Drug (note all that apply) 
• None 
• Dose reduced/delayed 
• Study drug temporarily interrupted 
• Study drug permanently discontinued 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering/Resolving/Improving 
• Ongoing 
• Death 
• Lost to follow-up 
9.1.8 Follow-Up of Adverse Events, Serious Adverse Events, and Adverse Events of Special 
Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; or, 
if a chronic condition, until fully characterized through 30 days after the last dose of rucaparib. 
Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed until resolution or 
stabilization, death, or until lost to follow-up. After the 30-day window, treatment-related SAEs 
and all AESIs, irrespective of causality, need to be reported. 
9.1.9 Regulatory Aspects of Serious Adverse Event and Adverse Events of Special Interest 
Reporting 
All SAEs and AESIs, regardless of relationship to the study drugs, must be reported to the 
sponsor/SAE designee within 24 hours of knowledge of the event, during the study through 30 


Version 5.0 (1-Apr-2020) 
46 
days after receiving the last dose of study treatment, according to the procedures below. After the 
30-day specified window, only SAEs considered to be treatment-related and all AESIs, regardless 
of treatment relationship, should be reported. It is important that the investigator provide an 
assessment of relationship of the SAE or AESI to study treatment at the time of the initial report. 
The Clovis study-specific Serious Adverse Event (SAE)/Adverse Events of Special Interest 
(AESI) Report Form must be used for reporting SAEs and AESIs to Clovis. The contact 
information for reporting of SAEs and AESIs can be found on the SAE/AESI Reporting Form and 
Pregnancy Report Forms. In addition, the Sponsor SAE/UP form must be used for reporting SAEs 
to the Sponsor. 
The Sponsor or its designee is responsible for submitting reports of AEs associated with the use 
of the drugs that are both serious and unexpected to the U.S. Food and Drug Administration (FDA), 
according to 21 Code of Federal Regulations (CFR) 312.32 
The Sponsor or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements. 
9.2 
Reporting of Serious Adverse Events 
All SAEs should be recorded on Clovis study-specific SAE/AESI Report Forms and faxed or 
emailed to: 
Clovis Oncology, Inc. 
Drug Safety Department 
Fax: 1-303-261-8319 
(Please use the safety reporting fax cover sheet attached to the SAE reporting form for your fax 
transmission) 
Email: drugsafety@clovisoncology.com 
In addition, all SAEs should be recorded on the Sponsor SAE/UP form together with the 
MedWatch Form 3500A and sent to SCC IIT Office through: 
E-mail: SCCIITreporting@ouhsc.edu or via fax at 1-405-271-1416 
9.3 
MED WATCH 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500a form: 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up information: 


Version 5.0 (1-Apr-2020) 
47 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e. D.O.B. initial, subject number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information 
is being submitted (The subject identifiers are important so that the new information is 
added to the correct initial report) 
Occasionally Clovis or the Sponsor may contact the reporter for additional information, 
clarification, or current status of the subject for whom an adverse event was reported. 
Assessing Causality: Investigators are required to assess whether there is a reasonable possibility 
that rucaparib combined treatment caused or contributed to an adverse event. The general guidance 
is described in section 9.1. 
9.4 
Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, IND safety reporting requirements will be followed: 
9.4.1 Expedited IND Safety Reports: 
9.4.1.1 7 Calendar-Day Telephone or Fax Report: 
The Sponsor is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of rucaparib combined 
with bevacizumab. An unexpected adverse event is one that is not already described in the 
Investigator Brochure. Such reports are to be telephoned or faxed to the FDA and Clovis Oncology, 
Inc., within 7 calendar days of first learning of the event. Each telephone call or fax transmission 
(see fax number below) should be directed to the FDA new drug review division in the Center for 
Drug Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever is responsible for the review of the IND. 
9.4.1.2 15 Calendar-Day Written Report: 
The Sponsor is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered possibly related to the use of 
rucaparib. An unexpected adverse event is one that is not already described in the list of expected 
events in the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed with the IND concerning similar 
events should be analyzed. The new report should contain comments on the significance of the 
new event in light of the previous, similar reports. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Clovis 
Drug Safety, and all participating investigators within 15 calendar days of first learning of the 


