Clinical trial NCT04099836
Conditions: Non Small Cell Lung Cancer
Keywords: EGFR Mutation Atezolizumab Bevacizumab exon L858R exon 21 L858R
Sponsor: Duke University
Start date: 2020-07-09; Completion date: 2023-06-15
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the safety and efficacy of giving atezolizumab combined with bevacizumab in patients with stage 4 epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) whose cancer has gotten worse while receiving osimertinib.

Detailed description:
This study will be single arm, open label, phase 2 study which will include patients with stage 4 NSCLC patients with EGFR mutations and who have progressed on osimertinib.

Although both atezolizumab and bevacizumab are approved for the treatment of NSCLC, the combination of atezolizumab and bevacizumab has not been approved by the FDA for the treatment of specific non-small cell lung cancer (NSCLC).

Patients who have one of the following EGRF mutations: exon 19 or exon 21 L858R with progressive disease on osimertinib may be eligible to participate in this study. If enrolled into the study, the study team will give the patient atezolizumab (1200 mg) combined with bevacizumab (15 mg/kg) every 3 weeks intravenously. As part of this study, the patient will have blood samples, other tests, exams, and procedures done for study purposes and their standard of care. Patient participation in the study will last for up to 2 years after completion of the last dose of the study drug or until your condition worsens or intolerable adverse events as deemed by the study doctor.

There are possible patient risks to this study that include but are not limited to diarrhea, itching, rash, and a feeling of weakness.

Arms: arm 1: Atezolizumab 1200 mg IV every 3 weeks and bevacizumab 15 mg/kg IV every 3 weeks (1 cycle=3 weeks)
Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab
Intervention descriptions: intervention 1: 1200 mg IV every 3 weeks intervention 2: 15 mg/kg IV every 3 weeks

Protocol documents:
ICF_001.pdf: 
Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 1 of 18
Subject*Initials_________
Form
M0345
You are being asked to take part in this research study because you have lung cancer (a type called non-
small cell lung cancer or NSCLC) and your cancer has gotten worse while receiving treatment with 
osimertinib.  Research studies are voluntary and include only people who choose to take part.  Please 
read this consent form carefully and take your time making your decision. As your study doctor or study 
staff discusses this consent form with you, please ask him/her to explain any words or information that 
you do not clearly understand.  We encourage you to talk with your family and friends before you 
decide to take part in this research study.  The nature of the study, risks, inconveniences, discomforts, 
and other important information about the study are listed below.
Please tell the study doctor or study staff if you are taking part in another research study.
Dr. Thomas Stinchcombe will conduct the study and it is funded by Genentech and Roche. Genentech 
and Roche will pay Duke University to perform this research, and these funds may reimburse part of Dr. 
Stinchcombe’s salary. Genentech is supplying the study drug atezolizumab and Roche is supplying the 
study drug bevacizumab.
CONCISE SUMMARY
This is a research study to find out the safety and efficacy of giving atezolizumab in combination 
with bevacizumab in patients with EGFR-mutant NSCLC whose cancer has gotten worse while 
receiving osimertinib.
You will be asked to return every 21 days to receive the study drugs intravenously (IV) and for 
regularly scheduled check-ups and lab assessments. Blood samples and possibly a small piece of 
tissue may be collected to determine what type of cancer cells you have.  You will also have other 
tests, exams, and procedures for study purposes and your standard of care. You will be in this 
research study from the  time of your first dose of the study drugs, until your condition worsens, or 
you experience intolerable side effects as deemed by the study doctor.
There are risks to this study that are described in this document. Some risks include diarrhea, 
itching, rash, and a feeling of weakness.  If you are interested in learning more about this study, 
please continue reading below.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 2 of 18
Subject*Initials_________
Form
M0345
WHO WILL BE MY DOCTOR ON THIS STUDY?
If you decide to participate, Dr. Thomas Stinchcombe or a member of his study team will be your doctor 
for the study and will be in contact with your regular health care provider throughout the time that you 
are in the study and afterwards, if needed.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to investigate the safety and efficacy of giving atezolizumab 
combined with bevacizumab in patients with epidermal growth factor receptor (EGFR) mutant non-
small cell lung cancer (NSCLC) whose cancer has gotten worse while receiving osimertinib. The use of 
atezolizumab combined with bevacizumab in this study is considered investigational. The word 
“investigational” means the study drugs are still being tested in research studies and are not approved by 
the U.S. Food and Drug Administration (FDA). 
Atezolizumab is an antibody which is a protein to fight foreign tissue including tumor cells. This 
particular antibody affects your immune system by blocking the activity of PD-L1. The PD-L1 is
involved in regulating your body’s natural immune response, but tumors can disrupt this pathway and 
partially resist or evade the immune system by producing excessive amounts of PD-L1. Atezolizumab 
may help your immune system stop or reverse the growth of tumors by blocking the PD-L1. 
Bevacizumab is a monoclonal antibody that blocks the formation of blood vessels that cancer cells need 
to grow. 
In this study, atezolizumab will be given to you in combination with bevacizumab. It is hoped that when 
atezolizumab is combined with bevacizumab, the study drugs will have anti-tumor activity in EGFR 
mutant NSCLC in patients who have experienced disease progression on osimertinib.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Approximately 39 people will take part in this research study at Duke. 
WHAT IS INVOLVED IN THE STUDY?

Screening Visit: You will have medical tests and procedures done to determine if you are 
suitable to participate in the study. Whether you can be in the study will depend on the results of 
your medical history, the judgment of the study doctor, and screening tests, which must be 
performed within 28 days of the beginning of the study. All the procedures that you will need to 
undergo are described in the table below. The study doctor and/or study staff will discuss these 
procedures with you.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 3 of 18
Subject*Initials_________
Form
M0345

Treatment Period Visits: If you meet the requirements to enter the study and agree to 
participate, you will return to the study site to begin the study. The treatment visits will occur on 
cycles of 21 days (3 weeks). You will be requested to visit the study site on day 1of all the 
cycles. The study drugs will be given by an injection into a vein (IV) on day 1 of all the cycles. 
All the procedures that you will need to undergo are described in the table below. The study 
doctor and/or study staff will discuss these procedures with you. 

Post-treatment Period Visits: When you permanently discontinue study treatment, regardless 
of whether you are terminating the study early or you have completed the study, you will 
undergo end of treatment evaluations 28 days after the last dose of study drug or prior to starting 
any subsequent anticancer therapy, you will return for a Safety Follow-up Visit, and information 
related to adverse events, the medications that you might be taking, and ongoing cancer 
treatments will be collected. After the Safety Follow up Visit, you will move into the Follow-up 
Period and will be contacted by telephone, email, or site visit approximately every 3 months, for 
up to 2 years, if you have come off the study for disease progression to check for any possible 
new serious adverse events, record all subsequent anticancer therapies, and to check on your 
long-term health status. 
All the procedures that you will need to undergo during each visit are described in the table below. The 
study doctor and/or study staff will discuss these procedures with you.
Active Monitoring Phase
Tests and Procedures
Screening
≤28 days prior to 
starting study 
therapy5
Day 1 of 
each 
cycle14
Re-staging every 
3 cycles for 17 
cycles (1 year)  
from cycle 1 day 
1 then every 6 
cycles until 
disease 
progression
End of treatment (EOT)
(28 days after the last 
treatment) 4
Informed Consent
X
Inclusion/Exclusion
X
Demography & Medical History 
including prior therapies and 
smoking history 
X
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 4 of 18
Subject*Initials_________
Form
M0345
Active Monitoring Phase
Tests and Procedures
Screening
≤28 days prior to 
starting study 
therapy5
Day 1 of 
each 
cycle14
Re-staging every 
3 cycles for 17 
cycles (1 year)  
from cycle 1 day 
1 then every 6 
cycles until 
disease 
progression
End of treatment (EOT)
(28 days after the last 
treatment) 4
Local documentation of EGFR 
exon 19 deletion or exon 21 L858R 
and histology 
X
ECOG PS
X
X
X
Physical Exam including weight, 
blood pressure, temp, P, O2 sat5
X
X
X
Adverse event assessment
X
X9
X
Prior/concomitant medications
X
X
X
Urine protein creatinine ratio 
X
X12
Hematology: CBC/ differential8
X
X8
X
PT/INR, PTT6
X6
Chemistry: SGOT (AST), SGPT 
(ALT), alk phos, T. bili, creatinine
X
X 7
X
TSH10
X
X10
Tumor measurement 3
X
X3
X
MRI or CT scan of brain11
X
X11
Pregnancy test1
X1
X1
Research Blood sample2, 
X2
X
Tissue sample (only if a stored 
tumor sample is available) 13
X
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 5 of 18
Subject*Initials_________
Form
M0345
1. For women of childbearing potential only.  Must be done within 48 hours of the first dose of the 
study drugs. It will be repeated on day 1 of each cycle.
2. Blood sample for research will be drawn at 3 time points: baseline (cycle 1 day 1), at time of first 
imaging (9 weeks), and at time of disease progression on study therapy 
3. You will undergo CT imaging with chest and abdomen scans to check for disease progression 
every 3 cycles for the initial 17 cycles (1 year), and then every 6 cycles until disease progression 
is found. Tumor measurements should be done 28 days or less prior to starting study drugs. If 
you discontinue the study drugs prior to disease progression, the study would like to follow you  
with imaging scans until disease progression is found. The schedule of follow-up imaging is at 
the discretion of your physician, but may be done at an interval of 6 to 12 weeks.
4. All patients (including those who have left the study because of progressive disease, 
unacceptable toxicity, patient refusal, investigator’s decision to remove patient, etc.) should have 
an end of treatment visit. However, if it is not feasible due to decline in health, if you have 
initiated another therapy, or you are being treated at another the end of treatment visit need not 
occur. This study visit can occur +/- 3 days due to patient convenience and travel.
5.  Baseline/screening assessments are to be performed ≤ 28 days prior to starting study therapy 
unless otherwise specified
6. PT (prothrombin time)/INR (international normalized ratio), PTT (partial thromboplastin time), 
required at baseline and then only as clinically indicated, discretion of the investigator, or 
institutional practice. PT/INR and PTT are blood tests to detect a bleeding disorder or excessive 
clotting disorder.
7. Blood tests to measure only AST (aspartate aminotransferase, aka SGOT [serum glutamic-
oxaloacetic transaminase]), ALT (alanine aminotransferase, aka SGPT [serum glutamic-pyruvic 
transaminase]), alk phos (alkaline phosphatase), T. bili (bilirubin test), and creatinine will be 
done on Day 1 of each cycle for first 4 cycles, and then every other cycle to measure liver 
function. More intensive monitoring per investigator discretion. 
8. A blood test to measure blood cell counts called a CBC (complete blood count) is required at 
baseline then day 1 of cycles 1-4, then every other cycle and as clinically indicated, at the 
discretion of the investigator. CBC is a blood test to check your overall health 
9. Prior to subsequent cycle.
10. A blood test to measure TSH (thyroid-stimulating hormone) should be done every 9 weeks. 
Additional testing may be done at the discretion of the investigator. TSH will test your thyroid 
gland hormone function.
11. MRI is the preferred test for imaging for brain metastases, but CT scan with contrast is 
acceptable for patients who are unable or intolerant of undergoing MRI of the brain. Patients 
must have either MRI or CT scan prior to starting study therapy. MRI and CT scans should be 
done less than 28 days prior to start of study drugs. Patients with untreated brain metastases 
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 6 of 18
Subject*Initials_________
Form
M0345
should undergo repeat imaging every 12 weeks or sooner if clinically indicated to assess disease 
status. Patients without brain metastases or treated brain metastases can undergo repeat imaging 
at the discretion of the investigator or per institutional practice 
12. Urine protein/creatinine ratio should be checked on every 3 cycle
13. Tumor tissue (if available). Archival tissue will be used and analyzed only if a stored (archival) 
tumor sample was obtained within 60 days of disease progression on osimertinib and prior to Day 1 
of study therapy. If a tumor sample is not available, you can still enroll in this research study.
14. The study visits can occur +/- 3 days to accommodate holidays, travel schedule, family events, 
etc. as necessary
END OF STUDY VISIT
1. A review of interval medical history since the last visit and assessment of performance status 
(quality of life)
2. A directed physical examination will be performed at the visit with vital signs including pulse, 
blood pressure, temperature, oxygen saturation, weight
3. Laboratory: chemistry and hematology
FOLLOW-UP PERIOD
After discontinuing study therapy, you will be followed for overall survival every 3 months by 
telephone or review of medical records until death or a maximum of 2 years from completion of 
study therapy. Subsequent therapy and survival status will be documented. If molecular testing 
performed (e.g. molecular testing of tumor biopsy or circulating tumor DNA) as part of standard of 
care the results of the testing will be recorded if available.  Patients who discontinue therapy for 
reasons other than disease progression will be followed for disease progression. The imaging 
schedule is at the discretion of the treating physician, but the recommended interval is every 6 to 12 
weeks.
HOW LONG WILL I BE IN THIS STUDY?
The duration will vary depending on how you are tolerating the study drugs. Patients will stay on the 
study as long as they are tolerating the study drugs.
Once you complete these phases of the study, you will enter the Follow-Up phase of the study for 
approximately 2 years. (We will contact you approximately every 3 months.)
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 7 of 18
Subject*Initials_________
Form
M0345
WHAT ARE THE RISKS OF THE STUDY?
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider, if you choose. 
During the study, the study drugs may cause you to experience discomforts and risks (side effects). 
Common side effects are listed below, but there may be others that we cannot predict. Your study doctor 
and your study team will be watching you carefully for side effects. The side effects may vary from 
person to person. You may experience some, none or all of these side effects and they may be mild to 
severe and, in some cases, life-threatening. It is also possible that you may experience side effects that 
have not been seen previously in clinical studies. Your study doctor may order other medications to treat 
side effects and to make you feel more comfortable. For more information about risks and side effects, 
please ask your study doctor. 
Atezolizumab may cause some, all or none of the side effects listed below.
This information is based on information collected from subjects in other clinical trials with 
atezolizumab.  In addition, there may be side effects that are not yet known that may occur.  You should 
tell your doctor or nurse about any side effects you experience.
Very common side effects of atezolizumab include: (More than 1 out of 10 people [10%]):

Tiredness

Infection
Common side effects of atezolizumab include: (More than 1 out of 100 people [1%] to less than 1 out 
of 10 people [10%])

Anemia which may require blood transfusion

Diarrhea, nausea, vomiting

Difficulty swallowing

Fever

Flu-like symptoms including body aches

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat

Reaction during or following a drug infusion which may cause fever, chills, rash

Loss of appetite

Pain in back

Cough, shortness of breath, stuffy nose
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 8 of 18
Subject*Initials_________
Form
M0345

Itching, acne, rash
Atezolizumab may cause your immune system to attack normal organs and cause side effects in many 
parts of the body. These problems may include but are not limited to:

Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and pancreas). 
Signs and symptoms may include: headaches that will not go away or unusual headaches, 
extreme tiredness or changes in mood or behavior decreased sex drive; weight loss or weight 
gain; excessive thirst or urine; dizziness or fainting

Pain in belly

Pain or swelling of the joints

Rash that develops on skin, nails, scalp and inside of mouth or vagina that may be painful
Uncommon side effects of atezolizumab include: (More than 1 out of 1,000 people [0.1%] to less than 
1 out of 100 [1%])

Bruising, bleeding
Atezolizumab (MPDL3280A) may cause your immune system to attack normal organs and cause side 
effects in many parts of the body. These problems may include but are not limited to:

Heart problems including swelling and heart failure. Symptoms and signs of heart problems may 
include: Shortness of breath, swelling of the ankles and body

A condition with high blood sugar which leads to tiredness, frequent urination or excessive thirst

Swelling and redness of the eye

Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. Signs and 
symptoms of colitis may include: diarrhea or increase in bowel movements, blood in your stools 
or dark, tarry, sticky stools, severe belly pain or tenderness

Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of hepatitis may 
include: yellowing of your skin or the whites of your eyes, severe nausea or vomiting; 
drowsiness; pain in the right upper belly

Swelling of the brain (meningitis/encephalitis), which may cause: headache, confusion, 
sleepiness, seizures, and stiff neck

Problem of the muscle, including swelling, which can cause muscle pain and severe muscle 
weakness sometimes with dark urine

Problem of the nerves that can cause paralysis. Signs and symptoms may include: numbness, 
tingling of hands and feet; weakness of the arms, legs

Kidney problems, including nephritis and kidney failure requiring dialysis. Signs of kidney 
problems may include: decrease in the amount of urine, blood in your urine, ankle swelling
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 9 of 18
Subject*Initials_________
Form
M0345

Lung problems (pneumonitis and pleural effusion). Symptoms may include: new or worsening 
cough, chest pain, shortness of breath.

Skin: blisters on the skin
Bevacizumab may cause some, all or none of the side-effects listed below.
Very common side effects of bevacizumab include: (More than 1 out of 10 people [10%]):

High bold pressure which may cause headaches, dizziness, blurred vision
Common side effects of bevacizumab include: (More than 1 out of 100 people [1%] to Less than 1 out 
of 10 people [10%])

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

Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration

Internal bleeding which may cause black tarry stool, blood in vomit, coughing up of blood, or 
blood in urine

Bleeding from other sites, including the vagina 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

 Muscle weakness

Damage to organs which may cause loss of teeth 

Headache

Numbness, tingling, or pain in the fingers or toes

Hoarseness, stuffy nose, or cough

Dry skin

Swelling and redness of the skin

Blood clot in limbs or lungs which may cause swelling, pain, or shortness of breath

Leakage of protein in the urine, which can rarely lead to damage to the kidney
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 10 of 18
Subject*Initials_________
Form
M0345
Uncommon side effects of bevacizumab include: (More than 1 out of 1,000 people [0.1%] to less than 
1 out of 100 people [1%])

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.

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

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

Damage to organs (bone, lungs, others) which may cause loss of function

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
For Those of Reproductive Potential: 
Reproductive Risks
For women:  In animal studies, atezolizumab is associated with an increased risk of pregnancy 
complications, including miscarriage and stillbirth. Whether these complications affect a developing 
pregnancy or breastfeeding infant in humans is not known. Women who are pregnant, planning a 
pregnancy, or breastfeeding are not allowed to participate in studies of the drug.
If you are a woman who could possibly become pregnant (you have not completed menopause, or you 
have not had a hysterectomy and/or both tubes and/or both ovaries removed) and you have a partner 
who is able to father children, a blood pregnancy test will be performed, and it must be negative in order 
to continue in the study. In women 40 years old and older, blood pregnancy tests can sometimes give a 
false positive or indeterminate result, and additional testing may be required. You will also have urine 
pregnancy tests at follow-up visits as described above, and these also must be negative.
You and your partner must agree to either abstain completely from vaginal intercourse for the duration 
of the study and for 7 months after the last dose of study drugs, or one of the following methods of 
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 11 of 18
Subject*Initials_________
Form
M0345
contraception: (a) partner vasectomy, (b) bilateral tubal ligation, (c) intrauterine device (IUD), (d) 
hormonal implants, or (e) condoms and spermicide PLUS a progestin-only birth control pill or 
injection. Hormonal methods that contain estrogen may increase the risk of blood clots and are not 
considered safe in women taking other drugs that may also increase those risks.  If you are not currently 
using one of these methods, or if you are using a method which is not considered safe when used with 
the study drugs, Dr. Stinchcombe will discuss options with you, given your medical condition, your 
personal preferences, and the level of effectiveness required by this study. 
Because no method of birth control is 100% effective, you should notify the study team immediately if 
you think there is any chance you could be pregnant, even if you have had a recent negative pregnancy 
test. If pregnancy is confirmed, the study drug(s) will be stopped, but Dr. Stinchcombe will continue to 
follow you to collect information on your health during the pregnancy, and, if appropriate, the health of 
the baby.
 
For men: The effects of the study drugs on developing pregnancies that began while the father was 
taking the drugs are not known. If you have a partner who could possibly become pregnant (she has not 
completed menopause, or she has not had a hysterectomy and/or both tubes and/or both ovaries 
removed) and you have not had a vasectomy, you must agree to either abstain completely from vaginal 
intercourse for the duration of the study and for 7 months after the last dose of study drug, or use a 
condom with spermicide for the same length of time. This is true even if your partner is using another 
method of birth control. You should inform your partner about your participation in this study and the 
potential risks to a pregnancy. If she is not using another method of birth control, she should discuss 
options with her doctor. If she does become pregnant during the study, you should inform the study 
doctor immediately. He will ask her permission to collect information on her health during the 
pregnancy and, if appropriate, the health of the baby. 
Risks of Drawing Blood:
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising.  
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely.
Drug and Food Interactions:
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 12 of 18
Subject*Initials_________
Form
M0345
Radiation Risks:
You will have a number of CT scans and MRI scans that are part of the regular care for your condition 
and you would have them whether or not you participate in this research. These studies will not add to 
the risk due to participating in the research. However, if you have concerns about the total radiation 
exposure you will get, you should discuss them with your physician. The PET, CT or MRI scans are 
being done as part of your routine medical care for cancer and will be done whether you choose to 
participate in this study or not.
There may be risks, discomforts, drug interactions or side effects that are not yet known.
Computed tomography (CT) scan, PET scan: These are radiology procedures which use X-rays (CT) 
to create pictures of the inside of your body. PET scan is a type of imaging test that uses a radioactive 
substance called a tracer to look for disease in the body. These pictures will allow your doctor to 
monitor your disease before, during, and after you receive your study drug and to see if the tumors 
change in size. A brain CT (or MRI) will also be required to check for any areas of disease in your brain. 
MRI:  Magnetic resonance imaging (MRI) uses a magnet and radio waves to make diagnostic medical 
images of the body. There have been no ill effects reported from exposure to the magnetism or radio 
waves used in this test. However, it is possible that harmful effects could be recognized in the future. A 
known risk is that the magnet could attract certain kinds of metal. Therefore, we will carefully ask you 
about metal within your body including medical implants, devices such as pacemakers and internal 
defibrillators, or certain dyes found in in tattoos. We will also keep the MR room locked so that no one 
carrying metal objects enters the room while you are in the scanner.
If there is any question about potentially hazardous metal within the body, you will not undergo the 
MRI. This may exclude you from participation in this research study. The MRI involves entering a large 
room in which a magnet is present. You will be placed on a narrow bed and then slid into a small tunnel 
approximately 6 feet in length and 25 inches in diameter. You will be asked to lie still for about one 
hour on this bed. You will hear a loud machine-like noise. You may be asked to have a harmless 
monitoring device applied during the study. During the study, you can have voice contact and physical 
contact with someone in attendance if you desire. Let the study doctor know if you have a fear of 
enclosed spaces.
A rare but serious adverse reaction has been observed in patients that received a gadolinium-based 
contrast material during MRI examinations, a reaction called nephrogenic systemic fibrosis (NSF). 
Patients with kidney disease are at increased risk of developing NSF. NSF may cause skin thickening, 
joint pain and/or swelling. In rare cases, NSF can lead to lung and heart problems and cause death. To 
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 13 of 18
Subject*Initials_________
Form
M0345
minimize the likelihood that you will be affected, you will have a blood test to measure your kidney 
function. If your blood test is abnormal, you will not be permitted to receive gadolinium.
Radiation Exposure Risks: 
If you take part in this research, you will have one or more medical imaging studies which use radiation. 
For this study, a type of scan called an FDG PET (fluorodeoxyglucose-positron emission tomography) 
CT scan will be done. This involves injection into a vein of a radioactive tracer liquid inside the body 
that collects at tumors and other sites where cells divide more quickly than usual. About an hour after 
the injection, you will undergo the scan as described. 
The radiation dose from an FDG PET CT scan is about 20 millisievert. To give you an idea about how 
much radiation you will get, we will make a comparison with an every-day situation. Everyone receives 
a small amount of unavoidable radiation each year. Some of this radiation comes from space and some 
from naturally-occurring radioactive forms of water and minerals. This research gives your body the 
equivalent of about 7 extra years' worth of this natural radiation. The radiation dose we have discussed is 
what you will receive from this study only, and does not include any exposure you may have received or 
will receive from other tests.
A possible health problem seen with radiation exposure is the development of a second cancer later in 
life. This extra cancer risk is higher at younger ages and for girls and women. The extra lifetime risk of 
dying of a fatal cancer due to the radiation exposure from this research is low. At such low radiation 
exposures, scientists disagree about the amount of risk. These estimates are very uncertain, and there 
may be no extra risk at all.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may be direct medical benefit to you. This approach has not 
been tested in people with lung cancer before and it is not known if there will be any benefit. There is 
the possibility the study drugs, atezolizumab and bevacizumab, may delay the growth of your cancer. 
However, no benefit to you can be guaranteed. We hope that in the future the information learned from 
this study will benefit other people with your condition. 
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY?
You do not have to participate in this study to be treated for your cancer. You may receive standard 
chemotherapy or surgery without being in this study. Other investigational studies with chemotherapy, 
hormones, radiation therapy, or new anticancer drugs may be available for your disease. Your study 
doctor is very willing to discuss the benefits, risks, and side effects of alternative treatments including 
the option of treating your symptoms only, with no further cancer therapy. If you decide that you don’t 
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 14 of 18
Subject*Initials_________
Form
M0345
want any more active treatment, one of your options is called “comfort care.” Comfort care includes 
pain medication and other support. It aims to maintain your comfort and dignity rather than cure disease. 
Usually this care can be provided at home. If you think you might prefer comfort care, please discuss 
this with your family, friends and your doctor.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
As part of the study, results of your study-related laboratory tests, x-rays, and procedures may be 
reported to Genentech or Roche and their affiliates. In addition, your records may be reviewed in order 
to meet federal or state regulations. Reviewers may include representatives from the Food and Drug 
Administration, representatives and affiliates of Genentech or Roche, the Duke University Health 
System Institutional Review Board, the Duke Cancer Institute, the Duke Office of Audit, Risk and 
Compliance (OARC), and others as appropriate. If any of these groups review your research record, they 
may also need to review your entire medical record.
As part of this study, you will be asked to have certain tests, x-rays, and/or procedures performed. Some 
of these tests, x-rays and/or procedures would have been done as part of your regular care. The study 
doctor will use these test results both to treat you and to complete this research.  These test results will 
be recorded in your medical record. If serious adverse events arise, that data will be collected and 
reported to Genentech and Roche. Results of tests and studies done solely for this research study and not 
as part of your regular care will not be included in your medical record.
The study results will be retained in your research record forever.  Any research information in your 
medical record will also be kept indefinitely.
This information may be further disclosed by the sponsor (PI-Duke Cancer Institute) of this study.  If 
disclosed by the sponsor, the information is no longer covered by federal privacy regulations.
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 15 of 18
Subject*Initials_________
Form
M0345
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed.
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information.
WHAT ARE THE COSTS?
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. Stinchcombe.  At your request, a Financial Counselor in the clinic may provide you with 
an estimate of costs for routine services.
Genentech and Roche has agreed to support Duke for services and procedures that are done solely for 
research purposes and that have been reviewed and captured in the contract between Duke and 
Genentech and Roche. Please talk with the Dr. Stinchcombe and/or the study team about the specific 
services and procedures (including the device, if applicable) that will be covered by Duke and the ones 
for which you or your insurance will be responsible.
We will monitor your DUHS patient care charges to make sure that costs are directed appropriately.  If 
you have any questions or concerns about appropriate billing, contact your study team coordinator so 
that he or she can help find a resolution.
Genentech will provide the study drug, atezolizumab, and Roche will provide the study drug 
bevacizumab free of charge to you.  Your study doctor may request that you return for a checkup before 
you stop your study drug if he thinks that stopping it suddenly may harm you and may ask you to 
complete the tests that would ordinarily occur when a person completes the study.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 16 of 18
Subject*Initials_________
Form
M0345
WHAT ABOUT COMPENSATION?
You will not be paid to take part in this research study. Your expenses for parking may be reimbursed. 
WHAT ABOUT RESEARCH RELATED INJURIES?
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., Genentech/Roche, or your Duke physicians to 
provide monetary compensation or free medical care to you in the event of a study-related injury.
For questions about the study or research-related injury, contact Dr. Thomas Stinchcombe at (919) 681-
9509 during regular business hours and at (919) 970-2829 after hours and on weekends and holidays.
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY?
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.  
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you contact Dr. Stinchcombe in writing and let him know that you are 
withdrawing from the study. His mailing address is:
Thomas Stinchcombe, MD
Box 3198
                                                            Duke University Medical Center
                                                            Durham, North Carolina 27710
Dr. Stinchcombe or your study doctor may also ask you to complete the tests that would ordinarily occur 
when a person completes the study. 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study.
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.  
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 17 of 18
Subject*Initials_________
Form
M0345
Genentech, Roche or regulatory agencies may stop this study at any time without your consent. If this 
occurs, you will be notified and your study doctor will discuss other options with you. 
For withdrawal of tumor tissue samples: Your coded tissue samples will be stored in a secure location,  
at Duke (in MSRB1) with all having alarm systems with on- and off-site monitoring for up to 15 years 
after the end of the study.  If you want to withdraw your samples from storage, you must contact your 
study doctor, Dr. Thomas Stinchcombe, in writing and let him know you are withdrawing your 
permission for your samples to be stored. His mailing address is stated on the preceding page. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Thomas Stinchcombe at (919) 681-9509 during regular 
business hours and at (919) 970-2829 after hours and on weekends and holidays.
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111.
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023


Consent to Participate in a Research Study
ADULT
Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor 
(EGFR) mutant non-small cell lung cancer in patients with progressive disease after receiving 
osimertinib (TOP 1901)
PI: Thomas Stinchcombe 
Page 18 of 18
*
Form
M0345
STATEMENT OF CONSENT
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form."
__________________________________________
Printed Name of Subject
__________________________________________
___________       ___________
Signature of Subject
Date                     Time
__________________________________________
Printed Name of Person Obtaining Consent
__________________________________________
___________       ___________  
Signature of Person Obtaining Consent
Date                     Time
DUHS IRB
IRB NUMBER: Pro00103723
IRB REFERENCE DATE: 11/17/2022
IRB EXPIRATION DATE: 12/11/2023

Prot_SAP_002.pdf: 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol   TOP 1901 
Version 1, 09Oct2019 
 
 
Title: Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal 
Growth Factor Receptor (EGFR) mutant non‐small cell lung cancer in patients 
with progressive disease after receiving osimertinib 
[Genentech Protocol Number: ML41358] 
Thoracic Oncology Program (TOP) Protocol Number: TOP 1901 
 
Sponsor: Funding 
Source: Protocol 
Source: Duke 
IRB#: 
PI – Duke Cancer Institute 
Thomas Stinchcombe 
PI ‐ Duke Cancer Institute 
Pro00103723 
 
Principal Investigator 
Thomas Stinchcombe, MD 
DUMC 3198 
25178 Morris Building 
Durham, NC 27710 
Telephone: 919‐681‐9509 
Fax: 919‐684‐5163 
Email address: Thomas.stinchcombe@duke.edu 
 
Sub‐Investigator(s) 
Neal Ready MD, PhD 
Jeffrey Clarke MD 
Jeffrey Crawford MD 
Scott Antonia, MD, PhD 
Jennifer Tenhover ANP 
Yeshu Conn ANP 
Susan Blackwell MHS, PA‐C 
Jeana Schneider MHS, PA‐C 
Deborah Ballard ANP 
 
Statisticians 
Xiaofei, Wang PhD 
Department of Biostatistics & Bioinformatics 
Duke University Medical Center 
xiaofei.wang@duke.edu 
 
Ben Neely, MS 
Senior Biostatistician  
Duke Cancer Institute  
ben.neely@duke.edu 


2 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
 
 
Lead Study Coordinator 
Carol Alonso MSN, RN 
Thoracic Oncology 
Fax: 919.684.8926 
carol.alonso@duke.edu 
 
Regulatory Coordinator 
Eun Young Song 
Candice Singletary Lucas 
David 
Regulatory Coordinators 
Thoracic Oncology Research Program 
Duke Cancer Institute 
Hock Plaza, Room 8089 
2424 Erwin Road 
Durham, NC 27705 
(919) 668-1069 
E-mail: eunyoung@neuro.duke.edu 
 
Data Management 
Thoracic Oncology Clinical Trials Room 
00541, Duke South 
Duke Cancer Institute 
Durham, NC 
 
 
 
 
 
 
 
 
 
Original version: 
10/9/2019 
Amended version 1: 


3 
CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
 
Statement of Compliance and Signature Page 
 
Title: Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor 
Receptor (EGFR) mutant non‐small cell lung cancer in patients with progressive disease after 
receiving osimertinib 
[Genentech Protocol Number: ML41358] 
Thoracic Oncology Program (TOP) Protocol Number: TOP 1901 
 
 
This study will be conducted in compliance with the protocol approved by the Institutional Review Boards of 
Duke University Health System, and external sites according to Good Clinical Practice standards. No deviation 
from the protocol will be implemented without the prior review and approval of the IRB except where it may be 
necessary to eliminate an immediate hazard to a research subject. In such case, the deviation will be reported 
to the IRB as soon as possible. The signature below  constitutes the approval (by the PI) of this protocol and the 
attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to local and state legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guideline 
 
 
Duke Sponsor Investigator: Thomas Stinchcombe, 
MD Duke University Thoracic Oncology Program 
 
 
 
 
Thomas Stinchcombe, MD, DukeSponsor Investigator Date 
 
 
 
 
Site Principal Investigator 
Date 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
4 
 
1 
TABLE OF CONTENTS 
4 
2 
LIST OF ABBREVIATIONS 
6 
3 
PROTOCOL SYNOPSIS AND SUMMARY 
8 
3.1 
Design and Procedure 
10 
3.2 
Objectives and endpoints 
10 
3.3 
Subject eligibility 
11 
3.4 
Registration Procedure 
14 
3.5 
Duration of study 
14 
4 
STUDY SCHEMA 
14 
5 
STUDY THERAPY 
15 
5.1 
Atezolizumab background 
15 
5.1.1 
Pre‐clinical experience 
15 
5.1.2 
Clinical experience 
16 
5.2 
Bevacizumab background 
18 
5.2.1 
Preclinical experience 
18 
5.2.2 
Clinical experience 
19 
6 
CLINICAL MANAGEMENT OF STUDY THERAPY 
23 
6.1 
Discontinuation for adverse events 
23 
6.2 
Management ofatezolizumab adverse events 
23 
6.2.1 
Dose modifications 
23 
6.2.2 
Management ofatezolizumab adverse events 
23 
6.3 
Management of bevacizumab adverse events 
30 
6.3.1 
Dose modifications 
30 
6.3.2 
Management of bevacizumab‐related adverse events 
30 
6.4 
Management of bevacizumab adverse events 
33 
6.5 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
34 
7 
RATIONALE FOR TRANSLATIONAL MEDICINE STUDIES 
34 
8 
EARLY STUDY TERMINATION 
38 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
5 
 
9 
STUDY THERAPIES PHARMACY MANAGEMENT 
38 
9.1 
Atezolizumab and bevacizumab 
38 
9.2 
Packagingand Labeling 
39 
9.3 
Supply, Receipt, and Storage 
39 
9.4 
Dispensing and Preparation 
39 
9.5 
Complianceand Accountability 
39 
9.6 
Disposal and Destruction 
39 
10 
SCREENING AND ON‐STUDY TESTS AND PROCEDURES 
39 
10.1 
Schedule of time and events table (Table 9) 
40 
10.2 
Screening Examination 
42 
10.3 
On study treatment period 
42 
10.4 
End of Study Treatment 
43 
10.5 
Follow‐up Period 
43 
10.6 
End of Study 
43 
10.7 
Early Withdrawal of Subject(s) 
43 
10.7.1 
Criteria for Early Withdrawal 
43 
10.7.2 
Follow‐up Requirements for Early Withdrawal 
44 
10.7.3 
Replacement of Early Withdrawal(s) 
44 
11 
SAFETY MONITORING AND REPORTING 
44 
11.1 
Adverse Events 
44 
11.2 
Serious Adverse Events 
45 
11.3 
Adverse Events of Special Interest 
47 
11.4 
Safety Oversight Committee (SOC) 
49 
11.5 
Quality control andassurance 
50 
11.6 
Data Management and Processing 
52 
12 
STATISTICAL METHODS AND DATA ANALYSIS 
53 
13 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
55 
14 
REFERENCES 
59 
15 
APPENDICES 
62 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
6 
 
 
2 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ACTH 
Adrenocorticotropic hormone 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BAL 
Bronchoscopic alveolar lavage 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CHF 
Congestive Heart Failure 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIPC 
Duke Immune Profiling Core 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
ECMO 
Extracorporeal membrane oxygenation 
EGFR 
Epidermal Growth Factor Receptor 
H&P 
History& Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
IVIG 
intravenous immunoglobulin 
LFT 
Liver function test 
MDSC 
Myeloidderived suppressor cells 
MRI 
Magnetic resonanceimaging 
MTD 
MaximumTolerated Dose 
NCI 
National Cancer Institute 
NSCLC 
Non‐Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
7 
 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRES 
Posterior Reversible EncephalopathySyndrome 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SOP 
Standard Operating Procedure 
SPGT 
Serum Glutamic Pyruvic Transaminase 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
8 
 
TKI 
Tyrosine Kinase Inhibitor 
TSH 
Thyroid stimulatinghormone 
UPC 
Urineprotein:creatinine 
VAD 
Ventricular assist device 
WBC 
White Blood Cells 
WHO 
World Health Organization 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
9 
 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
 
Synopsis: This single arm, open label, phase 2 study will prospectively investigate the activity of the combination 
atezolizumab and bevacizumab in patients with stage 4 epidermal growth factor receptor (EGFR) mutant non‐small 
cell lung cancer (NSCLC) who have progressed  after osimertinib.  The purpose  of the phase 2 is to determine if further 
investigation of the combination in a phase 3 trial is warranted 
 
Primary Objectives: To assess the Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 as assessed by investigator 
 
Secondary Objectives: 
1. Progression‐free survival (PFS) 
2. Overall survival (OS) 
3. Treatment related adverse events 
 
Exploratory 
Investigation of immune and angiogenesis markers and association with response 
 
Hypotheses 
The combination of bevacizumab and atezolizumab will have activity in EGFR mutant NSCLC in patients who have 
experienced disease progression on osimertinib. This study will obtain preliminary data to assist in determining if 
a larger prospective clinical trial should be pursued. 
 