Version 5.0 (1-Apr-2020) 
48 
event. The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
9.4.2 IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation. 
10 STATISTICAL CONSIDERATIONS 
10.1 Sample Size 
The study hypothesis will be evaluated in a 2-stage design, a method provided by Sill et al. [77]. 
This will be used to decide whether there are sufficient numbers of patients progression- free at 6 
months or with objective responses to continue study in a second stage (at the interim analysis) or 
deem the drug worthy of further investigation in a phase III study (at the end of the study). In 
particular, the null hypothesis is H0: πr≤11% and πs≤24% and the alternative hypothesis is H0: πr ≥ 
31% (=11%+20%) or πs ≥ 44% (=24%+20%), where πr is the objective response rate, πs is the PFS 
rate at 6 months, 11% and 24% are the response rate and PFS rate at 6 months respectively from a 
previous study [58]. The following decision rule will be applied where Xs(1) is the number of 
patients progression-free at 6 months after the first stage, Xr(1) is the number of patients with 
objective tumor responses (partial or complete) after the first stage, Xs is the cumulative number 
of patients progression-free at 6 months after stage 2, Xr is the cumulative number of patients with 
responses after stage 2, Cs(1) is the critical value for Xs(1), Cr(1) is the critical value for Xr(1), 
Cs is the critical value for Xs, and Cr is the critical value for Xr: Decision Rule: If either Xs(1) > 
Cs(1) or Xr(1) > Cr(1) after the first stage, then the study will open to a second stage of accrual to 
further evaluate the activity of the drug. If either Xs > Cs or Xr > Cr after the second stage and 
clinical judgment indicates, then the agent will be deemed clinically interesting and worthy of 
further investigation. 
For a flexible design with 0.1 alpha level and at least 90% power, the targeted accrual for the first 
stage (denoted by n(1)) will be 28 eligible and evaluable patients, but is permitted to range from 24 
to 31. The cumulative targeted accrual for the first and second stage combined (denoted by n) will 
be 50 eligible and evaluable patients, but is permitted to range from 46 to 53. Critical values for 
each stage are provided below: 
 
Stage 1 
Stage 1 + Stage 2 
n(1) 
24 
25 
26 
27 
28 
29 
30 
31 
n 
46 
47 
48 
49 
50* 51** 52 
53 
Cr(1) 3 
4 
4 
4 
4 
4 
5 
4 
Cr 
9 
9 
9 
9 
10 
10 
10 
10 
Cs(1) 6 
6 
7 
7 
7 
8 
8 
9 
Cs 
15 
15 
16 
16 
16 
16 
17 
17 
*(Cr, Cs) = (9, 16) when n(1) = 25 or 26; **(Cr, Cs) = (10, 17) when n(1) = 24, 28 or 30; (Cr, Cs) = (9, 
17) when n(1) = 25 


Version 5.0 (1-Apr-2020) 
49 
 
To account for up to 50% dropout and non-evaluable patients, up to 100 patients may be accrued 
to the clinical trial. Patient evaluability will be determined per Section 8.3. 
Following first stage accrual, an interim analysis will be performed to assess activity as well as 
interest in proceeding with the second stage and/or to a randomized study design. 
10.2 Data Analysis Plan 
10.2.1 Patient Disposition 
Patient disposition will be summarized and include the number dosed, the number in each patient 
population for analysis, the number who withdrew prior to completing the study and reason(s) for 
withdrawal. 
10.2.2 Demographic and Baseline Characteristics 
Patient demographic and characteristics at study entry will be summarized with frequency tables 
for categorical variables, and with descriptive statistics such as the mean, standard deviation, 
median, and range as appropriate, for quantitative variables. 
10.2.3 Medical History and Cancer History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The count and percentage of subjects under each history term, coded by system organ class (SOC) 
and preferred term (PT), will be summarized. 
Cancer history data will also be summarized, including the primary site of cancer, the stage and 
grade of cancer at study entry, time from initial diagnosis of cancer to Day 1 of the study in days, 
duration of metastatic disease in days (first dose date – date of diagnosis of metastatic disease + 
1), the extent of metastatic disease, and the histology. 
10.2.4 Study Drug Administration and Compliance 
Study drug administration, both rucaparib and bevacizumab, will be summarized in terms of the 
actual doses administered and the proportion of drug actually taken relative to the amount that 
should have been taken; these data will be summarized in frequency distributions by cycle. The 
total number of cycles administered; the median (range) of cycles administered; dose 
modifications, dose delays, and dose omissions; and reasons for deviations from planned therapy 
will be summarized. 
10.2.5 Safety Analyses 
10.2.5.1 Adverse Events 
Adverse events will be tabulated using MedDRA. The severity of the AE will be graded by the 
Investigator using the NCI CTCAE v4.0. The frequency of patients experiencing a specific AE 
will be tabulated by dose level, cycle, system organ class, preferred term, seriousness, worst 
severity, timing of occurrence, outcome, and relationship to study drugs. In addition, the number 
and percentage of patients experiencing a specific AE will be tabulated similarly. 


Version 5.0 (1-Apr-2020) 
50 
10.2.5.2 Laboratory Abnormalities 
The severity of laboratory abnormalities will be graded using the NCI CTCAE v4.0 whenever 
possible. The frequency of patients experiencing a specific laboratory abnormality will be 
tabulated by dose level, cycle, worst severity, and timing of occurrence. In addition, the number 
and percentage of patients experiencing a specific laboratory abnormality will be summarized 
similarly. 
10.2.5.3 Other Safety Assessments 
The results of vital sign measurements, body weight assessments, ECOG performance status 
determinations, physical examinations, and ECGs will be summarized by cycle and dose level, 
using appropriate descriptive statistics. 
The baseline QT interval value will be the mean QT interval obtained from three ECGs in the hour 
just prior to first dose. 
10.2.6 Biomarkers 
Pre-dose assessments of biomarkers from tumor biopsies, such as level of DNA damage, PARP 
and BRCA in tumor, will be summarized for each patient at each dose level.  
10.2.7 Antitumor Evaluation 
The objective tumor response (complete and partial response) will be summarized as the 
proportion (and 95% CI based on Clopper-Pearson method) of patients with a tumor response. The 
duration of response will be summarized descriptively by Kaplan-Meier method. These 
assessments will be performed by CT or MRI every 2 cycles and for all patients treated in the 
study. Results will be presented in tabular and graphic form, as appropriate. 
Progression-Free Survival (PFS) rate at six month or EOS is defined as the percentage of patients 
who are alive and progression-free at six months or EOS (estimated by the Kaplan-Meier method). 
Patients who are still alive without progression at EOS will be censored on the date of the last 
evaluable response assessment that is not progressive disease (PD). Median PFS together with a 
95% CI will also be provided. 
Primary efficacy endpoints (objective response and six month PFS rates) of rucaparib and 
bevacizumab combination will be compared with those in patients previously treated with 
bevacizumab single agent (retrospective data) via Chi-square or log-rank test. 
Overall survival (OS) rate is defined as the percentage of patients who are alive at End of Study 
(EOS) and 2 years follow-up. Patients who are still alive at EOS or 2 years post EOS are censored 
on the date they were last known to be alive. An exploratory analysis to determine OS at EOS will 
be estimated by the Kaplan-Meier method. 
Analyses involving translational research endpoints will be considered exploratory and will be 
carried out with notable associations highlighted as being worthy of further follow-up and possible 
confirmation. Associations between marker expressions levels (alone or in combination) and 
efficacy endpoints (objective response, PFS and OS) will be assessed by Chi-square or log- rank 
test as appropriate. 


Version 5.0 (1-Apr-2020) 
51 
11 DATA AND SAFETY MONITORING PLAN 
Safety oversight will be performed by Stephenson Cancer Center’s (SCC) internal Data and Safety 
Monitoring Committee (DSMC). The DSMC is composed of individuals with the appropriate 
expertise in adult and pediatric hematology and medical oncology, radiation oncology, 
translational and correlative science, pharmacy, nursing and biostatistics. The DSMC operates 
under the rules of an approved data safety monitoring plan which complies with the National 
Cancer Institute (NCI) guidelines published as Essential Elements of a Data and Safety Monitoring 
Plan for Clinical Trials Funded by NCI as of January 2005 and the “NIH Policy for 
Data 
and 
Safety 
Monitoring,” 
NIH 
Guide 
for 
Grants 
and 
Contracts, 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html. 
The Data Safety Monitoring Committee is charged with oversight of participant safety, study 
conduct and the validity and integrity of data for clinical trials at SCC. While the focus of the 
DSMC is to monitor interventional investigator initiated trials (IITs) that are not subject to external 
monitoring, it has the authority to monitor any SCC protocol when potential concerns are 
identified. The DSMC also has the authority to suspend or close a study until the principal 
investigator addresses any issues that may cause harm or increase risks to subjects. The DSMC 
reports all findings to the Institutional Review Board (IRB). 
Under the direction of the DSMC chair, a full board meeting is convened on a biannual basis to 
review the accumulated safety data, accrual information, and additional information as stated in 
the DSMC plan. 
11.1 DSMC Auditing 
In addition to monitoring, the DSMC oversees an internal auditing process to ensure subject safety 
and data quality. All cancer-related clinical trials active at the SCC are eligible for audit; however, 
priority is placed on those clinical trials that are not monitored or audited by an outside entity. If 
an external entity conducts an audit of a clinical trial at the SCC, then the findings of that audit are 
reported to the DSMC, either through the formal audit report provided by the external auditing 
entity, if available, or from the PI, who will report any findings communicated during the audit 
process. 
12 DATA HANDLING AND RECORD KEEPING 
12.1 Data Quality Assurance 
Stephenson Cancer Center (SCC) will be responsible for clinical monitoring of data for this study. 
12.2 Electronic Case Report Forms 
The Principal Investigator will develop electronic case report forms for study data entry. All study 
data will be stored in a 21 CFR 11-compliant database. Only Investigator and assigned research 
staff will have access to study data. The electronic case report forms will be available to sponsor, 
IRB or regulatory authorities in case of an audit or inspection. Site staff should contact the Sponsor 
for information regarding access to the electronic data capture system. 