Disease Background 
For patients NSCLC with an activating epidermal growth factor receptor (EGFR) mutation, defined as exon 19 
deletion or exon 21 L858R point mutation, osimertinib is the standard of care in the United States.2 The median 
PFS observed with osimertinib is approximately 19 months, and at the time of disease progression multiple 
mechanisms of resistance have been detected.3 Current studies are investigating targeted therapies or combination 
of targeted therapies for specific mechanisms of resistance. Currently, a post‐osimertinib targeted therapy is not 
available. 
 
In subset analyses of phase 3 trials of single immunotherapy compared to single agent chemotherapy the PFS and OS 
in patients with known EGFR mutant NSCLC were similar, and the ORR is approximately 5%.4‐7 Even in patients with 
an EGFR mutant NSCLC and high PD‐L1 score single agent immunotherapy has limited activity.8 Patients with EGFR 
mutant NSCLC were excluded from the phase 2 and phase 3 trials of carboplatin, pemetrexed, and pembrolizumab 
so the activity of this combination has not been established.9,10 The standard therapy is a platinum‐based 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
10 
 
chemotherapy doublet which results in an objective response rate (ORR) of approximately 30% and a median 
progression‐free survival (PFS) of approximately 5 months.11 
 
Preclinical data suggest inhibition of angiogenesis may overcome primary and acquired resistance to EGFR tyrosine 
kinase inhibitors.12,13 Previous clinical studies have revealed an improvement in PFS  in  treatment naïve patients with 
EGFR mutant NSCLC with the combination of erlotinib and bevacizumab compared to erlotinib alone.14,15 There is an 
interest in combining angiogenesis with immunotherapy based on preclinical models which suggest synergism 
between anti‐angiogenic therapy and immunotherapy.16‐18 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
11 
 
A recent phase 3 trial of carboplatin, paclitaxel, bevacizumab alone or with atezolizumab enrolled patients with EGFR 
mutant NSCLC who had previously received an EGFR TKI.19,20 In a subset analysis of 59 patients with activating EGFR 
mutations, patients assigned to the atezolizumab‐containing arm compared to standard arm had an improvement 
in progression‐free PFS (HR of 0.41, 95% confidence interval (CI)  0.22 to 0.87; median PFS of 10.3 and 6.1 months, 
respectively). In contrast the combination of carboplatin, paclitaxel and atezolizumab compared to carboplatin, 
paclitaxel and bevacizumab in the same trial did not reveal an improvement in PFS in the EGFR mutant NSCLC (HR of 
1.01, 95% CI 0.61‐1.70; median of 6.0 and 6.1, respectively. In patients with an activating EGFR mutation when 
carboplatin, paclitaxel, bevacizumab, and atezolizumab wascompared to carboplatin, paclitaxel and bevacizumab 
the overall survival (OS) favored the 4‐drug combination (HR of .31, 95% CI 0.11 to 0.83; median non‐evaluable and 
17.5 months, respectively). In the similar analysis of carboplatin, paclitaxel and atezolizumab compared to 
carboplatin, paclitaxel and bevacizumab a difference in OS was not observed (HR of 0.90, 95% CI 0.47 to 1.74; median 
21.2 and 17.5 months, respectively). A different phase 3 trial of carboplatin and nab‐paclitaxel alone or with 
atezolizumab in patients with in patients with an EGFR or anaplastic lymphoma kinase rearrangement did not reveal 
an improvement PFS (HR of 0.75, 95% CI: 0.36 to 1.54; median 7.0 and 6.0 months) or OS (HR of 0.98, 95% CI 0.41 
to 2.31; median 14.4 and 10 months, respectively).21 
These subset analyses suggests the benefit was related to the combination of atezolizumab and bevacizumab since 
the same benefit was not observed in the comparison of chemotherapy and atezolizumab compared to 
chemotherapy alone or with bevacizumab. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
12 
 
3.1 Design and Procedure 
The primaryobjective of this single‐arm phase II trial is to determine ORR, defined as all patients with a 
confirmed partial or complete response as assessed by investigator using RECIST 1.1, in patients with stage 
4 NSCLC patients with EGFR mutations and who have progressed on osimertinib. Secondary objectives include 
(1) evaluation of progression‐free survival; (2) overall survival; and (3)  adverse events due to the protocol 
treatments. 
 
Abbreviated Title 
TOP 1901 
Trial Phase 
II 
Clinical Indication 
Stage IV NSCLC with EGFR mutation (exon 19 or exon 21 L858R) with 
progressive disease on osimertinib 
Trial Type 
Therapeutic treatment 
Type of control 
Not applicable‐single arm study 
Route of administration 
IV every 3 weeks 
Trial Blinding 
Unblinded, open‐label 
Study Treatment Group 
Single Arm 
Atezolizumab 1200 mg IV every 3 weeks and bevacizumab 15 mg/kg IV 
every 3 weeks (1 cycle=3 weeks) 
Number of trial subjects 
39 
Estimated enrollment period Approximately 20‐41 months; first patient in Fourth Quarter 2019. 
Estimated duration of trial 
Estimated at 5 years from the first patient in to last subject’s final 2 year 
follow‐up 
Duration of Participation 
Active study treatment until progressionor study treatment not 
tolerated followedfor overallsurvival for a maximum of 2 years after 
completion of study therapy. 
3.2 Objectives and Endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
Objective response rate 
Patients experiencing a confirmed 
partial or complete response using 
RECIST 1.1 
See Section 12 
Key 
Secondary 
Progression‐free survival 
Time from startingstudytherapy until 
disease progressionusing RECIST 1.1 
or death (whichever occurs first) 
See Section 12 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
13 
 
Other 
Secondary 
Safety 
Common Terminology Criteria for 
Adverse Events (CTCAE ) 4.03 to assess 
treatment related adverseevents 
See Section 12 
Other 
Secondary 
Overall survival 
Time from study starting study therapy 
until deathor maximum of 2 years after 
study completion 
See Section 12 
Exploratory 
Investigation of immune 
and angiogenesis 
markers and association 
with response 
Exploratory analysis based on ORR and 
PFS observed on the studytherapy 
See Section 12 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
14 
 
3.3 Subject eligibility 
 
The following guidelines are to assist physicians in selecting patients from whom protocol therapy is safe 
and appropriate. Physicians should consider the risks and benefits of any therapy, and therefore only enroll 
patients for whom this study treatment is appropriate. For entry into the study, the following criteria MUST 
be met. 
 
Patients are eligible to be included in the study only if they meet all of the following criteria. 
 
Inclusion criteria 
 
1. Age ≥18 years 
 
2. Histologic documentation of primary lung carcinoma, non‐squamous histology with EGFR exon 
deletion 19 or exon 21 L858R mutation. 
Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement 
Amendments (CLIA) certified lab; either institutional or through a commercial laboratory. The 
laboratory report from the commercial laboratories report the specific mutations detected, and the 
method of detecting the exon 19 and exon 21 L858R point mutations must be available. Both 
circulating tumor DNA and tumor testing are acceptable 
 
3. Stage IV disease according to the 8th Edition of the American Joint Committee on Cancer staging 
system 
 
4. Disease progression on osimertinib1 
 
5. ECOG Performance Status 0 or 1 (appendix 1) 
 
6. Measureable disease as defined by RECIST 1.1 (appendix 2) 
 
7. The following laboratory values obtained ≤ 28 days prior to starting study therapy 
a. ANC ≥ 1, 500 / mm3 
b. Platelet count, ≥ 100,000 / mm3 
c. Hemoglobin ≥ 9.0 g / dL 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
15 
 
d. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 
e. SGOT (AST) and SGPT (ALT) ≤2.5 x ULN in patients without liver or bone metastases; < 5 x ULN 
in patients with liver or bone metastases. 
f. Cockcroft‐Gault calculated creatinine clearance of ≥ 45 ml/min (appendix 3) or creatinine ≤1.5 
x ULN 
g. Urine protein/creatinine (UPC) ratio ≤1. 
 
 
 
1 No limit to the number of prior lines of therapy. Osimertinib does not have to be most recent therapy prior to this study. 
There is no w ashout time period betw een prior therapy and initiating study treatment. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
16 
 
8. Negative pregnancy test done ≤7 days (or per institutional policy)  prior  to start of study therapy,  for 
women of childbearing potential only. Female subjects should be using highly effective contraceptive 
measures, and must have a negative pregnancy test of must have evidence of non‐child bearing 
potential by fulfilling one of the following criteria at screening: 
a. 
Post‐menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments; 
b. 
Women under 50 years of age would be considered post‐menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and LH 
and FSH levels in the post‐menopausal range for the institution; 
c. 
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
 
9. Male subjects should be willing to use barrier contraception. 
 
10. Provide informed writtenconsent 
 
 
Patients will be excluded from the study if they meet any of the following criteria: 
 
Exclusion Criteria 
 
1. Mixed, non‐small cell and small cell tumors or mixed adenosquamous carcinomas with a 
predominant squamous component. 
 
2. Any of the following because this study involves an investigational agent whose genotoxic, mutagenic 
and teratogenic effects on the developing fetus and newborn are unknown: pregnant women, nursing 
women, men or women of childbearing potential who are unwilling to employ adequate contraception 
 
3. Other active malignancy ≤ 2 years prior to study cycle 1 day 1 of study therapy. EXCEPTIONS: Non‐ 
melanotic skin cancer or carcinoma‐in‐situ of the cervix, or adequately treated stage I or II cancer. 
NOTE: If there is a history of prior malignancy, they must not be receiving other specific  treatment (i.e. 
hormonal therapy) for their cancer. 
 
4. History of myocardial infarction or other evidence of arterial thrombotic disease (angina), 
symptomatic congestive heart failure (New York Heart Association ≥ grade 2), unstable angina pectoris, 
or ventricular arrhythmia with ≤ 6 months 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
17 
 
 
5. History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to 
study cycle 1 day 1 of study therapy. 
 
6. History of bleeding diathesis or coagulopathy. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
18 
 
7. Inadequately controlled hypertension (systolic blood pressure of >160 mmHg or diastolic pressure 
>100 mmHg on anti‐hypertensive medications). Note: History of hypertensive crisis or hypertensive 
encephalopathy not allowed. 
 
8. Serious non‐healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open 
biopsy, or significant traumatic injury ≤ 28 days or core biopsy ≤ 7 days prior to starting therapy 
 
9. History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess ≤6 months 
prior to study cycle 1 day 1 of study therapy. 
 
10. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human 
antibodies. 
 
11. History of hemoptysis ≥ grade 2 (defined as bright red blood of at least 2.5 mL) ≤ 3 months prior 
to cycle 1 day 1 of study therapy. 
 
12. Symptomatic untreated brain metastases which is defined as persistent  neurological symptoms or 
requiring ongoing use of steroids. Asymptomatic untreated brain metastases are allowed if ≤ 1cm 
 
13. Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial 
thrombosis) ≤6 months prior to starting study therapy 
 
14. Radiotherapy to any site for any reason ≤ 14 days prior to study cycle 1 day 1 of study therapy. 
 
15. Pre‐existing and clinically active interstitial lung disease 
 
16. Autoimmune condition requiring ongoing or intermittent systemic treatment. Participants with a 
condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) 
or other immunosuppressive medications within 14 days of study treatment initiation. Inhaled or topical 
steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease. 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
19 
 
Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
 
17. Prior therapy with anti‐PD‐1 or anti‐PD‐L1 immunotherapy, 
 
18. Prisoners, participants who are involuntarily incarcerated, or participants who are compulsorily 
detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
 
Protocol Eligibility Waivers 
 
No waivers of inclusion or exclusion criteria will be granted. All prospective patients must meet all entry 
criteria prior to enrollment in the study. If there are any questions regarding the interpretation 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
20 
 
of an eligibility criterion for a potential patient, contact the principal investigator to discuss the potential 
patient to confirm eligibility. 
 
3.4 Registration Procedure 
 
Patient registration for all patients signing informed consent will be completed through the Duke Cancer 
Institute (DCI) Clinical Research Unit (CRU) into EPIC and ONCORE systems within 1 business day of 
obtaining consent. Patients will be enrolled only after all pre‐treatment evaluations are completed and all 
eligibility criteria are met. 
 
Registration for Outside Sites 
All patients signing informed consent at outside sites must be registered with Duke (including screen failures‐ 
indicate screen failure status on last page of eligibility checklist). The following  documents are to be 
completed by the investigator and/or designee and faxed to (919)‐684‐8926 or scanned/emailed to the 
Thoracic Oncology Protocol Office (Thoracic‐multisite@dm.duke.edu): All supporting documents should be 
sent de‐identified. 
 
• 
TOP 1703 Eligibility Checklist with supporting source documents 
• 
Signed Informed Consent 
 
3.5 Duration of Study 
 
All patients will be followed for disease progression and death (whichever occurs first) from the date that the 
subjects were enrolled (cycle1 day 1) on study. Patients will remain on study until disease progression, 
unacceptable adverse event or withdrawal of consent. Patient discontinuing study therapy for reasons other 
than disease progression will be followed for disease progression. Once patients are no longer on study 
therapy, they will be followed for OS for a maximum 2 years from discontinuation of study therapy. Follow‐
up for OS can be through review of medical records or  contacting patient and does require visit to the study 
center. 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
21 
 
4 
STUDY SCHEMA 
 
EGFR exon 19 deletion or exon 21 L858R 
Stage 4 NSCLC (non-squamous) 
Performance status 0 or 1 
Progression on osimertinib
Study Treatment 
Atezolizumab 1200 mg IV every 3 weeks 
Bevacizumab 15 mg/kg IV every 3 weeks 
Duration 
Until disease progression, unacceptable 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
22 
 
5 
STUDY THERAPY 
 
5.1 Atezolizumab background 
 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD L1 and inhibits 
the interaction between PD‐L1 and its receptors, PD‐1 and B7‐1 (also known as CD80),  both of which 
function as inhibitory receptors expressed on T cells. Therapeutic blockade  of PD L1 binding by atezolizumab 
has been shown to enhance the magnitude and quality of tumor specific T cell responses, resulting in 
improved anti‐tumor activity.22,23 Atezolizumab has minimal binding to Fc receptors, thus eliminating 
detectable Fc effector function and associated antibody‐mediated clearance of activated effector T cells. 
 
Atezolizumab shows anti‐tumor activity in both nonclinical models and cancer patients and is being 
investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being studied as a 
single agent in the advanced cancer and adjuvant therapy settings, as well as in combination with 
chemotherapy, targeted therapy, and cancer immunotherapy. 
 
Atezolizumab is approved in the United States for the treatment of patients with locally advanced or 
metastatic urothelial carcinoma who fit the following criteria: 1) are not eligible for cisplatin‐ containing 
chemotherapy and whose tumors express PD‐L1 (PD‐L1 stained tumor‐ infiltrating immune cells [IC] 
covering ≥ 5% of the tumor area), as determined by an FDA‐ approved test, or 2) are not eligible for any 
platinum‐containing chemotherapy regardless of PD‐L1 status, or 3) have disease progression during or 
following any platinum‐containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
chemotherapy. Atezolizumab is also approved the treatment of previously treated locally advanced or 
metastatic NSCLC and in combination with carboplatin, paclitaxel and bevacizumab in patients with 
metastatic non‐ small cell lung cancer with non‐squamous histology 
 
Atezolizumab has been generally well tolerated. Adverse events with potentially immune‐ related causes 
consistent with an immunotherapeutic agent, including rash, influenza‐like illness endocrinopathies, hepatitis 
or transaminitis, pneumonitis colitis, and myasthenia gravis, have been observed (see Atezolizumab 
Investigator's Brochure for detailed safety results). To date, these events have been manageable with 
treatment or interruption of atezolizumab treatment. 
 
5.1.1 
Pre‐clinical 
Exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, 
including the fixed dose of 1200 mg administered every 3 weeks (q3w). On the basis of a population 
pharmacokinetic (popPK) analysis that included 472 patients in the dose range of 1 mg/kg to 20 mg/kg, the 
typical population clearance (CL) was 0.20 L/day, the volume of distribution at steady state (Vss) was 6.9 L, 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
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Protocol TOP 1901 
23 
 
and the terminal half‐life (t1/2) was 27 days. The popPK analysis suggested that steady state was obtained 
after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. 
 
The systemic accumulation in area under the concentration‐time curve (AUC), maximum concentration 
(Cmax), and trough concentration (Cmin) was 1.91, 1.46, and 2.75‐fold, respectively. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
24 
 
Based on an analysis of exposure‐safety and exposure‐efficacy data, the following factors had no clinically 
relevant effect: age (21‐89 years), body weight, sex, positive ADA status, albumin levels, tumor burden, 
region or ethnicity, renal impairment, mild hepatic impairment, level of PD‐L1 expression, or Eastern 
Cooperative Oncology Group (ECOG) status. 
 
Reproductive and Developmental Toxicity 
Reproductive and developmental toxicity studies with atezolizumab have not been conducted. The PD‐
L1/PD‐1 signaling pathway is well established as essential in maternal/fetal tolerance and embryo‐ fetal 
survival during gestation. Administration of atezolizumab is expected to have an adverse effect on pregnancy 
and poses a risk to the human fetus, including embryo‐lethality. 
 
5.1.2 
Clinical experience 
As of the CCOD of this IB update (17 May 2018) > 16,000 patients with solid tumors or hematologic 
malignancies have received atezolizumab as a single agent or in combination with cytotoxic chemotherapy 
and/or targeted therapy through participation in a clinical trial. Please refer to atezolizumab IB for 
additional details 
 
Safety findings of single‐agent atezolizumab across multiple tumor types in the clinical development 
program are consistent with the known mechanism of action of atezolizumab and the underlying disease. 
Overall, treatment with atezolizumab is well tolerated with a manageable adverse event profile. Currently, 
no maximum tolerated dose, no dose‐limiting toxicities (DLTs), and no clear dose‐ relatedtrends in the 
incidence of adverse events (AEs) have been determined. Among 3075 patients treated with single‐agent 
atezolizumab for whom pooled safety data are available, the most commonly reported AEs (> 10%) include 
fatigue, decreased appetite, cough, nausea, dyspnea, constipation, diarrhea, pyrexia, vomiting, arthralgia, 
back pain, asthenia, anemia, pruritus, rash, headache, and peripheral edema. 
 
The AEs observed with atezolizumab in combination with chemotherapy and/or targeted therapies are 
consistent with the known risks of the individual study treatment. Systemic immune activation, characterized 
by an excessive immune response, is a potential risk associated with atezolizumab when used in combination 
with another immunomodulating compound. 
 
Atezolizumab‐related AEs were comparable between patients who received atezolizumab monotherapy 
and those who were treated with atezolizumab in combination with targeted therapy and/or 
chemotherapy. There are no atezolizumab‐related AEs that are exacerbated when used in combination 
with other agents. 
 
Immune‐related AEs are consistent with the role of the PD‐L1/PD‐1 pathway in regulating peripheral 
tolerance. Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune‐related AEs are closely monitored during the atezolizumab clinical program. As of this IB update, 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
25 
 
immune‐related AEs associated with atezolizumab include pneumonitis, hepatitis, colitis, pancreatitis, 
diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain‐Barré 
syndrome, myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis and nephritis. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
26 
 
In the overall population, Grade 3 AEs were reported by 24.3% of patients and Grade 4 by 6.1% of patients. 
The most common (> 2% of patients) events being dyspnea (3.7%), anemia (5.1%), fatigue (3.5%), asthenia 
(2%), UTI (2.3%), hyponatremia (3.1%), and pneumonia (2.6%). 
 
The overall incidence of Grade 5 AEs occurring within 30 days of last study drug intake or prior to initiation 
of non‐protocol therapy was 3.9% (121/3075). Grade 5 AEs were reported in a variety of System Organ 
Classes (SOCs), and the following events were reported for more than 1 patient: pneumonia (12), death (19), 
disease progression (3), myocardial infarction (2), cardiac arrest (5), sepsis (8), sudden death (3),septic shock 
(5), respiratory failure (5), lung infection (2),cardiac failure (3), pulmonary embolism (2), pneumonia 
aspiration (2), respiratory distress (2) and pulmonary sepsis (2), 
cerebrovascular accident (2), ischemic stroke (2), cerebral hemorrhage (2), hepatic failure (2) and embolism 
(2). Eleven events were considered by the investigator as treatment related; one case each of constrictive 
pericarditis, cardiac failure, pneumonia, death, intestinal perforation, TEN, general physical condition 
abnormal, pulmonary hypertension, respiratory failure, hepatic failure and sepsis. 
 
Hepatic impairment 
No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. Ina popPK 
analysis, there were no clinically important differences in the clearance of atezolizumab between patients 
with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 X ULN and any AST [n = 
71]) and normal hepatic function (bilirubin and AST ≤ ULN [n = 401]). No data were available in patients with 
either moderate or severe hepatic impairment. The effect of moderate (bilirubin > 1.5 to 3 × ULN and any 
AST) or severe (bilirubin> 3 × ULN and any AST) hepatic impairment on the pharmacokinetics of atezolizumab 
is unknown. Hepatic impairment was defined by the National Cancer Institute criteria of hepatic dysfunction 
 
Renal Impairment 
No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In a popPK 
analysis, no clinically important differences in the clearance of atezolizumab were found in patients with 
mild (eGFR 60‐89 mL/min/1.73 m2; n = 208) or moderate (eGFR 30‐59 mL/min/1.73 m2; n = 116) renal 
impairment compared with patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2; n = 140). Only 
a few patients had severe renal impairment (eGFR 15‐29 mL/min/1.73 m2; n = 8). 
 
Concomitant use with other medications 
Because antibodies are cleared principally by catabolism (i.e., cleavage to small peptides and amino acids), 
atezolizumab is not expected to show pharmacokinetic interactions with other drugs, and is therefore not 
expected to interact with other drugs through protein binding, effects on cytochrome P450 activity, renal 
excretion or competition for common drug transporter proteins. 
 
Please refer to the atezolizumab IB for additional details. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
27 
 
5.2 Bevacizumab background 
 
Bevacizumab is classified as an Anti‐VEGF Monoclonal Antibody and a Vascular Endothelial Growth Factor 
(VEGF) Inhibitor. Bevacizumab is a recombinant, humanized monoclonal immunoglobulin G1 (IgG1) antibody 
which binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing its association with 
endothelial receptors, Flt‐1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the 
formation of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of 
all tissues (including metastatic tissue). 
 
The initial development program included studies sponsored and conducted by Genentech Inc. and 
F. Hoffmann‐La Roche Ltd., as well as the National Cancer Institute (NCI) in the United States. On the basis 
of these studies, bevacizumab received Marketing Authorization in > 100 countries (including the United 
States and the European Union) for the treatment of patients with metastatic carcinoma of the colon or 
rectum. Subsequently, Marketing Authorization has also been received worldwide for other indications (e.g. 
unresectable, locally advanced, recurrent or metastatic non‐squamous NSCLC; locally recurrent or 
metastatic breast cancer; advanced and/or metastatic renal cell carcinoma; epithelial ovarian, fallopian tube 
or primary peritoneal cancer; malignant glioma [World Health Organization; WHOGrade IV glioblastoma], 
and cervical cancer). 
 
5.2.1 
Preclinical 
Bevacizumab 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 A4.6.1). Approximately 93% of the amino‐acid sequence, including most of the 
antibody framework, is derived from human IgG1, and approximately 7% of the sequence is derived from 
the murine antibody 
 
Pregnancy 
Angiogenesis has been shown to be critically important to fetal development. The inhibition of 
angiogenesis following administration of bevacizumab could result in an adverse outcome of pregnancy. 
 
There are no adequate and well‐controlled studies in pregnant women. IgGs are known to cross the 
placental barrier, and bevacizumab may inhibit angiogenesis in the fetus. In the post‐ marketing setting, 
cases of fetal abnormalities in women treated with bevacizumab alone or in combination with known 
embryotoxic chemotherapeutics have been observed. 
 
Therefore, bevacizumab should not be used during pregnancy. In women of childbearing potential and male 
partners of such women, appropriate contraceptive measures should be used during bevacizumab therapy. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
28 
 
Based on pharmacokinetic considerations, contraceptive measuresshould be used for at least 6 months 
following the last dose of bevacizumab. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
29 
 
 
5.2.2 
Clinical experience 
 
Pharmacokinetics 
The pharmacokinetics of bevacizumab waswell described by a biphasic concentration‐time profile that 
exhibits dose–proportional exposure (two‐compartment, linear, PK model) at doses of 1 mg/kg/week to 10 
mg/kg/week, which includes the clinical doses of 2.5 to 5.0 mg/kg/week administered at 2‐ to 3‐week 
intervals (Q2W‐Q3W). For a typical patient, bevacizumab pharmacokinetics was  characterized with a slow 
clearance (Cl = 0.22 L/day)  and  a  volume  of  distribution  that approximates the plasma volume (Vd = 3.28 
L), resulting in long systemic persistence (elimination half‐ life [t1/2,elimination] of 3‐4 weeks) with a 
predicted time to steady state of 100 days. 
 
The pharmacokinetics of bevacizumab in pediatric patients was characterized using a comprehensive PopPK 
model that was developed using data from 152 patients across four pediatric studies who were administered 
doses of 5 to 15 mg/kg every 2 to 3 weeks. Generally; pediatric pharmacokinetics was comparable to adult 
pharmacokinetics when normalized by body weight with a slow CL, a limited Vd, and a long serum terminal 
half‐life (t1/2; approximately 21 days). On the basis of model predictions, bevacizumab exposure trended 
lower as body weight decreased. No additional PK‐associated covariates with significant impact on 
bevacizumab exposure were observed for the pediatric patients other than those already known for adult 
patients (body weight, sex, and albumin levels) with primary CNS tumors found to be a specific covariate in 
the pediatric PopPK model. Age was not  associated with bevacizumab pharmacokinetics when body weight 
was taken into account. 
 
Concomitant therapy 
The co‐administration of bevacizumab with various chemotherapeutic and other anti‐cancer agents 
resulted in similar values of CL and volume of distribution for the central compartment (Vc) for 
bevacizumab. The peripheral volume (Vp) was found to be smaller when bevacizumab was administered 
alone or with interferon (IFN) alfa‐2a compared with bevacizumab administered with other 
chemotherapeutic agents. Those results suggest that exposure to bevacizumab is not affected by 
concomitant dosing with doxorubicin, capecitabine, 5‐fluorouracil (5‐FU)/leucovorin (LV), 5‐ 
FU/LV/irinotecan (IFL), erlotinib, carboplatin, cisplatin, oxaliplatin; paclitaxel, gemcitabine, temozolomide 
(TMZ), or IFN alfa‐2a. 
Accumulating data do not suggest that bevacizumab affects disposition of anti‐neoplastic agents. 
Hepatic and renal impairment 
The safety and efficacy of bevacizumab has not been studied in patients with renal or with hepatic 
impairment 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
30 
 
Safety 
Clinical experience with bevacizumab has shown significant AEs associated with its use. Patients particularly 
vulnerable to significant AEs, such as those with recent pulmonary hemorrhage/hemoptysis or evidence of 
inherited bleeding diathesis or significant coagulopathy at risk of bleeding, have been excluded from the 
study. Study patients will be assessed by prior medical history, physical examinations, monitoring of vital signs, 
performance statusevaluations, hematology and chemistry laboratory testing, and urinalyses. 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
31 
 
• Hypertension will be monitored through routine evaluation of blood pressure prior to each 
bevacizumab treatment. Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without bevacizumab. 
• Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick at least every 6 
weeks. 
• If patients on treatment with bevacizumab require elective major surgery, it is recommended 
that bevacizumab be held for 4‐8 weeks prior to the surgical procedure. Patients undergoing a major 
surgical procedure should not begin/restart bevacizumab until 4 weeks after  that procedure (in the case 
of high risk procedures such as liver resection, thoracotomy, or neurosurgery, it is recommended that 
chemotherapy be restarted no earlier than 6 week and bevacizumab no earlier than 8 week after 
surgery 
 
Hypertension: An increased incidence of hypertension (all grades) of up to 42.1% has been observed in 
patients treatedwith bevacizumab compared to up to 14% in the comparator arm. In clinical trials 
across all indications the overall incidence of NCI‐CTC Grade 3 and 4 hypertension in patients receiving 
bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 
1.0% of bevacizumab‐treated patients, compared to up to 0.2% of patients treated with the same 
chemotherapy alone. Very rare cases of hypertensive encephalopathy have been reported, some of 
which were fatal. The risk of bevacizumab‐associated hypertension did not correlate with the patients’ 
baseline characteristics, underlying disease or concomitant therapy. 
 
Analyses of the clinical safety data suggest that the occurrence of hypertension with bevacizumab 
therapy is likely to be dose‐dependent. Monitor blood pressure every two to three weeks during 
treatment with bevacizumab. Treat with appropriate anti‐hypertensives such as angiotensin‐ converting 
enzyme inhibitors, diuretics and calcium‐channel blockers and monitor blood pressure regularly. 
Continue to monitor blood pressure at regular intervals in patients with bevacizumab ‐ induced or –
exacerbated hypertension after discontinuation of bevacizumab. 
 
Temporary interruption of bevacizumab therapy is recommended in patients with hypertension 
requiring medical therapy until adequate control is achieved. Bevacizumab should be permanently 
discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive 
therapy. Bevacizumabshould be permanently discontinued in patients who develop hypertensive crisis 
or hypertensive encephalopathy. 
 
Proteinuria: In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients 
receiving bevacizumab. Proteinuria ranged in severity from clinically asymptomatic, transient, trace 
proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to 8.1% of treated patients. 
Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. In the event of 
Grade 4 proteinuria Bevacizumab treatment should be permanently discontinued. The proteinuria 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
32 
 
seen in bevacizumab clinical trials wasnot associated with renal impairment and rarely required 
permanent discontinuation of bevacizumabtherapy. 
 
Analyses of the clinical safety data suggest that the occurrence of proteinuria with bevacizumab 
therapy is likely to be dose‐dependent. Patients with a history of hypertension may be at 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
33 
 
increased risk for the development of proteinuria when treated with bevacizumab. There is evidence 
suggesting that Grade 1 proteinuria may be related to bevacizumab dose. Testing for proteinuria is 
recommended prior to start of bevacizumab therapy. In most clinical studies urine protein levels of 
≥2g/24h led to the holding of bevacizumab until recovery to <2g/24h. 
 
Wound healing complications: Bevacizumab may adversely affect the wound healing process. Serious 
wound healing complications with a fatal outcome have been reported. Necrotizing fasciitis including 
fatal cases, has rarely been reported in patients treated with Bevacizumab; usually secondary to wound 
healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be 
discontinued in patients who develop necrotizing fasciitis, and appropriate treatment should be promptly 
initiated. As bevacizumab may adversely impact wound healing, patients who had major surgery within 
the last 28 days prior to starting bevacizumab treatment were excluded from participation in Phase III 
trials. 
 
Hemorrhage: In clinical trials across all indications the overall incidence of NCI‐CTC Grade 3‐5 bleeding 
events ranged from 0.4% to 6.9% in bevacizumab‐treated patients, compared to 0 to 4.5% of patients 
in the chemotherapy control group. The hemorrhagic events that have been observed in bevacizumab 
clinical studies were predominantly tumor‐ associated hemorrhage (see below) and minor 
mucocutaneous hemorrhage (e.g.epistaxis). Bevacizumab should be permanently discontinued in 
patients who experience Grade 3 or 4 bleeding during Bevacizumab therapy. 
 
Tumor‐Associated Hemorrhage: Major or massive pulmonary hemorrhage or hemoptysis has been 
observed primarily in patients with NSCLC. Possible risk factors include squamous cell histology, 
treatment with anti‐rheumatic/anti‐inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumor location 
and cavitation of tumors prior to or during therapy. The only variables that showed statistically significant 
correlations with bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC 
of known squamous cell histology or mixed cell type with predominant squamous cell histology were 
excluded from  subsequent studies, while patients with unknown tumor histology were included. 
 
In patients with NSCLC excluding predominant squamous histology, all grade events were seen with a 
frequency of up to 9% when treatedwith bevacizumab plus chemotherapy compared with 5% in the 
patients treatedwith chemotherapy alone. Grade 3‐5 events have been observed in up to 2.3% of 
patients treated with bevacizumab plus chemotherapy as compared with <1% with chemotherapy 
alone. Major or massive pulmonary hemorrhage/hemoptysis can occur suddenly and up to two thirds 
of the serious pulmonary hemorrhages resulted in a fatal outcome. 
 
Patientswith non–small cell lung cancer treatedwith Bevacizumab may be at risk for serious, and in some 
cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ 
haemoptysis (>1/2 teaspoon red blood) should not  be treated with Bevacizumab. Of patients 
experiencing pulmonary hemorrhages requiring medical intervention, many had cavitation and/or 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
34 
 
necrosis of the tumor, either preexisting or developing during bevacizumab therapy. Patients developing 
lung cavitation on treatment should be assessed by the treating physician for risk‐benefit. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
35 
 
 
In Study E4599, in which squamous cell carcinoma was excluded, the rate of any type of Grade ≥ 3 
hemorrhage was 1.0% in the control arm (carboplatin and paclitaxel) versus 4.1% in the carboplatin 
and paclitaxel + bevacizumab arm. 
 
Brain metastases: The incidence of CNS bleeding in patients with untreated CNS metastases receiving 
bevacizumab has not been prospectively evaluated in randomized clinical studies. In an exploratory 
retrospective analysis of data from 13 completed randomized trials in patients with various tumor types, 
3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated 
with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to 
bevacizumab. In two subsequent studies in patients with treated brain metastases (which included 
around 800 patients), one case of Grade 2 CNS hemorrhage was reported. 
 
Posterior Reversible Encephalopathy Syndrome (PRES): PRES is a rare neurologic disorder that can 
present with the following signs and symptoms (among others): seizures, headache, altered mental 
status, visual disturbance, or cortical blindness, with or without associated hypertension. Brain imaging 
is mandatory to confirm the diagnosis of PRES. Two confirmed cases (0.8%) of PRES have been reported 
in one clinical study. Symptoms usually resolve or improve within days, although some patients have 
experienced neurologic sequelae. In patients who develop PRES, treatment of specific symptoms, 
including control of hypertension, is recommended along with discontinuation of bevacizumab. The 
safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. 
 
Refer to the bevacizumab Investigator’s Brochure for a more details. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
36 
 
6 
CLINICAL MANAGEMENT OF STUDYTHERAPY 
 
Agent 
Premedications 
Dose 
Route 
Schedule 
Cycle length 
Atezolizumab 
Per institutional 
1200 mg 
IV over 60 minutes for 
Day 1 
Every 21 
practice 
first infusion, and if first 
days 
infusion is tolerated all 
subsequent infusions 
can be used infused 
over 30 minutes or per 
institutional practice 
Bevacizumab 
Per institutional 
15 mg/kg * IV over 90 minutes (1st 
Day 1 
Every 21 
practice 
infusion), if the first 
days 
infusion is tolerated 
(2nd infusion) over 60 
minutes andif 2nd 
infusion is tolerated all 
subsequent infusions 
over 30 minutes or per 
institutional practice 
* The dose of bevacizumab will be based on the patient’s weight at screening and willremainthe same throughout the 
study unless the patient’s weight changes by > 10%. If weight changes > 10% then dose will be recalculated based on 
weight on day of treatment 
 
6.1 Discontinuation for adverse events 
 
If one of the study agents is permanently discontinued related to an adverse event than the study 
therapy should be discontinued. 
If the atezolizumab or bevacizumab is held for > 12 weeks the patient should discontinued from study 
therapy (both drugs). 
 
Patients may continue to receive one study agent if the second agent is temporarily being held for adverse 
event (i.e. patient can continue to receive bevacizumab if atezolizumab is being held related to adverse 
event). 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
37 
 
6.2 Management of atezolizumab adverse events 
 
6.2.1 
Dose modification and delays 
Dose modification e of atezolizumab is not permitted. Dose delays are permitted for maximum of ≤ 12 weeks. 
If study therapy cannot be resumed > 12 weeks study therapy (both agents) should be discontinued. Reasons 
for dose delays, the supportive measures taken and the outcomes will be documented in the patient’s chart 
and recorded on the eCRF. 
 
6.2.2 
Management of immune related adverse events 
The management of more common specific adverse events associated with atezolizumab are outlined 
Adverse events related to immune‐related pulmonary, hepatic, gastrointestinal, endocrine, dermatologic 
are outline below. The primary management is dose delay, use of prednisone when indicated, and 
appropriate supportive care. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
38 
 
 
Although most immune‐mediated adverse events observed with immunomodulatory agents have been mild 
and self‐limiting, such events should be recognized early and treated promptly to avoid potential major 
complications. Atezolizumab should be permanently discontinued in patientswith life‐ threatening immune‐
mediated adverse events. 
 
Additional information is available in the IB about the specific management of other adverse events. 
 
Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the 
administration of atezolizumab. Patients will be assessed for pulmonary signs and symptoms throughout the 
study and will also have CT scans of the chest performed at every tumor assessment. Management guidelines 
for pulmonary events are provided in table 1. 
 
All pulmonary events should be thoroughly evaluated for other  commonly  reported etiologies such as 
pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease, or pulmonary hypertension 
 
Table 1: Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
Event 
Management 
Pulmonary event, 
Grade 1 
• 
Continue atezolizumab and monitor closely. 
• 
Re‐evaluate on serial imaging. 
• 
Consider patient referral to pulmonary specialist. 
Pulmonary event, 
Grade 2 
• 
Withholdatezolizumab for up to 12 weeks after event onset.a 
• 
Refer patient to pulmonary andinfectious disease specialistsand consider 
bronchoscopy or BAL. 
• 
Initiate treatment with 1‐2 mg/kg/day oral prednisone orequivalent. 
• 
If event resolves to Grade 1 or better, resumeatezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks, permanently discontinue atezolizumab 
• 
For recurrent events, treat as a Grade 3 or 4 event. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
39 
 
Pulmonary event, 
Grade 3 or 4 
• 
Permanently   discontinueatezolizumab 
• 
Bronchoscopy or BAL is recommended. 
• 
Initiate treatment with 1‐2 mg/kg/day oral prednisone or equivalent. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
addingan immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
BAL=bronchoscopic alveolar lavage; a Atezolizumabmay be withheld for a maximum of ≤ 12 weeks to allow 
for corticosteroids (if initiated) to be reducedto ≤ 10 mg/day oral prednisone or equivalent. If study therapyis 
delayed > 12 weeks then studytherapy (bothagents) should be discontinued; b If corticosteroids have been 
initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before 
atezolizumab canbe resumed 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
40 
 
Hepatic Events 
Immune‐related hepatitis has been associated with the administration of atezolizumab. Eligible patients 
must have adequate liver function, as manifested by measurements of total bilirubin and hepatic 
transaminases. Liver function will be monitored throughout study treatment. Management guidelines for 
hepatic events are provided in table 2. 
 