Version 5.0 (1-Apr-2020) 
52 
12.3 Record Retention 
Investigator will retain all research documents and case report forms at study site for at least five 
years after study closure. The site must notify the Sponsor Institute prior to record destruction to 
store study records at Sponsor Institute’s expense. 
13 ADMINISTRATIVE AND REGULATORY CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572. Study medication may be administered only under the supervision of the Investigators 
listed on this form. Curriculum vitae must be provided to the Sponsor for the site Principal 
Investigator and made available for upon request for the sub-Investigators. 
13.2 Ethical Conduct of the Study 
The study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki in addition to the requirements of the 
ICH E2A guidelines. This study will also comply with U.S. FDA regulations under a U.S. 
Investigational New Drug (IND) application in addition to local, state, and federal laws. 
13.3 Informed Consent 
The informed consent document will be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. A model informed consent document will be provided for 
this study. The informed consent document used in this study, and any changes made during the 
course of the study, will be prospectively approved by the Sponsor and then submitted for approval 
to the IRB of record for approval. 
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each patient 
before any study-specific activity is performed. The study site will retain the original of each 
patient’s signed consent document. 
13.4 Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent document, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB by the Principal Investigator and 
reviewed and approved by the IRB before the study is initiated. 
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB. Investigators are also responsible for promptly informing the 
IRB of any protocol amendments. 
In addition to the requirements for reporting all adverse events to the Sponsor, investigators must 
comply with requirements for reporting serious adverse events to the local health authority and 
IRB of record per institutional standards and federal regulations. 


Version 5.0 (1-Apr-2020) 
53 
13.5 Confidentiality 
The Sponsor and site will maintain confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. Patient medical information 
obtained by this study is confidential and may only be disclosed to third parties as permitted by 
the Informed Consent document (or separate authorization for use and disclosure or personal health 
information) signed by the patient, unless permitted or required by law. 
13.6 Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol will not be made without agreement of the Sponsor. Changes to the protocol will require 
written IRB/EC approval prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. 
When immediate deviation from the protocol is required to eliminate an immediate hazard to 
patients, the Investigator will contact the Sponsor or its designee if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. 
 
 


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SAP_001.pdf: 
OU-SCC-Gunderson-Clovis 
STATISTICAL ANALYSIS PLAN 
 
A Phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium 
 
Version 1.2.0 
Version date: May 3, 2021 
 
 
IND Number:  
 
137278 
NCT Number: 
 
NCT03476798 
Sponsor:  
 
 
Stephenson Cancer Center  
800 NE 10th Street  
Oklahoma City, OK, 73104  
Funding Collaborator: 
Clovis Oncology 
Principal Investigator: 
Kathleen Moore 
 
 
 
 
800 NE 10th Street 
 
 
 
 
Oklahoma City, OK 73104 
 
 
 
 
Phone: 405-271-8707 
 
 
 
 
Kathleen-Moore@ouhsc.edu 
Translational Study Chair:  
Lurdes Queimado, MD, PhD 
Biostatistician  
 
Kai Ding, PhD  
SAP Author:  
 
Andrew Cohoon, MPH 
Study Products: 
Rucaparib 
 
Bevacizumab 
 
 


OU-SCC-Gunderson-Clovis 
Abbreviations 
 
CR 
 
Complete response 
EOS 
 
End of study 
OS 
 
Overall survival 
PFS 
 
Progression free survival 
PR 
 
Partial response 
SAP 
 
Statistical analysis plan 
 
 


OU-SCC-Gunderson-Clovis 
Contents 
 
1. 
Objectives 
4 
a. 
Primary Objectives 
4 
b. 
Major Secondary Objectives 
4 
c. 
Translational Research Objectives 
4 
2. 
Study End Points 
4 
a. 
Primary endpoint 
4 
b. 
Secondary endpoints 
4 
c. 
Translational endpoints: 
4 
3. 
Design Information 
4 
a. 
General statistical considerations 
4 
b. 
Sample Size and Power 
5 
4. 
Study Populations 
5 
a. 
Inclusion Criteria 
5 
b. 
Exclusion Criteria 
6 
5. 
Analysis Populations 
7 
6. 
Summary of Study Population 
8 
a. 
Patient Disposition 
8 
b. 
Demographic and Baseline Characteristics 
8 
c. 
Medical History and Cancer History 
8 
d. 
Study Drug Administration and Compliance 
8 
7. 
Antitumor Evaluation 
9 
8. 
Safety Analyses 
9 
a. 
Adverse Events 
9 
b. 
Laboratory Abnormalities 
9 
c. 
Other Safety Assessments 
10 
9. 
Biomarkers 
10 
10. 
Handling of Missing Data 
10 
 
 


OU-SCC-Gunderson-Clovis 
1. Objectives 
a. Primary Objectives  
i. To estimate the proportion of patients with persistent or recurrent cervical or 
endometrial cancer, who survive progression-free for at least 6 months, treated 
with combination bevacizumab and rucaparib. 
 
b. Major Secondary Objectives  
i. To estimate the proportion of patients with persistent or recurrent cervical or 
endometrial cancer, who have objective tumor response (complete or partial), 
treated with combination bevacizumab and rucaparib. 
ii. To determine the nature and degree of toxicity of combination rucaparib and 
bevacizumab in this cohort of patients. 
iii. To estimate the progression-free survival (PFS) of patients with persistent or 
recurrent cervical or endometrial cancer treated with combination rucaparib and 
bevacizumab. 
iv. To estimate the overall survival (OS) of patients with persistent or recurrent cervical 
or endometrial cancer treated with combination rucaparib and bevacizumab. 
 
c. Translational Research Objectives  
i. To obtain the fresh tumor biopsies after consent and prior to study treatment in 
eligible patients to determine MSI, HRD status, and degree of DNA damage via a 
novel DNA damage assay (PADDA) as well as RAD51C assay. 
ii. To determine whether these marker expression levels alone or in combination are 
associated with response, PFS, and/or overall survival. 
 
2. Study End Points 
a. Primary endpoint 
i. PFS rate at 6 months 
b. Secondary endpoints 
i. Objective response rate 
ii. Incidence and severity of adverse events  
iii. PFS 
iv. OS 
c. Translational endpoints:  
i. MSI 
ii. HRD status 
iii. Degree of DNA damage 
3. Design Information 
a. General statistical considerations 
The study hypothesis will be evaluated in a 2-stage design.  This will be used to decide whether 
there are sufficient numbers of patients progression free at 6 months or with objective 
responses to continue study in a second stage (at the interim analysis) or deem the drug worthy 
of further investigation in a phase III study (at the end of the study).  
 
Null hypothesis is H0: πr≤11% and πs≤24% 
Alternative hypothesis is Ha: πr ≥ 31% (=11%+20%) or πs ≥ 44% (=24%+20%), 


OU-SCC-Gunderson-Clovis 
where πr is the objective response rate, πs is the PFS rate at 6 months, and 11% and 24% are the 
response rate and PFS rate at 6 months respectively from a previous study.  
 
 
The following decision rule will be applied where Xs(1) is the number of patients progression-free 
at 6 months after the first stage, Xr(1) is the number of patients with objective tumor responses 
(partial or complete) after the first stage, Xs is the cumulative number of patients progression-
free at 6 months after stage 2, Xr is the cumulative number of patients with responses after 
stage 2, Cs(1) is the critical value for Xs(1), Cr(1) is the critical value for Xr(1), Cs is the critical value for 
Xs, and Cr is the critical value for Xr. Decision Rule: If either Xs(1) > Cs(1) or Xr(1) > Cr(1) after the first 
stage, then the study will open to a second stage of accrual to further evaluate the activity of 
the drug. If either Xs > Cs or Xr > Cr after the second stage and clinical judgment indicates, then 
the agent will be deemed clinically interesting and worthy of further investigation. 
 