Patients with right upper‐quadrant abdominal pain and/or unexplained nausea or vomiting should have LFTs 
performed immediately and reviewed before administration of the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree should 
be performed to rule out neoplastic or other causes for the increased LFTs 
 
Table 2: Management Guidelines for hepatic events 
 
Event 
Management 
Hepatic event, 
Grade 1 
• 
Continueatezolizumab. 
• 
Monitor LFTs until values resolve to within normallimits. 
Hepatic event, 
Grade 2 
All events: 
Monitor LFTs more frequently until return to baseline values. 
Events of > 5 days’ duration: 
• 
Withhold atezolizumab for up to 12 weeks afterevent onset.a 
• 
Initiate treatment with 1‐2 mg/kg/dayoral prednisone or 
equivalent. 
• 
If event resolves to Grade 1 or better, resume 
atezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks,permanently 
discontinue atezolizumab 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
41 
 
Hepatic event, 
Grade 3 
• 
Permanently discontinueatezolizumab 
• 
Consider patient referral to gastrointestinal specialist for 
evaluationandliver biopsy to establishetiology ofhepatic injury. 
• 
Initiate treatment with 1‐2 mg/kg/day oral prednisone or 
equivalent. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, tapercorticosteroids over ≥ 1 
month. 
a Atezolizumab may be withheld for a maximum of ≤ 12 weeks to allow for corticosteroids (if initiated) to be 
reduced to ≤ 10 mg/day oral prednisone or equivalent. If studytherapy is delayed > 12 weeks thenstudytherapy 
(both agents) should be discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 
month to ≤ 10 mg/day oral prednisone or equivalent before atezolizumabcan be resumed 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
42 
 
Gastrointestinal Events 
Immune‐related colitis has been associated with the administration of atezolizumab. Management 
guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly  evaluated for other more common  etiologies. For 
events of significant duration or magnitude or associated with signs of systemic inflammation or acute‐
phase reactants (e.g., increased CRP, platelet count, or bandemia): Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, with 3 to 5 specimens for standard paraffin block to 
checkfor inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Table 3: Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• 
Continueatezolizumab. 
• 
Initiate symptomatic treatment. 
• 
Endoscopy is recommended if symptoms persist for > 7days. 
• 
Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• 
Withholdatezolizumab for up to 12 weeks after event onset.a 
• 
Initiate symptomatic treatment. 
• 
Patient referral to GI specialist is recommended. 
• 
For recurrent events or events that persist > 5 days, initiate treatment with 1‐ 
2 mg/kg/day oral prednisone orequivalent. 
• 
If event resolves to Grade 1 or better, resumeatezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks, permanently discontinue atezolizumab 
Diarrhea or 
colitis, Grade 3 
• 
Withholdatezolizumab for up to 12 weeks after event onset.a 
• 
Refer patient to gastrointestinal specialist for evaluation and 
confirmatorybiopsy. 
• 
Initiate treatment with 1‐2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1‐2 mg/kg/day oralprednisone or equivalent upon 
improvement. 
• 
If event resolves to Grade 1 or better, resumeatezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks, permanently discontinue atezolizumab 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
43 
 
Diarrhea or 
colitis, Grade 4 
• 
Permanently discontinueatezolizumab 
• 
Refer patient to gastrointestinal specialist for evaluation and confirmationbiopsy. 
• 
Initiate treatment with 1‐2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1‐2 mg/kg/day oral prednisone or equivalent uponimprovement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressiveagent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab maybe withheld for a maximum of ≤ 12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 
mg/day oral prednisone or equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be 
discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
43
Endocrine Events 
Thyroid disorders, adrenal insufficiency, diabetes mellitus and pituitary disorders have been associated with 
the administration of atezolizumab. Management guidelines for endocrine events are provided in table 4. 
 
Patients with unexplained symptoms  such  as headache, fatigue, myalgias, impotence,  constipation, or 
mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies, as well as for hyponatremia or hyperkalemia. The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected. Thyroid‐ stimulating hormone (TSH) and free  T3 and T4 
levels should be measured to determine whether thyroid abnormalities are present. Pituitary hormone 
levels and function tests (e.g. TSH, growth hormone, luteinizing hormone,  follicle‐ stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to differentiate 
primary pituitary insufficiency from primary adrenal insufficiency. 
 
Table 4: Management Guidelines for Endocrine Events 
 
Event 
Management 
Asymptomatic 
hypothyroidism 
• 
Continueatezolizumab. 
• 
Initiate treatment with thyroid replacementhormone. 
• 
Monitor TSH 
Symptomatic hypothyroidism 
• 
Withholdatezolizumab. 
• 
Initiate treatment with thyroid replacementhormone. 
• 
Monitor TSH weekly. 
• 
Consider patient referral to endocrinologist. 
• 
Resumeatezolizumab when symptoms arecontrolledand 
thyroid functionis improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• 
Continueatezolizumab. 
• 
Monitor TSH every 4 weeks. 
TSH < 0.1 mU/L 
• 
Follow guidelines for symptomatic hyperthyroidism. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
44
Symptomatic hyperthyroidism 
• 
Withholdatezolizumab. 
• 
Initiate treatment with anti‐thyroiddrug suchasmethimazole or 
carbimazole as needed. 
• 
Consider patient referral to endocrinologist. 
• 
Resumeatezolizumab when symptoms arecontrolledand 
thyroid functionis improving. 
• 
Permanently discontinue atezolizumab for life‐threatening 
immune‐related hyperthyroidism. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
45
Symptomatic adrenal 
insufficiency, 
Grade 2‐4 
• 
Withholdatezolizumab for up to 12 weeks afterevent 
a 
onset. 
• 
Refer patient to endocrinologist. 
• 
Perform appropriate imaging. 
• 
Initiate treatment with 1‐2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1‐2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event resolves to Grade 1 or better andpatient is stable on 
replacement therapy, resumeatezolizumab.b 
• 
If event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy while withholding 
atezolizumab for > 12 weeks, permanentlydiscontinue 
atezolizumab 
Hyperglycemia Grade 1 or 2 
• 
Continueatezolizumab. 
• 
Initiate treatment with insulin if needed. 
• 
Monitor for glucosecontrol. 
Hyperglycemia, Grade 3 or 4 
• 
Withholdatezolizumab. 
• 
Initiate treatment with insulin. 
• 
Monitor for glucosecontrol. 
• 
Resume atezolizumab when symptoms resolve andglucose levels 
arestable. 
Hyperglycemia, Grade 3 or 4 
• 
Withholdatezolizumab. 
• 
Initiate treatment with insulin. 
• 
Monitor for glucosecontrol. 
• 
Resume atezolizumab when symptoms resolve andglucose levels 
arestable. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
46
Hypophysitis (pan‐
hypopituitarism), Grade 2‐3 
• 
Withholdatezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to endocrinologist. 
• 
Perform brain MRI (pituitaryprotocol). 
• 
Initiate treatment with 1‐2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1‐2 mg/kg/dayoral prednisone or 
equivalent upon improvement.a 
• 
Initiate hormone replacement therapyif clinically indicated. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks, permanently discontinue 
atezolizumab 
• 
For recurrent hypophysitis, treat as a Grade 4 event. 
MRI = magnetic resonance imaging; TSH = thyroid‐stimulating hormone, IV = intravenous a Atezolizumab may be withheld 
for a maximum of ≤12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or 
equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be discontinued b If 
corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
47
Dermatologic Events 
Treatment‐emergent rash has been associated with atezolizumab. The majority of cases of rash were mild 
in severity and self‐limited, with or without pruritus. A dermatologist should evaluate persistent and/or 
severe rash or pruritus. A biopsy should be considered unless contraindicated. Management guidelines for 
dermatologic events are provided in table 5. 
 
Table 5: Management Guidelines for Dermatologic Events 
 
Event 
Management 
Dermatologic event, 
Grade 1 (<10% BSA) 
• Continueatezolizumab. 
• Consider treatment with topical corticosteroids and/orother symptomatic 
therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2 (10‐30% BSA) 
• Continueatezolizumab. 
• Consider patient referral to dermatologist. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher‐potency topicalcorticosteroids if event 
does not improve 
Dermatologic event, 
Grade 3 (>30% BSA) 
• Withholdatezolizumab for up to 12 weeks after event onset.a 
• Refer patient to dermatologist. 
• Initiate treatment with 10 mg/dayoral prednisone or equivalent, 
increasingdose to 1‐2 mg/kg/day if event does not improve within 48‐72 
hours. 
• If event resolves to Grade 1 or better, resume atezolizumab.b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab for > 12 weeks,permanently 
discontinue atezolizumab 
Dermatologic 
event, Grade 4 
• Permanently discontinue atezolizumab andcontactprincipal 
investigator 
a Atezolizumab may be withheld for a maximum of 12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 
mg/day oral prednisone or equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be 
discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
48
 
6.3 Management of bevacizumab adverse events 
 
6.3.1 
Dose modifications 
Bevacizumab dose modifications are not permitted 
 
6.3.2 
Management of bevacizumab‐related adverse events 
The management of more common specific adverse events associated with bevacizumab are 
outlined below. 
 
To summarize, bevacizumab should be held temporarily or permanently discontinued in patients (as per 
the clinical judgment of the treating physician) experiencing any of the following events: 
• 
Febrile grade 4 neutropenia and/or grade 4 thrombocytopenia regardless of the 
relationship to treatment (hold treatment temporarily) 
• 
Grade ≥ 2 fistula (hold temporarily or permanently discontinue) 
• 
GI perforation (permanently discontinue) 
• 
Major surgery or wound healing complications (hold temporarily or permanently 
discontinue) 
• 
Medically significant hypertension not controlled with antihypertensive therapy, 
hypertensive crisis or hypertensive encephalopathy (permanently discontinue) 
• 
Grade ≥ 3 left ventricular dysfunction (CHF) (permanently discontinue) 
• 
Nephrotic syndrome (permanently discontinue) 
• 
Arterial thrombosis/embolism (any grade) (permanently discontinue) 
• 
Grade ≥ 3 venous thrombosis/embolism (hold temporarily or permanently 
discontinue for grade 4) 
• 
CNS bleeding (any grade) or ≥ grade 3 bleeding of any kind (permanently 
discontinue) 
• 
Grade ≥ 2 hemoptysis (permanently discontinue) 
• 
Hypersensitivity/allergic 
reactions 
related 
to 
bevacizumab 
(permanently 
discontinue) 
• 
PRES (or RPLS) (permanently discontinue) 
Additional information is available in the IB about the specific management of other adverse events. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
49
Table 6: Bevacizumab Treatment Management for Proteinuria 
 
NCI CTCAE 
v. 4.03 
Urinalysis 
Treatment Action 
Grade 1 
Urine protein creatinine 
ratio ≤ 1.0 
No bevacizumab dose modification 
Grade 2 
Urine protein creatinine 
ratio> 1.0 to 3.4) 
For urine protein/creatinine ratio > 1.0 to <2.0 monitor 
urine protein/creatinine ratio with each cycle 
Suspend bevacizumab for urine protein /creatinine 
ratio ≥ 2.0. Resume bevacizumab when urine 
protein/creatinine ratio is < 2. Permanently 
discontinue study therapy if therapy held > 12 weeks 
Grade 3 
Urine protein/creatinine 
ratio ≥3.5 
Suspend bevacizumab. 
Resume bevacizumab when urine/protein creatinine 
ratio < 2.0 
Nephrotic syndrome 
Permanently discontinue bevacizumab 
UPC ratio of spot urine is an estimation of the 24 urine protein excretion. A UPC ratioof 1 is roughly equivalent 
to a 24‐hour urine protein of 1 g. UPC ratio is calculated usingof the following formulas: 
[urine protein]/[urine creatinine]‐ if both protein and creatinine are reported inmg/dL 
[(urine protein) x 0.0088]/[urine creatinine] ifurine creatinine is reported in mmol/L. 
Bevacizumab maybe held for a maximum of 12 weeks. If study therapy delayed> 12 weeks then study 
therapy (both agents) shouldbe discontinued. 
 
Arterial thrombosis/embolism 
Bevacizumab should be discontinued in patients who develop arterial thromboembolic events. 
 
Venous thrombosis/embolism 
Bevacizumab should be held in patients developing a grade 3  thrombosis/embolism.  Bevacizumab may be 
resumed once the patient is adequately anti‐coagulated and on a stable level of anticoagulation for at least 
2 weeks prior to restarting study drug treatment. Patients on heparin treatment should have an aPTT 
between 1.5‐2.5 x ULN (or patient value before starting heparin treatment). Patients on coumadin 
derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1‐4 days 
apart. Patients on full dose low molecular  weight  heparins should receive the appropriate dose based on 
the weight of the patient according to package insert. 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
50
An increased risk of venous thromboembolic events and bleeding in patients receiving anti‐ coagulation 
therapy after first venous thromboembolic event while receiving bevacizumab has been observed. 
 
In the event of recurrent grade 3 thrombosis/embolism, the patient should be discontinued from 
bevacizumab. 
 
Bevacizumab should be discontinued in patients with life‐threatening (grade 4) pulmonary embolism. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
51
Hemorrhage 
An increased incidence of bleeding events was observed in study  patients treated with bevacizumab as 
compared to control treatment arms. The hemorrhagic events observed in bevacizumab studies were 
predominantly tumour‐associated hemorrhage and minor mucocutaneous hemorrhage. 
 
Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, 
based on imaging procedures or signs and symptoms. Therefore, the risk of CNS hemorrhage in such 
patient has not been prospectively evaluated in randomized clinical studies. 
 
Bevacizumab should be permanently discontinued for: 
• grade 3 or 4 bleeding of any kind 
• any grade of CNS bleeding. Patients should be monitored for signs and symptoms of 
CNS bleeding\ 
• grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL bright red blood per episode). 
 
If hemorrhagic complications occur in patients on full dose anti‐coagulation therapy, permanently 
discontinue bevacizumab treatment and follow guidelines of the treating institution. Standard procedures 
such as antagonisation with protamin or vitamin K and infusion of vitamin K dependent factors should be 
considered dependent on the severity of the bleeding 
 
Posterior Reversible Encephalopathy Syndrome (PRES/RPLS) 
There have been rare reports of patients treated with bevacizumab developing signs and symptoms that are 
consistent with PRES, a rare neurological disorder. PRES is also known as reversible posterior 
leukoencephalopathy syndrome or RPLS). PRES can present with following signs and symptoms among others: 
seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated 
hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, 
treatment of specific symptoms including control of hypertension is recommended along with discontinuation 
of bevacizumab. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is 
not known. Adequate brain imaging using MRI must be performed as a follow‐up measurement for patients 
with PRES. 
 
Gastrointestinal Perforation 
Bevacizumab should be permanently discontinued in patients who develop GI perforation. 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
52
Fistula 
Bevacizumab use has been associated with serious cases of fistulae including events resulting in death. 
Fistulae within the GI tract or GI tract and skin are common in patients with mCRC and ovarian cancer, but 
are uncommon or rare in other indications. Other fistulae (e.g. tracheoesophageal,  bronchopleural, 
urogenital, biliary) have been reported uncommonly in bevacizumab clinical trials patients and in post‐
marketing reports. 
1. Temporarily discontinue bevacizumab in patients with grade 2 or 3 non‐ tracheoesophageal 
fistula until resolution to ≤ grade 1. 
2. Permanently discontinue bevacizumab in patients with tracheoesophageal fistula or any 
grade 4 fistula. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
53
 
Limited information is available on the continued use of bevacizumab in patients with other fistulae. In cases 
of internal fistula not arising in the GI tract, discontinuation of bevacizumab should be considered. 
 
Wound Healing Complications 
In patients who experience wound healing complications during bevacizumab treatment, bevacizumab 
should be withheld until the wound is fully healed. If the wound does not fully heal despite withholding 
treatment, should be permanently discontinued. 
 
Bevacizumab therapy should be withheld for an interval of at least two half‐lives (approximately six weeks) 
before conducting major elective surgery. Emergency surgery should be performed as appropriate without 
delay after a careful risk‐benefit assessment. 
 
Hypertension 
In most cases hypertension is controlled adequately using standard antihypertensive treatment 
appropriate for the individual situation of the affected patient. Bevacizumab should be permanently 
discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive 
therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy. 
 
Congestive Heart Failure (CHF) 
Bevacizumab should be permanently discontinued in patients with ≥ grade 3 CHF. 
 
6.4 Concomitant Medications 
 
Use of the following concomitant therapies is prohibited as described below: 
1. Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), whether 
health authority‐approved or experimental, is prohibited during study treatment, until the patient 
has discontinued study treatment 
2. Investigational therapy (other than protocol‐mandated study treatment) is prohibited within 
14 days prior to initiation of study treatment and during study treatment. 
3. Live, attenuated vaccines are prohibited within 4 weeks prior to initiation of study treatment, 
during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab. 
4. Systemic immunostimulatory agents (including, but not limited to, interferons and IL 2) are 
prohibited within 4 weeks or five half‐lives of the drug (whichever is longer) prior to initiation of 
study treatment and during study treatment because these agents could potentially increase the 
risk for autoimmune conditions when given in combination with atezolizumab. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
54
5. Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, and thalidomide) are prohibited during study treatment because 
these agents could potentially alter the efficacy and safety of atezolizumab. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
55
6.5 Rationale for Selection of Dose, Regimen, and Treatment Duration 
 
Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (1200 mg on Day 1 of each 21‐
day cycle), which is the approved dosage for atezolizumab (see U.S. Package Insert). Bevacizumab will be 
administered at 15 mg/kg every 3 weeks which is the approved dose for bevacizumab (see US package 
insert). The doses and schedule of bevacizumab and atezolizumab were investigated in the phase 3 trial in 
combination with carboplatin and paclitaxel which lead to FDA approval of carboplatin, paclitaxel, 
bevacizumab and atezolizumab 
 
7 RATIONAL FOR TRANSLATIONAL MEDICINE STUDIES 
 
The translational medicine researchproposed below representsideas based upon the state of the field to date. 
However, the exact correlative research that will be done may be modified based upon the best science at the time 
these assays are ready to be performed. The specific cell surface markers, genes, and proteins that may be assayed 
for are suggested below, but as the immune checkpoint and specifically knowledge around the PD‐1/PD‐L1 axis 
expands in the upcoming years, these specifics may be modified to provide the most useful data. At this time, we are 
capable of conducting all proposed assays, but external collaborations would be welcome. Given the small sample size 
of the trial the proposed analyses will be considered exploratory. 
 