b. Sample Size and Power 
For a flexible design with 0.1 alpha level and at least 90% power, the targeted accrual for the 
first stage [denoted by n(1)] will be 28 eligible and evaluable patients, but is permitted to range 
from 24 to 31. The cumulative targeted accrual for the second stage (denoted by n) will be 50 
eligible and evaluable patients, but is permitted to range from 46 to 53. Critical values for each 
stage are provided below: 
 
 
Stage  1 
Stage 2 
n(1) 
24 
25 
26 
27 
28 
29 
30 
31 
n 
46 
47 
48 
49 
50* 
51ˠ 52 
53 
Cr(1) 
3 
4 
4 
4 
4 
4 
5 
4 
Cr 
9 
9 
9 
9 
10 
10 
10 
10 
Cs(1) 
6 
6 
7 
7 
7 
8 
8 
9 
Cs 
15 
15 
16 
16 
16 
16 
17 
17 
* (Cr, Cs) = (9, 16) when n(1) = 25 or 26; ˠ(Cr, Cs) = (10, 17) when n(1) = 24, 28 or 30; (Cr, Cs) = (9, 17) when 
n(1) = 25 
4. Study Populations 
Inclusion and exclusion criteria are sometimes modified during the duration of the protocol.  
Before beginning analysis, the statistical team will review the criteria in the SAP (current version 
5.0) to confirm it is up to date with the current criteria. 
a. Inclusion Criteria 
i. Patients with histologically-documented carcinoma of the cervix or endometrium. 
ii. Patients with measurable and/or evaluable lesions as defined by RECIST 1.1. 
iii. Women at least 18 years of age. 
iv. Patient with persistent or recurrent squamous cell or adenocarcinoma of the cervix, 
or any carcinoma or carcinosarcoma of the endometrium who has undergone at 
least one prior line of systemic therapy. Prior bevacizumab is allowed. (Note: 
previous cisplatin during radiation therapy should NOT count as a prior line of 
systemic therapy). 
v. ECOG performance status of 0, 1, or 2. 


OU-SCC-Gunderson-Clovis 
vi. Patient should agree to have tumor biopsy and baseline blood draw for correlative 
studies. If unable to be safely biopsied and patient desires enrollment, may be 
enrolled per principal investigator discretion. 
vii. Adequate organ function should be confirmed by the following laboratory values 
obtained ≤ 14 days prior to first dose of rucaparib. Suggested criteria for adequate 
organ function include: 
1. Bone Marrow Function 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Platelets > 100 x 109/L 
c. Hemoglobin ≥ 9 g/dL independent of transfusion ≤ 14 days prior to 
screening hemoglobin assessment 
2. Hepatic Function 
a. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3 x upper limit of normal (ULN); if liver metastases, then ≤ 5 
x ULN 
b. Bilirubin ≤ 1.5 x ULN; < 2 x ULN if hyperbilirubinemia is due to 
Gilbert’s syndrome 
c. Serum albumin ≥ 30 g/L (3.0 g/dL) 
3. Renal Function 
a. Serum creatinine ≤ 1.5 x ULN 
b. Measured or calculated creatinine clearance (CrCL) ≥ 30 ml/min. For 
calculated CrCL, the Cockcroft Gault formula or institutional 
standard formula can be used.  Patients must have a life expectancy 
of at least 3 months (to be able to complete one cycle of study 
treatment). 
viii. Patients must have a life expectancy of at least three months (to be able to 
complete one cycle of study treatment). 
ix. Patients should have no major existing co-morbidities or medical conditions that will 
preclude therapy in the view of the principal investigator. 
x. Prior bevacizumab is allowed if off drug ≥ 28 days prior to study enrollment. 
xi. Ability to understand and the willingness to sign a written informed consent 
document. 
xii. Women of childbearing potential must not be considering getting pregnant and 
must avoid pregnancy during the study and for at least six months after the last 
dose of rucaparib or longer if requested by local authorities. 
 
b. Exclusion Criteria 
i. Have active second malignancy, i.e., patient known to have potentially fatal cancer 
present for which she may be (but not necessarily) currently receiving treatment; 
However patients with a history of malignancy that has been completely treated, 
with no evidence of that cancer currently, are permitted to enroll in the trial 
provided all chemotherapy was completed >6 months prior and/or bone marrow 
transplant (BMT) >2 years prior to first dose of rucaparib. 
ii. Prior treatment with any PARP inhibitor.  
iii. Untreated or symptomatic central nervous system (CNS) metastases. Patients with 
asymptomatic CNS metastases are eligible provided they have been clinically stable 
for at least 4 weeks.  


OU-SCC-Gunderson-Clovis 
iv. Received treatment with chemotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C); or radiation, biologic/targeted agents, experimental drugs within 3 
weeks prior to first dose of rucaparib; and/or ongoing adverse effects from such 
treatment > NCI CTCAE V5.0 Grade 1 (Grade 2 non-hematologic toxicity to most 
recent treatment may be permitted with prior advanced approval from Sponsor).  
v. Hospitalization for bowel obstruction within 3 months prior to enrollment.  
vi. Patients must have no history of gross hemoptysis (defined as bright red blood of a 
½ teaspoon or more) or coagulopathy. Patients with history of major tumor-related 
bleeding that is not controlled despite locoregional treatment or at high risk of 
recurrent tumor related bleeding will be excluded.  
vii. Patients with history of hypertension must be well-controlled (≤150/100) on a 
stable regimen of anti-hypertensive therapy. 
viii. Patients with tumors that invaded major vessels (e.g. the carotid) as shown 
unequivocally by imaging studies will be excluded due to the possibility of increased 
risk for tumor bleeding with bevacizumab therapy.  
ix. Patients should not have a major surgical procedure, open biopsy, or significant 
traumatic injury within 28 days prior to study enrollment, or anticipation of need for 
major surgical procedure during the course of the study. No history of abdominal 
fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior 
to registration. No serious non-healing wound, ulcer, or bone fracture.  
x. Patients should not have unstable angina or myocardial infarction within the 
previous 6 months; no uncontrolled hypertension; no symptomatic congestive heart 
failure; no serious cardiac arrhythmia requiring medication; no clinically significant 
peripheral vascular disease; no history of any CNS cerebrovascular ischemia or 
stroke within the last 6 months; no active serious infection.  
xi. Patients should not have other coexisting medical condition that would preclude full 
compliance with the study.  
xii. Patients may not be receiving any other investigational agents.  
xiii. Patients should not have a history of prior severe infusion reaction to a monoclonal 
antibody. Patients with known hypersensitivity of Chinese hamster ovary cell 
products or other recombinant human antibodies.  
xiv. Pregnant women are excluded from this study because rucaparib and bevacizumab 
have the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with rucaparib and bevacizumab, breastfeeding should be 
discontinued if the mother is treated with rucaparib and bevacizumab. Should a 
woman become pregnant or suspect she is pregnant while in this study, she should 
inform her treating physician immediately.  
xv. HIV-positive patients receiving combination anti-retroviral therapy are excluded 
from the study because of possible drug interactions with rucaparib and 
bevacizumab. 
 
5. Analysis Populations 
 
The analysis populations are defined as below.  
 


OU-SCC-Gunderson-Clovis 
• Evaluable population: Evaluable patients will be defined as patients with measurable and/or 
evaluable lesions who received at least cycle 1 doses of study treatment (one dose of IV 
bevacizumab and 21 days of rucaprib, PO, BID) and complete the first post-treatment CT 
or MRI for tumor assessment.  Patients who discontinued study treatment due to 
toxicity incurred by previous therapy will still be evaluated but will be replaced by 
additional patients for efficacy analysis. 
 
Patients who did not receive at least one cycle doses of study treatment will be 
considered unevaluable for efficacy analysis and will be replaced unless the missed 
doses were due to development of grade 3-4 adverse events related to study treatment.  
Patient who missed doses but have more than 80% total drug accountability will still be 
considered evaluable. 
 
• Safety population: All patients who receive at least one dose of combination bevacizumab and 
rucaparib will be included in the analyses of compliance and safety.  For efficacy 
analysis, patients removed from study for early withdraw or hypersensitivity reactions 
will be replaced if they have received less than one cycle of study treatments during 
cycle 1, but will be included in the safety analysis. 
 
• Biomarker population: Patients with sufficient pre-dose biomarker data will be included in 
biomarker analysis. 
 