Tumor samples 
Pre‐treatment tumor samples ≤ 60 days after disease progression on osimertinib and before day 1 of study 
therapy (if available) will be used. There are no specific requirements associated with the type of biopsy. IHC 
for expression of proteins that may be associated with sensitivity or resistance to atezolizumab, including 
but not limited to immune cell populations including CD3, CD4, CD8, Treg, Th17 T‐cells and 
monocyte/macrophage and neutrophil populations, as well as immune and tumor cell expression of PD‐1, 
and PD‐L1 and PD‐L2, respectively. In addition, if sufficient tumor tissue exists, we will isolate tumor‐derived 
RNA and/or DNA for downstream analyses.  While  NGS analyses may not be possible due to input limitations, 
focused RT‐PCR or ddPCR assays may be  employed  to evaluate specific gene expression levels or known 
mutations or indels. 
 
Circulating Immune Cell Analysis 
Two fifteen color polychromatic flow cytometry panels will be used to analyze changes in the immune cell 
subtypes that are expected to be altered by treatment (please see lab manual for additional details). The 13‐
color base panels to identify immune cell types and related markers are listed in Table 7 (lymphoid) and Table 
8 (myeloid). The lymphoid panel focuses on T‐cell activation, maturation, regulation, and exhaustion. The 
myeloid panel focuses on myeloid derived suppressor cells (MDSC), M1/M2 polarization, and dendritic cells 
(DC, pDC). The markersincluded in each respective panel have been reported to be of value in the context 
of prognostic or predictive immune markers in cancer studies.24‐26 While the majority of immune markers 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
56
reported are associated with the tumor microenvironment, measurement of peripheral MDSCs has been 
associated with progression free survival in the context of neoadjuvant ipilimumab therapy for melanoma. 
The two additional markers for each panel are included to include novel markers based on literature current 
at the time of funding as well as scientific data supporting the use for each additional marker. Data will be 
analyzed using novel computational methods developed at Duke that can be used to identify multi‐
dimensional populations and evaluate changes in these populations across treatment.27,28 Patient samples 
will be analyzed at baseline (cycle 1 day 1), at time of first imaging, and at the time of disease progression. 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
57
All immune cell correlates will be performed in collaboration with the Duke Immune Profiling Core (DIPC) 
laboratory under the direction of Dr. Kent J. Weinhold. The DIPC represents one of a limited few facilities 
nationwide offering highly standardized/validated assays for polyfunctional T‐cell analysis. The DIPC works 
directly with Duke CFAR/GAP Quality Assurance Program to ensure that all assays are performed in 
compliance with Good Clinical Laboratory Practice Guidelines.29 The DIPC has participated in/currently 
participates in regular proficiency testing and standardization programs including the NIAID/DAIDS 
Immunology Quality Assessment Proficiency Program (26+  yrs),  CDC Model Performance Evaluation 
Program T‐Lymphocyte Immunophenotyping (14+ yrs), NIH/NIAID‐ SeraCare Bioservices & BD Biosciences 
ICS Quality Assessment Program (6+ yrs), NIH/NIAID‐BD Biosciences CFSE Standardization Working Group 
(3.5 yrs), and Cancer Vaccine  Consortium Proficiency Panel Program (ICS & CFSE, 6+ yrs). Currently, the DIPC 
leads the Flow Cytometry External Quality Assurance Program for the NIH/NIAID/DAIDS sponsored External 
Quality Assurance Program Oversight Laboratory (EQAPOL) contract EQAPOL evaluates polychromatic 
antigen‐specific flow cytometry methods, such intracellular staining (ICS) and T‐ follicular helper assays. The 
DIPC has clearly focused its efforts on the development of and continued refinement of polychromatic flow 
cytometry‐based readout aimed at assessing phenotypic and functional reactivities, including intracellular 
cytokine staining and degranulation within a broad range of phenotypically‐defined  T‐ cell populations. 
Moreover, this Core is constantly developing new assays for novel immunologic endpoints 
(http://sciences.surgery.duke.edu/research/institutes‐and‐labs/weinhold‐lab) 
 
such 
as 
polychromatic ICS assays, lymphocyte activation/maturation, and T‐cell regulation.30‐32 
 
Collaboration with this core will leverage the unique experience of this facility as it applies to analysis of 
specimens derived from patients with solid  tumors. This will include  studies requiring the analysis of 
immunological reactivity in vivo and immune response in vitro. Cells to be used in flow‐based assays will be 
obtained from individual patient’s acid citrate dextrose anti‐coagulated fresh whole blood that has been 
processed to isolate PBMC, cryopreserved, and stored in LN2 freezers for batch processing. Cell thawing and 
overnight resting will be performed for all flow cytometry assays according to standardized and optimized 
standard operating procedures (SOPs). After the overnight rest, cells will be counted, assessed for viability 
and recovery, then aliquoted for flow cytometry assays. Flow cytometry assays will be performed following 
standardized/optimized SOPs. For efficiency and to minimize assay variability, all visits from a single patient 
will be assayed in the same batch. To assess variability across assays, cells from a normal donor (drawn, 
processed and cryopreserved from a  single visit), will be used as a control across all assay batches 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
58
 
Table 7: Markers for Lymphoid Cells to be Evaluated. Lymphoid markers that 
may be detected by flow cytometry are shown. There will also be 2 
additional markers included to be determined. The final panels will be 
determined based upon the best science at the time these analyses are 
performed. 
 
Marker 
Stain 
Purpose 
Fixable Live/Dead Cell Stain 
Surface 
Dead cell exclusion 
CD3 
Intracellular 
T cells 
CD4 
Intracellular 
Helper T cells 
CD45RO 
Surface 
Maturation 
CD38 
Surface 
Activation 
CD278 (ICOS) 
Surface 
Activation 
FoxP3 
Intranuclear 
Regulation 
CD25 
Surface 
Regulation, Activation 
Tim‐3 
Surface 
Regulation, Activation 
CD152 (CTLA‐4) 
Intracellular 
Regulation 
IDO 
Intracellular 
Apoptosis, Regulation (tryptophanase) 
CD223 (LAG‐3) 
Surface 
Exhaustion 
CD279 (PD‐1) 
Surface 
Exhaustion 
Additional Marker #1 
TBD 
TBD based on most recent literature or scientific results at time of 
analysis 
Additional Marker #2 
TBD 
TBD based on most recent literature or scientific results at time of 
analysis 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
59
 
 
Table 8: Markers for Myeloid Cells to be evaluated. Myeloid markers that may be detected by flow 
cytometry are shown. There will also be 2 additional markers included to be determined. The final 
panels will be determined based upon the best science at the time these analyses are performed. 
 
Marker 
Stain 
Purpose 
Fixable Live/Dead Cell Stain Surface 
Dead cell exclusion 
Lineage (CD3, CD14, CD16, 
CD56, CD19, CD20) 
Surface 
Exclusion gate to identify MDSC 
CD11b 
Surface 
MDSC 
CD33 
Surface 
MDSC 
HLA‐DR 
Surface 
MDSC, DC 
CD123 
Surface 
DC 
CD11c 
Surface 
DC 
CD304 (BDCA‐4) 
Surface 
pDC (neuropilin‐1) 
CD86 
Surface 
M1 (co‐stimulatory for T cell activation) 
CD163 
Surface 
M2a, activation(hemoglobin‐haptoglobin scavenger receptor) 
CD206 
Surface 
M2a (mannose receptor) 
CD16 
Surface 
M1 (FcγRIII) 
CD68 
Intracellular 
M1 (macrosalin) 
Additional Marker #1 
TBD 
TBD based on most recent literature or scientific results at time of 
analysis 
Additional Marker #2 
TBD 
TBD based on most recent literature or scientific results at time of 
analysis 
 
Circulating Protein Analysis 
Plasma samples will be obtained from all subjects at baseline (cycle 1 day 1), at first imaging, and at disease 
progression on study therapy. Plasma will be isolated within 2 hours of  collection and stored at ‐80°C until 
analyzed. The Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew Nixon has developed a 
multiplex ELISA approach to analyze 24 inflammatory and angiogenic growth factors (termedthe Angiome) 
in less than 1.0 ml of plasma. Coefficients of variation for all analytesare 
<10%. Our group has pioneered the analysis of blood‐ based inflammatory and angiogenesis factors and is 
one of the largest and most experienced academic laboratories in the world at performing multiplex 
protein analyses in cancer patients on clinical trials. 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
60
We have applied our Angiome multiplex array to dozens of Phase I‐III studies conducted by the National 
Cancer Institute’s early and late stage clinical trials networks (ET‐CTN and NCTN), pharma, biotech, and 
other investigator‐initiated trials that we have organized.33‐35 The Angiome multiplex array (Table 9) has 
already gone through a rigorous evaluation to ensure data quality and last year, we were approved by the 
NCI Biomarker Review Committee (BRC) to incorporate our Angiome panel as an integrated biomarker in 
more than 14 trials, including the ongoing NRG studies, GY‐004 and GY‐ 005, evaluating the combination of 
cedarinib andolaparib. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
61
Table 9: Angiome multiplex array 
 
For the proposed study, analyte levels at baseline and changes in analyte levels along the continuum of care will 
be correlated with clinical outcome(ORR, PFS, OS). In addition, longitudinal samples will be evaluated for key 
pharmacodynamic changes that occur in response to therapy. In addition to performing the Angiome analysis, 
plasma willalso be evaluatedby ELISAfor protein markers that may be associated with sensitivityor resistance 
to atezolizumab. These may include measurement of soluble checkpoints (i.e., PD1, PDL1, PDL2) as well as CRP 
and other markers of inflammation, including but not limited to IFNγ, IL1β, IL4, IL6, IL7, IL10, IL12, IL17A, IL17E, 
and IL23. 
 
8 EARLY STUDY TERMINATION 
 
This study can be terminated at any time for any reason by the PI‐sponsor. If this occurs, all subjects on study 
should be notified as soon as possible. 
 
9 STUDY THERAPIES PHARMACY MANAGEMENT 
9.1 Atezolizumab and bevacizumab 
 
The atezolizumab 1200 mg drug product will be supplied. . Eur. Type 1 glass vial as acolorless to slightly yellow, 
sterile, preservative‐free clear liquid solution intended for IV administration. The vial is designed to deliver 
20 mL (1200 mg) of atezolizumab solution but may contain more than the stated volume to enable delivery 
of the entire 20‐mL volume. 
 
Bevacizumab drug product will be supplied. Bevacizumab is manufactured by recombinant DNA technology, 
using a genetically engineered Chinese hamster ovary (CHO) cell line. The protein is purified from the 
cellculture 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 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
62
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, andsterile waterfor injection (SWFI). Vials contain no preservative and are suitable for single 
use only 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
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9.2 Packaging and Labeling 
 
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory guidelines. 
The labels will fulfill Good Manufacturing Practice Annex 13 requirements for labeling. The label will include 
the Name of the Sponsor, Study Code, For Clinical trial use only and /or any other market specific 
requirements. All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the pack specifies the appropriatestorage. 
9.3 Supply, Receipt, and Storage 
 
Atezolizumab and bevacizumab will be provided by Genentech/Roche free of charge and will be ordered 
through the research pharmacy. Both atezolizumab and bevacizumab receipt and storage should be per 
standard institutional practice and consistent with the package insert. 
 
9.4 Dispensing and Preparation 
 
The atezolizumab and bevacizumab will be prepared and dispense as per package insert and institutional 
practice Please refer to the atezolizumab and bevacizumab package inserts and IB for additional details. 
 
9.5 Compliance and Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful record of 
the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another 
comparable drug accountability form. (Refer tothe NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
9.6 Disposal and Destruction 
 
Unused atezolizumab and bevacizumab will returned to the research pharmacy for disposal as per 
institutional standards. 
 
10 SCREENING AND ON‐STUDY TESTS AND PROCEDURES 
 
Both atezolizumab and bevacizumab are approved for the treatment of NSCLC. The time and events table 
reflectsstandard of care testing associated with each of the agents, and imaging for response is performed at 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
64
intervals and using modalities consistent  with standard of  care. Investigators can perform additional  testing if in his 
or her clinical judgement it is indicated. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
65
10.1 Schedule of time and events table (Table 9) 
 
Tests and Procedures 
Active Monitoring Phase 
Screening 
≤ 28 days prior 
to starting study 
therapy5 
Day 1 of 
each 
cycle14 
Re-staging every 
3 cycles for 17 
cycles (1 year) 
from cycle 1 day 
1 then every 6 
cycles until 
disease 
progression 
End of treatment (EOT) 
(28 days after the last 
treatment) 4 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Demography & Medical History 
including prior therapies and 
smoking history 
X 
Local documentation of EGFR 
exon 19 deletion or exon 21 L858R 
and histology 
X 
ECOG PS 
X 
X 
X 
Physical Exam including weight, 
blood pressure, temp, P, O2 sat5 
X 
X 
X 
Adverse event assessment 
X 
X9 
X 
Prior/concomitant medications 
X 
X 
X 
Urine protein creatinine ratio 
X 
X12 
Hematology: CBC/ differential8 
X 
X8 
X 
PT/INR, PTT6 
X6 
Chemistry: SGOT (AST), SGPT 
(ALT), alk phos, T. bili, creatinine 
X 
X 7 
X 
TSH10 
X 
X10 
Tumor measurement 3 
X 
X3 
X 
MRI or CT scan of brain11 
X 
X11 
Pregnancy test1 
X1 
X1 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
66
Research Blood sample2 
X2 
X 
Tissue sample (if available) 13 
X 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
67
1. For women of childbearing potential only. Must be done ≤ 7 days prior to starting therapy. Then day 
1 of each cycle or per institutional guidelines 
2. Research blood sample should be drawn at 3 time points: baseline (cycle 1 day 1), at time of first 
imaging (9 weeks), and at time of disease progression on study therapy. Kits are required for this 
collection. Research blood sample to be drawn prior to treatment. Samples should be drawn at time 
of disease progression if disease occurs on a visit not associated with planned tumor imaging 
3. Patients should undergo imaging with CT chest and abdomen for disease progression every 3 cycles 
for the initial 17 cycles (1 year) then every 6 cycles until disease progression. Tumor measurements 
should be done < 28 days prior to starting study therapy. Patients who discontinue study therapy 
prior to disease progression should be followed with imaging until disease progression. The schedule 
of follow‐up imaging is at the discretion of  physician,  but an interval of 6 to 12 weeks is 
recommended 
4. All patients (including those who have left the study because of progressive disease, unacceptable 
toxicity, patient refusal, investigator’s decision to remove patient, etc.) should have an end of 
treatment visit. However, if it is not feasible due to decline in performance status, patient has 
initiated another therapy, or patients is being treated at another center patient can be exempted 
for the visit. This study visit can occur +/‐ 3 days due to patient convenience and travel 
5. Baseline/screening assessments are to be performed ≤ 28 days prior to starting study therapy unless 
otherwise specified. 
6. PT/INR, PTT required at baseline  
7. Only SGOT (AST), SGPT (ALT), alk phos, T. bili, and creatinine checked on Day 1 of each cycle forfirst 4 cycles, and 
then every other cycle. More intensive monitoring per investigator discretion or institutional practice. 
8. CBC required at baseline then day 1 of cycles 1‐4, then every other cycle and as clinically indicated, 
at the discretion of the investigator or institutional practice. 
9. Prior to subsequent cycle. 
10. TSH should be check every 3 cycles. Additional testing at the discretion of the investigator or per 
institutional standard 
11. MRI is the preferred test for imaging for brain metastases, CT scan with contrast is acceptable for 
patients who are unable or intolerant of undergoing MRI of the brain. Patients must have either 
MRI or CT scan prior to starting study therapy. MRI and CT scans should be  done  < 28 days prior to 
start of study therapy. Patients with untreated brain metastases should undergo repeat imaging 
every 12 weeks or sooner if clinically indicated to assess disease status. Patients without brain 
metastases or treated brain metastases can undergo repeat imaging at the discretion of the 
investigator or per institutional practice 
12. Urine protein/creatinine ratio should be checked on every 3 cycles. 
13. Biopsy tissue obtained < 60 days after disease progression on osimertinib and before day 1 of study 
therapy (if available). There are no specific requirements related to the biopsy 
14. The study visits can occur +/‐ 3 days to accommodate holidays, travel schedule, family events, etc. 
as necessary 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
68
10.2 Screening Examination 
 
The following procedures and tests are to be performed < 28 days prior to starting study therapy to 
confirm eligibility (unless otherwise specified). Baseline and Cycle 1 Day 1 procedures may be completed 
on the same day, however, screening assessments to confirm eligibility MUST have already been 
determined. Informed consent is to be obtained before any screening procedures are performed. If 
laboratory or imaging procedures were performed for  alternate reasons prior  to signing consent, these 
may be used for screening purposes  with consent  of patient. Refer to Time and events table for details. 
1. Informed consent 
2. Review of past medical history and previous therapies for NSCLC 
3. Eligibility criteria review (Inclusion/exclusion) 
4. Baseline characteristics, smoking history 
5. A directed physical examination will be performed at the visit with vital signs including pulse, 
blood pressure, temperature, oxygen saturation, weight 
6. ECOG Performance status 
7. Routine blood work (CBC, chemistries) and PT/INR and PTT as clinically indicated 
8. Urine protein/creatinine ratio 
9. Thyroid stimulating hormone 
10. Pregnancy test if applicable 
11. Tumor Histology 
12. EGFR mutation status 
13. Review of baseline sign/symptoms 
14. Review of concomitant medications 
15. Disease assessment: Brain MRI, CT scan of chest and abdomen 
10.3 On study treatment period: Day of each cycle as noted in time and events table 
 
1. Review of interval medical history, concomitant medications and assessment of performance 
status 
2. A directed physical examination will be performed at the visit with vital signs including pulse, 
blood pressure, temperature, oxygen saturation, weight 
3. Laboratory: chemistry, and hematology.  
4. Thyroid stimulating hormone every 3 cycles. Additional testing as clinically indicated or as per institutional 
standard 
5. Urine protein/creatinine ratio  every 3 cycles. 
6. MRI of the brain to be performed with every 12 weeks in patients with known and untreated brain metastases 
to assess for intracranial disease progression. Patients without brain metastases or treated brain metastases 
will undergo repeat brain imaging as clinically indicated or per institutional standard. 
7. CT Chest/abdomen every 3 cycles for the first 17 cycles (approximately 1 year) and then every 6 cycles until 
disease progression. 
8. Adverse event assessment 
9. Pregnancy test (if applicable) 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
69
10. Research blood sample baseline (cycle 1day 1), at time of first imaging (9 weeks) and at time of disease 
progression on study therapy in provided kits 
11. Research blood sample at time of disease progression in provided kit 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
70
10.4 End of Study Treatment 
 
1. Review of interval medical history since the last visit and assessment of performance status 
2. A directed physical examination will be performed at the visit with vital signs including pulse, 
blood pressure, temperature, oxygen saturation, weight 
3. Laboratory: chemistry and hematology 
10.5 Follow‐up Period 
 
After discontinuing study therapy patients will be followed for overall survival every 3 months by telephone 
or review of medical records until death or a maximum of 2 years from completion of study therapy. 
Subsequent therapy and survival status will be documented. If molecular testing performed (e.g. molecular 
testing of tumor biopsy or circulating tumor DNA) as part of standard of care the results of the testing will 
be recorded if available.  
Patients who discontinue therapy for reasons other than disease progression will be followed for disease 
progression even if patient starts on new treatment. The imaging schedule is at the discretion of the 
treating physician, but the recommended interval is every 6 to 12 weeks. For patients not returning to the 
treatment center the assessment of disease progression will be based on interpretation of radiographic 
report by the investigator. 
Investigators should report SAE’s that are attributed to the study treatment for 100 days after the last dose 
of study therapy. 
10.6 End of Study 
 
The end of study will be defined as the time at which all patients have discontinued study therapy and study 
report is accepted for publication. 
10.7 Early Withdrawal of Subject(s) 
 
10.7.1 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject 
from the study at any time based on his/her discretion. Reasons for PI‐initiated withdrawal may 
include, but is not limited to the following: 
− 
Subject or legal representative withdraws consent 
− 
Confirmed radiographic disease progression 
− 
There is toxicity deemed by the investigator or subject to be unacceptable 
− 
Concurrent illness that prevents further administration of treatment 
− 
The subject, for any reason, requires treatment with another systemic agent potentially 
effective for treatment of the study indication. In this case, discontinuation from the study 
occurs immediately upon introduction of the new agent 
− 
Noncompliance with trial treatment or procedure requirements 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
71
− 
Abnormal laboratory values 
− 
Abnormal test procedure results 
− 
Protocol deviation 
− 
Administrative issues 
− 
Pregnancy 
− 
Subject is lost tofollow‐up 
− 
The investigator for any reason, stops the study 
− 
Termination of the study by Genentech/Roche 
− 
If the atezolizumab is held for ≥ 12 weeks the patient should discontinued from study 
therapy. 
If the bevacizumab is held ≥ 12 weeks the patient should discontinue study therapy. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
72
 
10.7.2 Follow‐up Requirements for Early Withdrawal 
Patients who do not start study drug will not have any study follow‐up requirements. Patients who 
discontinue therapy for reasons other than disease progression will be followed for disease progression 
every 6‐12 weeks at the discretion of the treating physician. Once patient stops study therapy they will 
be followed for overall survival every 3 months by telephone or by review of medical records for a 
maximum of 2 years. 
 