6. Summary of Study Population 
a. Patient Disposition 
i. Patient disposition will be summarized and include the number dosed, the number 
in each patient population for analysis, the number who withdrew prior to 
completing the study and reason(s) for withdrawal. 
b. Demographic and Baseline Characteristics 
i. Patient demographic and characteristics at study entry will be summarized with 
frequency tables for categorical variables, and with descriptive statistics such as the 
mean, standard deviation, median, and range as appropriate, for quantitative 
variables. 
c. Medical History and Cancer History 
i. Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The count and percentage of subjects under each history term, coded by 
system organ class (SOC) and preferred term (PT), will be summarized.  
ii. Cancer history data will also be summarized, including the primary site of cancer, 
the stage and grade of cancer at study entry, time from initial diagnosis of cancer to 
Day 1 of the study in days, duration of metastatic disease in days (first dose date – 
date of diagnosis of metastatic disease + 1), the extent of metastatic disease, and 
the histology 
d. Study Drug Administration and Compliance 
i. Study drug administration, both rucaparib and bevacizumab, will be summarized in 
terms of the actual doses administered and the proportion of drug actually taken 
relative to the amount that should have been taken; these data will be summarized 
in frequency distributions by cycle. The total number of cycles administered; the 


OU-SCC-Gunderson-Clovis 
median (range) of cycles administered; dose modifications, dose delays, and dose 
omissions; and reasons for deviations from planned therapy will be summarized.  
 
7. Antitumor Evaluation 
i. The objective tumor response (complete and partial response) will be summarized 
as the proportion (and 95% CI based on the Clopper-Pearson exact method) of 
evaluable patients with a tumor response. The duration of response will be 
calculated as time from the date of first response (complete response (CR), or 
partial response (PR)) to the date of disease progression. Duration of response will 
be summarized using the Kaplan-Meier method.  Median duration of response with 
95% CI will be computed if data allows. The disease assessments will be performed 
by CT or MRI every 2 cycles using RECIST 1.1. Results will be presented in tabular 
and graphic form, as appropriate.   
ii. Progression-Free Survival (PFS) rate at 6 months is defined as the proportion of 
evaluable patients who were progression free 6 month after study enrollment. 95% 
CI based on the Kaplan-Meier method will be reported.  
iii. Progression-Free Survival (PFS) is defined as the time in months from date of 
enrollment to the date of death or the first documented date of progression, 
whichever comes first.  For patients who did not die and did not have progression, 
the PFS is censored at the last documented tumor assessment.  
Survival curve for PFS will be generated using the Kaplan-Meier method.  Median 
PFS with 95% CI will be computed. 
iv. Overall survival (OS) is defined as time in months from date of enrollment to the 
date of death. Patients who are still alive at EOS or 2 years post EOS are censored on 
the date they were last known to be alive. 
Survival curve for OS will be generated using the Kaplan-Meier method.  Median OS 
with 95% CI will be computed. 
 
8. Safety Analyses 
The safety population will be used.  
a. Adverse Events 
i. Adverse events will be tabulated using MedDRA. The severity of the AE will be 
graded by the investigator using the NCI CTCAE v4.0. The frequency of patients 
experiencing a specific AE will be tabulated by cycle, system organ class, preferred 
term, seriousness, worst severity, timing of occurrence, outcome, and relationship 
to study drugs. In addition, the number and percentage of patients experiencing a 
specific AE will be tabulated similarly. 
b. Laboratory Abnormalities 
i. The severity of laboratory abnormalities will be graded using the NCI CTCAE v4.0 
whenever possible. The frequency of patients experiencing a specific laboratory 
abnormality will be tabulated by dose level, cycle, worst severity, and timing of 
occurrence. In addition, the number and percentage of patients experiencing a 
specific laboratory abnormality will be summarized similarly. 


OU-SCC-Gunderson-Clovis 
c. Other Safety Assessments 
i. The results of vital sign measurements, body weight assessments, ECOG 
performance status determinations, physical examinations, and ECGs will be 
summarized by dose level and cycle, using appropriate descriptive statistics. 
ii. The baseline QT interval value will be the mean QT interval obtained from three 
ECGs in the hour just prior to first dose. 
9. Biomarkers 
i. The pre-dose assessments in tumor biomarkers from tumor biopsies, such as level 
of DNA damage, PARP and BRCA in tumor, will be summarized for each patient at 
each dose level.  
ii. Analyses involving translational research endpoints will be considered exploratory 
and will be carried out with notable associations highlighted as being worthy of 
further follow-up and possible confirmation.  Associations between marker 
expressions levels (alone or in combination) and efficacy endpoints (objective 
response, PFS and OS) will be assessed by Wilcoxon rank-sum test, Chi-square test, 
or Cox proportional hazards model as appropriate. 
 
10. Handling of Missing Data 
Every effort will be made to collect information at all defined visits including at early withdrawal or 
dropout. Reasons for missing data will be summarized. However, there will be no imputation of 
missing data.