10.7.3 Replacement of Early Withdrawal(s) 
Patients who do not start study drug will be replaced and will be considered non‐evaluable. They 
will be classified as “consented but not treated.” 
 
11 SAFETY MONITORING AND REPORTING 
 
The PI is responsible for the identification and documentation of adverse events and serious adverse  events, 
as defined below. At each study visit, the PI or designee must assess, through non‐suggestive inquiries of the 
subject or evaluation of study assessments, whether an AE or SAE has occurred. Adverse events that are 
judged to be Serious Adverse Events by the institutional PI are to be reported to the Duke Cancer Institute 
Safety Desk for Reporting Procedures for Adverse Events and Serious Adverse Events by Participating Sites. 
11.1 Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does 
not necessarily have a causal relationship  with this treatment. For this protocol, the  definition of AE also 
includes worsening of any pre‐existing medical condition. An AE can therefore be any unfavorable and 
unintended or worsening sign (including an abnormal laboratory finding),  symptom, or disease temporally 
associated with the use of study drug, whether or not related to use of the study drug. Abnormal laboratory, 
physical exam, or vital sign findings without clinical significance (based on the provider judgment) should not 
be recorded as AEs 
 
AEs will be documented from the date of first dose of study drug through 28days after the last dose of study 
drug. All grade 1‐5 AEs as well as special reporting circumstances, such as exposure via a parent during 
pregnancy or breast feeding, overdose, medication error, misuse, abuse, off‐label use or occupational 
exposure must be recorded in theCRF. 
 
AEs will be assessed according to the CTCAE version 4.03. If CTCAE grading does not exist for an AE, the 
severity of the AE will be graded as mild (1), moderate (2), severe (3), life‐threatening (4), or fatal (5). 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
73
 
Attribution of AEs will be indicated as follows: 
− 
Definite:  The AE is clearly related to the study drug 
− 
Probably:   The AE is likely related to the study drug 
− 
Possible: The AE may be related to the study drug 
− 
Unlikely: The AE is doubtfully related to the study drug 
− 
Unrelated: The AE is clearly NOT related to the study drug 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
74
Reporting of AEs 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case 
report forms. AEs reported through expedited processes (e.g., reported tothe IRB, FDA, etc.) must also be 
reported in routine study data submissions. 
Abnormal laboratory results are to be recorded as AEs if any of the following conditions are met: 
 
• 
The abnormal laboratory value leads to a therapeutic intervention (e.g. corrective therapy). 
• 
The abnormal laboratory value is considered to be clinically significant by the Investigator. 
• 
Any lab test result that is clinically significant or meets the definition of an SAE. 
• 
Any laboratory test result abnormality that required the subject to have study treatment 
discontinued or interrupted 
 
11.2 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
 
1) Results in death (i.e., the AE actually causes or leads to death). 
2) Is life‐threatening (i.e., in the opinion of the Investigator, the AE places the subject at immediate 
risk of death; it does not include a reaction that, had it occurred in a more severe form, might have 
caused death). 
3) Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
4) Results in persistent or significant disability or incapacity. (Note: The term “disability” refers to 
events that result in a substantial disruption of a subject’s ability to conduct normal life function.) 
5) Is a congenital anomaly or birth defect  in a neonate/infant born to a mother exposed to the study  
therapy 
6) Is an important medical event (Note: The term “important medical event” refers to an event that, 
based upon appropriate medical judgment, may not be immediately life‐threatening or result in 
death or hospitalization, but may jeopardize the subject or require intervention to prevent one of the 
other serious outcomes listed under the definition of SAE. Examples of important medical events 
include intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias, or convulsions that do not result in hospitalization; or development of product dependency 
or product abuse.) 
 
Methods and timing for assessing and recording safety variables  
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in accordance 
with CFR 312.32 (IND Safety Reports). 


CONFIDENTIAL 
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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
75
Adverse Event Reporting Period 
The study period during which AE’s and SAEs and/or follow up to SAEs including death due to any cause 
other than progression of the cancer under study, that occurs from the date of the first dose of study drug 
through 28 days following the last dose of study drugs (atezolizumab and bevacizumab), whether or not 
related to study drug(s), must be recorded on the CRF and must be reported within 24 hours to DCI Safety 
Desk and within 2 working days to supporting companies. After the 28 day period, investigators should 
report SAE’s that are attributed to the study treatment for 100 days after the last dose of study therapy. 
All SAEs must be followed until resolution, return to baseline condition, or stabilization. Any SAEs that are 
ongoing at the time the clinical database is closed will be reported to supporting companies as unresolved. 
 
All adverse events (AEs)/Serious Adverse Events (SAE’s), AEs of Special Interest (AESIs), Special Situation 
Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the 
Study for the Product will be sent to DCI Safety Desk.  
 
Events which are unequivocally due to disease progression should not be reported as an AE during the study. 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered an SAE 
 
Assessment of adverse events  
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, or 
detected through physical examination, laboratory test, or other means will be reported appropriately. Each 
reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if 
applicable, suspected relationship to the atezolizumab and bevacizumab (see following guidance), and actions 
taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the following general 
guideline: 
 
Yes (Definite, Probably, Possible, Unlikely) 
 
There is a plausible temporal relationship between the onset of the AE and administration of the atezolizumab 
and bevacizumab, and the AE cannot be readily explained by the subject’s clinical state, intercurrent illness, or 
concomitant therapies; and/or the AE follows a known pattern of response to the atezolizumab and 
bevacizumab or with similar treatments; and/or the AE abates or resolves upon discontinuation of the 
atezolizumab and bevacizumab or dose reduction and, if applicable, reappears upon re- challenge. 
 
No (not related) 
 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
76
Evidence exists that the AE has an etiology other than the atezolizumab and bevacizumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no 
plausible temporal relationship to atezolizumab and bevacizumab administration (e.g., cancer diagnosed 2 
days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package Insert (P.I) or 
current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This includes adverse 
events for which the specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated hepatic 
enzymes or hepatitis. 
 
 
Procedures for eliciting, recording, and reporting adverse events  
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. Examples of 
non-directive questions include: 
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid colloquialisms 
and abbreviations. 
 
a.   Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, it is acceptable to report the information that is currently available. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
 
b.   Deaths 
 
All deaths that occur during the protocol-specified AE reporting period, with the exception of disease progression, 
will be reported to the appropriate parties. When recording a death, the event or condition that caused or 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
77
contributed to the fatal outcome should be reported as the single medical concept. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, report “Unexplained Death”. 
 
c.   Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such conditions should be reported 
as medical and surgical history. A preexisting medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study. 
When reporting such events, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., “more frequent headaches”). 
 
d.   Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE. 
If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible 
for the procedure, not the procedure itself, should be reported as the SAE. For example, if a subject is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting 
conditions 
 • Hospitalization for < 24 hours (observation admissions)  
` 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study o 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study 
 
 
 
e.   Assessment of Severity of Adverse Events 
 
 
  
The adverse event severity grading scale for the NCI CTCAE version 4.03 will be used for assessing adverse event 
severity. Below Table should be used for assessing severity for adverse events that are not specifically listed in 
the NCI CTCAE. 
 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
 
Grade 
Severity 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
78
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v 4.03)   
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event  
d. Grade 5 events must be reported as serious adverse events  
 
f. Pregnancy 
 
If a female subject or female partner of a male study subject becomes pregnant while receiving the study drug 
or within 6 months after the last dose of study drug, a report should be completed and expeditiously submitted 
to Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to the study drug 
should be reported as an SAE. 
 
 
Reporting of SAEs 
SAEs, deaths, and grade 4 unknown reactions or unexpected events that occur in the course of any patient’s 
treatment on study (from the time of enrollment) or within 28 days following cessation of study treatment are 
reportable. All sites will complete DCI SAE Report Form and Page 1 of the DCI Safety Review Form. 
 
Sub‐sites will submit both forms to the DCI Safety Desk (Fax #: 919‐681‐9357 or email dcccsafe@dm.duke.edu) 
and to the Lead PI, Dr. Stinchcombe Fax: 919‐684‐5163 and Thoracic‐ multisite@dm.duke.edu). 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
79
 
Note: It is imperative that initial SAE reports are submitted as soon as possible (within 24 hours of knowledge of the event) 
with available information to the DCI Safety Desk. Missing and/or clarified event information may be provided in a follow‐up 
report. 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
80
 
 
If the safety desk cannot be reached within 24 hours, the Duke PI, Dr. Thomas 
Stinchcombe, should be contacted (thomas.stinchcombe@duke.edu, Pager (919) 
970‐ 2829, Office: (919) 681‐ 9509. 
 
The initial report for each SAE or death should include at minimum the following information: 
• 
protocol (TOP 1901) 
• 
patient initials, study identification number, sex, age 
• 
date the event occurred 
• 
description  of the event 
• 
study drug name(s) 
• 
dose level and cycle number at the time the event occurred 
• 
description of the patient’s condition 
• 
indication whether the patient remains on study 
• 
event causality or causal relationship 
• 
responsible investigator name and contact details 
De‐identified source documentation (i.e. admission notes, discharge notes, applicable laboratory results, 
radiology/diagnostic testing results, etc.) must be sent with the DCI SAE Report Form. Follow‐ up information 
including severity, action taken, concomitant medications, and outcome should be communicated to DCI 
Safety Desk as soon as possible using the same formsmentioned above. 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
SAE Reporting Procedure for Lead PI and DCI Safety Desk 
Duke as the lead center is responsible for reporting the serious adverse event to the FDA in accordance with 
21CFR 312.32. Any SAE that is possibly related and unexpected must be submitted to the FDA. This will be 
done by DCI Safety Desk and/or coordinate with study team regulatory coordinator. 
 
Reporting SAEs at participating institutions 
Each site is responsible for reporting unexpected and/or serious adverse events to their individual IRB 
according to their institutional guidelines. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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Expedited Reporting Procedure for Duke Cancer Institute (Coordinating Center) 
Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs to the FDA 
in accordance with 21CFR 312.32. Any SAE that is possibly related and unexpected must be submitted to the 
FDA. If the SAE meets criteria for reporting to the FDA, the DCI Safety Desk will complete the Form FDA 
3500A (MedWatch) and send to the Principal Investigator and the Sponsor that are noted above. This 
submission of the Form FDA 3500A to the FDA will be completed by the designee. 
 
• 
All unexpected, drug related SAEs that are fatal or life‐threatening will be reported to the FDA 
by phone or fax within 7 calendar days of initial receipt of the information and will provide a 
complete report within 8 days of the initial report submission (by calendar day 15). 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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And Duke Cancer Institute will be responsible for the distribution of safety information to 
Site IRB: 
The Duke Safety Desk will complete Form 3500A (21CFR 312.32) as needed.  
 
Duke Safety Desk Contact Information: 
DCI Safety Desk:  Fax (919) 681-9357;   email dcccsafe@dm.duke.edu.  
With a copy being sent to:  (919) 660-9246 or (insert coordinator email here) 
External Site(s): Refer to Study Manual 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
REPORTING SAEs to Genentech 
The Duke Safety Desk will be responsible for reporting Adverse Events (AEs)/Serious Adverse Events (SAEs), 
AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product 
Complaints (with or without an AE) originating from the Study for the Product.  
 
Investigators/Duke Safety Desk must report all the above mentioned single case reports adequately to 
Genentech within the timelines described below. The completed MedWatch reporting forms should be 
faxed/emailed immediately upon completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product 
Complaints should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, AESIs, 
Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) 
originating from the study.  
 
These single case reports will be exchanged between the parties as outlined below so that regulatory 
obligations are met. 
 
SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15) 
calendar days of the awareness date. 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty (30) 
calendar days of the awareness date. 
 
AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. 
 
Special Situation Reports 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined herein, any 
reports of pregnancy (including pregnancy occurring in the partner of a male study subject), where the 
fetus may have been exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar 
days of the awareness date. Pregnancies will be followed up until the outcome of the pregnancy is known, 
whenever possible, based upon due diligence taken to obtain the follow-up information. 
 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 30 days after the last dose of 
study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and submitted to Genentech 
within thirty (30) calendar days of the awareness date. 
• 
Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports should 
be collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30) 
calendar days: 
• 
Data related to the Product usage during breastfeeding 
• 
Data related to overdose, abuse, misuse or medication error (including potentially exposed or 
intercepted medication errors) 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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• 
In addition, reasonable attempts should be made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population 
 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen (15) 
calendar days of the awareness date. 
 
A Product Complaint is defined as any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or 
performance of a product after it has been released and distributed to the commercial market or clinical 
trial. 
 
Case Transmission Verification of Single Case Reports 
The Investigator-Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via Investigator-Sponsor  emailing Genentech a 
Quarterly line-listing documenting single case reports sent by Investigator-Sponsor  to Genentech in the 
preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time 
period. Confirmation of receipt should be received within the time period mutually agreed upon. 
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. 
The responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory 
resolution.  The sponsor shall receive reconciliation guidance documents within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which have not been received by Genentech 
shall be forwarded by Investigator-Sponsor to Genentech within five (5) calendar days from request by 
Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech 
 
 
Duke Safety Desk Contact Information 
DCI Safety Desk: Fax (919) 681‐9357; email dcccsafe@dm.duke.edu. 
With a copy being sent to: Dr. Stinchcombe fax (919) 660‐9246 and scanned to 
Thoracic‐multisite@dm.duke.edu 
External Site(s): Refer to Safety packet 
 
11.3 Adverse Events of Special Interest 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for 
which ongoing monitoring  and rapid communication by  the Investigator to the Sponsor  is required. Such an 
event might require 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., Regulatory Authorities) 
may also be warranted. The following AEs are considered of special interest and must be reported to the 
Genentech Drug Safety expeditiously, irrespective of regulatory seriousness criteria: 
 
Immediately upon awareness of an AESI, the Investigator (or designee) completes the DCI SAE Report 
Form and Page 1 of the DCI Safety Review Form and will submit both forms within 24 hours of 
knowledge of the event to DCI Safety Desk (contact information is above). 
 
Note: It is imperative that initial AESI reports are submitted as soon as possible (within 24 hours of 
knowledge of the event) with available information to the DCI Safety Desk. Missing and/or clarified event 
information may be provided in a follow‐up report. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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De‐identified source documentation (i.e. admission notes, discharge notes, applicable laboratory results, 
radiology/diagnostic testing results, etc.) must be sent with the DCI SAE Report Form. 
Follow‐up information including severity, action taken, concomitant  medications,  and  outcome should be 
communicated to DCI Safety Desk as soon as possible using the same forms mentioned above. 
 
ECI Reporting Procedure for DCI Safety Desk: 
The Lead PI will review the report form with accompanying source document, complete Page 2 of the DCI 
Safety Review Form and promptly submit it to the DCI Safety Desk. 
Within two business days of receipt, the DCI Safety Desk will also submit the SAE report form and 
other relevant safety information to the following supporting company: 
 
Genentech/Roche Drug Safety: 
Fax: 650‐238‐6067 
Email: usds_aereporting‐d@gene.com 
 
Events of Special Interest are 
• Cases of potential drug‐induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and based on the 
following observations: 
• Treatment‐emergent ALT or AST > 3 x ULN (or > 3 X baseline value in disease states where LFTs 
may be elevated at baseline) in combination with total bilirubin > 2 X ULN (of which ≥ 35% is direct 
bilirubin) 
• Treatment‐emergent ALT or AST > 3 X ULN (or > 3 x baseline value in disease states where LFTs 
may be elevated at baseline) in combination with clinical jaundice 
• Suspected transmission of an infectious agent by the study treatment, as: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non‐pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or  laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only when a contamination of 
study treatment is suspected. 
• Systemic  lupus erythematosus 
• Events suggestive of hypersensitivity, infusion‐related reactions, cytokine release syndrome, 
macrophage activating syndrome, hemophagocytic lymphohistiocytosis  
• Nephritis 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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• Ocular toxicities (e.g. uveitis, retinitis, optic neuritis) 
•Grade ≥ 2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis) 
• Vasculitis 
• Autoimmune hemolytic anemia 
• Severe cutaneous reactions (e.g., Stevens‐Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
 
 
Development Safety Update Report 
 
Duke Cancer Institute, as the Sponsor of the Study, will be responsible for the preparation of their own Development 
Safety Update Report (DSUR) for the Study and for the submission of the report to the regulatory authorities and Ethics 
Committees of the concerned Member States, where applicable. Duke Cancer Institute, agrees to share a copy of their 
own DSUR with Genentech as soon as reasonably possible after completion.  
Genentech agrees to forward to Duke Cancer Institute an executive summary of the Genentech DSUR upon request. 
Furthermore, Genentech agrees that Duke Cancer Institute may cross-reference the executive summary of the 
Genentech/Roche DSUR, as applicable 
 
 
Other Reports 
Events which are unequivocally due to disease progression should not be reported as an AE during the 
study. 
 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered an 
SAE. 
11.4 Safety Oversight Committee (SOC) 
 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor‐ 
investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety 
Monitoring Board (DSMB). These reviews occur at a minimum annually and more frequently for the high risk 
studies. The SOC safety reviews include review of safety data, enrollment status, stopping rules if 
applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor‐
investigator. The SOC, at a convened meeting, assigns a rating of satisfactory when adequate accrual with 
lack of excessive toxicity is present. The SOC in concert with the DCI Monitoring Team oversees the conduct 
of DUHS cancer‐related, sponsor‐investigator greater‐than‐minimal‐risk intervention studies that do not  
have an external monitoring  plan, ensuring  subject  safety and that the protocol is conducted, recorded 
and reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice 
(GCP), and applicable regulatory requirements. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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11. 5 QUALITY CONTROL AND QUALITY 
ASSURANCE Monitoring 
This clinical research study will be monitored both internally by the PI, and institutionally by the Duke Cancer 
Institute (DCI). In terms of internal review the PI will continuously monitor and tabulate adverse events. Appropriate 
reporting to the Duke University Medical Center IRB will be made. If an unexpected frequency of Grade III or IV 
events occur, depending on their nature, action appropriate to the nature and frequency of these adverse events will 
be taken. This may require a protocol  amendment, dose  de‐escalation,  or  potentially closure of the study. The PI of 
this study  will also continuously  monitor  the conduct,  data, and safety of this study to ensure that: 
 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over‐accrual does not occur; 
• 
Under‐accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
 
DCI Protocol Review and Monitoring systems (PRMS) review of this protocol begins with an initial review by the 
Cancer Protocol Committee (CPC). CPC new protocol review focuses on scientific relevance, study design, adequacy of 
biostatistical input, protocol prioritization, feasibility of completing the study within a reasonable time frame and risk 
assessment of the trial. The PI will abide by CPC assessment of the level of risk, which will determine the intensity of 
subsequent DCI monitoring. CPC also conducts annual scientific progress reviews on protocols that are open to 
enrollment and focus on protocol prioritization, accrual and scientific progress. 
These reviews are conducted at the time of IRB annual renewals and documentation of all CPC reviews will be 
maintained in eIRB/iRIS systems. 
 
A determination for the degree of monitoring conducted by the DCI monitoring team is made at the time of initial 
CPC approval to commensurate with the type and level of intervention, phase, endpoints, degree of risk, size and 
complexity of the protocol. A formal, independent monitoring will be conducted by the DCI monitoring team 
according to the risk level and monitoring plan assigned by the CPC until the study is closed to enrollment or subjects 
are no longer receiving study drug or other interventions that are more than minimal risk. 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or 
unexpected toxicities, or other concerns. Monitoring visits may also be initiated upon request by DUHS and DCI 
Leadership, CPC, SOC, a sponsor, an investigator, or the IRB. 
 
The DCI monitoring team reviews the adequacy of informed consent, enrollment of eligible patients, implementation 
of protocol‐specified procedures and treatment, adequacy of data collection, and appropriateness of adverse event 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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monitoring and reporting. The DCI monitoring team presents final monitoring reports to the DCI Safety Oversight 
Committee (SOC) highlighting safety concerns and unresolved issues. The SOC, at a convened meeting, assigns an 
overall rating of satisfactory, marginal, or unsatisfactory to reflect the overall quality of data, regulatory, consent, 
eligibility, study conduct and AE reporting. Corrective action plans (CAPs) are developed, implemented, and evaluated 
as indicated. The SOC will  notify  the sponsor‐investigator and DUHS IRB when significant safety concerns are 
identified. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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90
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and 
DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, 
the Principal Investigator, or the IRB. All study documents must be made available upon request to the DCI 
Monitoring Team and other authorized regulatory authorities, including but not limited to the National 
Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain 
confidentiality during study monitoring. 
 
Please refer to the study specific external site monitoring plan for monitoring sites external to the Duke 
University Heath System. 
 
Audits 
 
The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) may conduct confidential audits 
to evaluate compliance with the protocol and the principles of GCP. The PI agrees to allow the OARC 
auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study 
team to the OARC auditor(s) in order to discuss findings and any relevant issues. 
 
OARC audits are designed to protect the rights and well‐being of human research subjects. OARC audits may 
be routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared 
towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated 
Investigational Drugs or Devices, federally‐funded studies, high degree of risk (based upon adverse events, 
type of study, or vulnerable populations), Phase I studies, or studies that involve Medicare populations. 
Directed audits occur at the directive of the IRB or an authorized Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess whether 
the research is conducted according to the protocol approved by the DUHSIRB. The primary purpose of the 
audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of 
data produced by the clinical trial research are met. The audit/review will serve as a quality assurance 
measure, internal to the institution. Additional goals of such audits are to detect both random and systemic 
errors occurring during the conduct of clinical research and to emphasize “best practices” in the 
research/clinical trials environment 
 
Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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11.6 Data Management and Processing 
 
Case Report Forms (CRFs) 
The electronic CRF will be the primary data collection document for the study. The CRFs will be updated 
within two weeks of acquisition of new source data. The electronic records of subject data will be 
maintained using a dedicated database (Medidata Rave and/or Redcap) which is housed in an encrypted 
and password protected DCI file server. Access to electronic databases will be limited to the PI and 
designated stud staff listed on key personnel. Subject data may be stored temporarily on encrypted and 
password‐protected portable memory devices such as flash drives and external hard drives, but only when 
absolutely necessary. Data stored on portable memory deviced will be de‐ identified. Subject data will be 
deleted from the portable memory device at the earliest opportunity. The security and viability of the IT 
infrastructure will be managed by the DCI and/or Duke Medicine. Only approved study staff, are permitted 
to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system (Medidata Rave 
and/or Redcap). Designated personnel will complete user training, as required or appropriate per 
regulations 
 
Data Management Procedures and Data Verification 
 
Designated personnel using the electronic CRF will have access based on their specific roles in the protocol. 
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted 
to the presence of data inconsistencies. Additionally, the data manager and study coordinator and/or PI will 
cross‐reference the data to verify accuracy. Missing or implausible data will be highlighted for the PI requiring 
appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that data is 
not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries. An audit trail will be kept of all subsequent changes to the data. 
 
Study Closure 
 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and unused study drugs 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated laboratories 
 
Upon completion of the study, research records will be archived and handled per DUHS (or participating 
Institution’s) HRPP policy. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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12 STATISTICAL METHODS AND DATA   ANALYSIS 
 
All statistical analysis will be performed under the direction of the statistician designated in key personnel. 
Any data analysis carried out independently by the investigator must be approved by the statistician before 
publication or presentation. 
 
The primary objective of the single‐arm phase II trial is to determine objective response rate, defined as all 
patients with a confirmed partial or complete response as assessed by investigator using RECIST 1.1, among 
stage 4 NSCLC patients with EGFR mutations and who have progressed on osimertinib. Secondary objectives 
include (1) evaluation of progression‐free survival; (2) overall survival; and (3) adverse events due to the 
protocol treatments. 
. 
Sample Size and Study Design 
The single‐arm phase II trial is designed to test the following hypothesis about the anti‐tumor activity of the 
experimental therapy: 
H0: ORR <= 30% versus H1: ORR >= 50%, 
 
where ORR is the true ORR for the experimental therapy. We will use Simon’s minimax 2‐stage design to 
evaluate the ORR.36 The 2‐stage design allow a futility test after stage I patients has been evaluated for tumor 
response. The specific design described below is also the design that yields the smallest maximum sample 
size under the null hypothesis (minimax) among all designs satisfying type I error rate of 0.10 and type II error 
rate of 0.10. 
 
Specifically, the first stage will enroll 28 patients. If there are 7 or fewer patients confirmed responders 
(complete or partial response) among the 28 patients, the trial will be terminated; otherwise, the trial will 
move forward to enroll additional 11 patients. If 15 or fewer patients among the total of 39 patients are 
confirmed responders, the experimental therapy will be concluded as not worthy of further investigation; 
otherwise it will be conducted that the experimental therapy has sufficient activity worthy of further 
investigation. The above design has expected sample size 39 under the null hypothesis. The early stopping 
probability at stage I is 0.3648 under the null hypothesis. The actual type I and type II error rates are 0.0943 
and 0.0999, respectively. 
 
Statistical Analysis Methods 
Patient characteristics at baseline will be summarized in tables. Categorical data will be summarized using 
frequency tables while summary statistics such as means, medians, standard deviation, range, etc. will be 
provided for continuous data. 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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All enrolled patients, except for those withdrawn prior to study treatment or fail to receive study treatment 
for various reasons, will be included in the efficacy analysis. The primary endpoint will be objective response 
rate (ORR) per RECIST 1.1. Patients with confirmed partial or complete responses will be considered 
responders and patients without a confirmed partial or complete response will be considered non‐responders. 
Patients who stop therapy prior to confirmation of response per RECIST will be considered non‐responders. 
Patients who are not able to get radiographic assessment for all reasons will be considered non‐responders. 
At the end of the trial, the ORR will be  estimated using  the UMVUE method, and the p‐value and 95% 
confidence interval will calculated.37,38 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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Progression free survival (PFS) using RECIST 1.1 as assessed by the investigator. Progression will be defined as 
time from start of study therapy to disease progression or death (whichever occurs first). Patients who are 
not able to get radiographic assessment for all reasons will be considered disease progression at the time 
they discontinue protocol therapy for the PFS analysis. Patients who stop therapy for reasons other than 
disease progression will be followed for disease progression. Patients who have not experienced an event of 
interest by the time of analysis will be censored at the date  they are last known to be alive and progression‐
free. Overall survival (OS) is defined as the time from start of study therapy to death from any cause, and 
patients who are alive at the time of analysis will be censored at the last date of contact. Time to event 
endpoints will be summarized using the method of Kaplan and Meier as well. The association of baseline 
covariates with time to event endpoints will be evaluated by multivariable Cox regression models. Potential 
baseline covariates to include in the models are smoking history, mutation subtype, gender, and performance 
status. 
 
The evaluation of safety using the AE using NCI CTCAE version 4.03. All patients who receive at least one dose 
of  study treatment will  be  included in the safety analysis. The frequencies and percentage of treatment‐
related adverse events by type and grade will be tabulated. 
 
Immune and angiogenesis biomarkers will be measured with the samples collected at baseline and during 
treatment. The changes (mean, SD, etc) of these biomarkers relative to baseline will be summarized by 
collection time. The trajectory of the changes and the effects of baseline risk factors on the trajectorywill be 
evaluated in linear mixed models. The measures at baseline and their changes during treatment relative to 
baseline will be correlatedwith clinical outcomes using logistic regression for ORR and Cox egression for PFS 
and OS with starting time reset to collection time. 
 
Accrual and Follow‐Up 
Taking into 5% ineligibility/cancelation rate, we will enroll approximately 41 patients to have 39 evaluable 
patients for the efficacy analysis of the trial. At a rate of 1 to 2 patients per month, we expect that trial will 
take approximately 20‐41 months to reach its target of 39 evaluable patients if it will not be terminated 
earlier based on the planned interim analysis. All patients will be followed for disease progression from the 
date that the subjects started on the study until disease progressiony. Patients will be followed for overall 
survival until death or for a maximum 2 years from discontinuation of study therapy (whichever occurs first). 
 
Handling of missing values, censoring, and discontinuations 
Ineligible subjects and subjects who do receive any study therapy will not be included in the efficacy 
analyses. Patients who receive at least one dose of the experimental therapy will be included in the safety 
analysis. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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13 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
Regulatory and Ethical Compliance 
 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
 
DUHS Institutional Review Board and DCI Cancer Protocol Committee 
 
The protocol, informed consent form, advertising material, and additional  protocol‐related  documents must 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for 
review. The study may be initiated only after the Principal Investigator has received written and dated 
approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form. The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical  analysis, etc.). 
 
The Principal Investigator must obtain protocol re‐approval from the IRB within 1 year of the most recent 
IRB approval. The Principal Investigator must also obtain protocol re‐approval from the CPC within 1 year 
of the most recent IRB approval, for as long as the protocol remains open to subject enrollment. 
 
Informed Consent 
 
The informed consent form must be written in a manner that is understandable to the subject population. 
Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of 
the research, methods, potential risks and benefits, subject concerns, and other study‐ related matters. This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility 
of coercion. Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired. Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as needed 
to make an informed decision about participation in the study. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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Before conducting any study‐specific procedures, the Principal Investigator must obtain written informed 
consent from the subject or a legally acceptable representative. The original informed consent form will be 
stored with the subject’s study records, and a copy of the informed consent form will be provided to the 
subject. The Principal Investigator is responsible for asking the subject whether the subject wishes to notify 
his/her primary care physician about participation in the study. If the subject agrees to such notification, the 
Principal Investigator will inform the subject’s primary care 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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physician about the subject’s participation in the clinical study. 
 
Protocol Deviations and Violations 
 
A protocol deviation is non‐adherence to protocol specific study procedures or schedules that does not involve 
inclusion/exclusion criteria, primaryobjective evaluation criteria, and/or Good Clinical Practice (GCP) 
guidelines. 
A protocol violation is any significant divergence from the protocol such as non‐adherence on the part of the 
subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary objective 
evaluation criteria, and/or GCP guidelines. 
 
As a matter of policy, the Lead PI (i.e. sponsor) will not grant exceptions to protocol specific entry criteria to 
allow subjects to enter a study. If it is found that a subject who did not meet protocol eligibility criteria was 
entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke Thoracic Oncology Clinical 
Trials Office must be informed immediately. Such subjects will be discontinued from the study, except in an 
exceptional instance following review and written approval by the Lead PI and the responsible IRB/IEC. 
 
Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s) at 
the Duke Thoracic Oncology Clinical Trials Office. 
 
In accordance with applicable regulations, Investigators must report protocol deviations and violations to 
their local IRB/IEC according to their institutional guidelines. 
 
Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI‐mandated “Regulatory Binder”, which includes but 
is not limited to signed protocol and amendments, approved and signed informed consent forms, FDA 
Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source documents include but are not limited to hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x‐rays, subject files, 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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and records kept at the pharmacy, at the laboratories and at medico‐technical departments involved in the 
clinical trial. When possible, the original record should be retained as the source document. However, a 
photocopy is acceptable provided that it is a clear, legible, and an exact duplication of the original document. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
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The electronic CRF will be the primary data collection document for the study. The CRFs will be updated 
within two weeks of acquisition of new source data. The electronic records of subject data will be maintained 
using a dedicated database (Medidata Rave and/or Redcap) which is housed in an encrypted and password 
protected DCI file server. Access to electronic databases will be limited to the PI and designated stud staff 
listed on key personnel. Subject data may be stored temporarily on encrypted and password‐protected 
portable memory devices such as flash drives and external hard 
drives, but only when absolutely necessary. Data stored on portable memory deviced will be de‐ identified. 
Subject data will be deleted from the portable memory device at the earliest opportunity. The security and 
viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine. Only approved study 
staff, are permitted to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system (Medidata Rave 
and/or Redcap). Designated personnel will complete user training, as required or appropriate per 
 
Privacy, Confidentiality, and Data Storage 
 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained. Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site 
Based Researchgroup. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the 
course of the study. Prospective participants will be consented in an exam room where  it is just the research 
staff, the patient and his family, if desired. For all future visits, interactions with research staff (study doctor 
and study coordinators) regarding research activities will take place in a private exam room. All research 
related interactions with the participant will be conducted by qualified research staff who are directly 
involved in the conduct of the researchstudy. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under  lock and key 
accessible only by the researchstaff. Subjects will be identified only by a unique study number and subject 
initials. Electronic records of subject data will be maintained using a dedicated database (required: please 
specify database application, i.e. Microsoft Excel, Microsoft Access,  eResearch, Oracle Clinical, Redcap, etc.), 
which is housed in an encrypted and password‐protected (required: please specify storage device, i.e. laptop 
computer, desktop computer, DCI file server). Access to electronic databases will be limited to (please 
specify). Subject data may be stored temporarily on encrypted and password‐protected portable memory 
devices such as flash drives and external hard drives, but only when absolutely necessary. Data stored on 
portable memory devices will be de‐ identified. Subject data will be deleted from the portable memory 
device at the earliest opportunity. The security and viability of the IT infrastructure will be managed by the 
DCI and/or Duke Medicine. 
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
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Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications 
in scientific journals. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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Protocol Amendments 
 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation. IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard. However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
Though not yet required, the CPC should be informed about any protocol amendments  that potentially affect 
research design or data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, 
agent administration, etc.). 
 
Records Retention 
 
The Principal Investigator will maintain study‐related records for the longer period of: 
• At least two years after the date on which a New Drug Application is approved by the 
FDA (if an IND is involved). 
• At least two years after formal withdrawal of the IND associated with this protocol (if 
an IND is involved). 
• At least six years after study completion (Duke policy). 
 
Publication Plan 
 
The results will be made public within 24 months of reaching the end of the study. The end of the study is 
the time point at which the last data items are to be reported, or after the outcome data are sufficiently 
mature for analysis, as defined in the section on statistical design. A report is  planned to be published in a 
peer‐reviewed journal, thus the initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. A full report of the outcomes is planned to be made 
public no later than three (3) years after the end of the study. Duke Cancer Institute will forward a copy of 
the Publication to Genentech/Roche upon completion of the Study.  
 
Study close out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech/Roche. This 
includes all IND annual reports and the Clinical Study Report (final study report). Additionally, any literature articles 
that are a result of the study should be sent to Genentech/Roche. Copies of such reports should be mailed to the 
assigned Clinical Operations contact for the study, and and to Genentech Drug Safety CTV oversight mail box at: 
ctvist_drugsafety@gene.com 
 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
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Queries  
 
Queries related to the Study will be answered by Investigator-Sponsor. However, responses to all safety 
queries  from  regulatory  authorities  or  for publications will be discussed and coordinated between the 
Parties. The Parties agree that Genentech/Roche shall have the final say and control over safety queries 
relating to the Product. Investigator-Sponsor agrees that it shall not answer such queries from regulatory 
authorities and other sources relating to the Product independently but shall redirect such queries to 
Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests for 
information or review of data are met. The Parties will clearly indicate on the request the reason for urgency 
and the date by which a response is required. 
 
Safety crisis Management  
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the 
conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the way in 
which the Product is used, or where there is media involvement, the Party where the crisis originates will 
contact the other Party as soon as possible. 
 
The Parties agree that Genentech/Roche shall have the final say and control over safety crisis management 
issues relating to the Product. Investigator-Sponsor agrees that it shall not answer such queries from media 
and other sources relating to the Product but shall redirect such queries to Genentech. 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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14. REFERENCES 
 
1. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
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Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in Untreated EGFR-Mutated Advanced 
Non-Small-Cell Lung Cancer. N Engl J Med, 2017 
3. 
Remon J, Steuer CE, Ramalingam SS, et al: Osimertinib and other third- generation 
EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol 29:i20-i27, 2018 
4. 
Gainor JF, Shaw AT, Sequist LV, et al: EGFR Mutations and ALK Rearrangements Are 
Associated with Low Response Rates to PD-1 Pathway Blockade in Non- Small Cell Lung Cancer: A 
Retrospective Analysis. Clin Cancer Res 22:4585-93, 2016 
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Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627-39, 2015 
6. 
Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 
387:1540-50, 2016 
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Rittmeyer A, Barlesi F, Waterkamp D, et al: Atezolizumab versus docetaxel in patients with 
previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled 
trial. Lancet 389:255-265, 2017 
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Lisberg A, Cummings A, Goldman JW, et al: A Phase II Study  of Pembrolizumab in EGFR-
Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naive Patients With Advanced NSCLC. J Thorac Oncol 13:1138-1145, 
2018 
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Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-
label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016 
10. 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al: Pembrolizumab plus 
Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med, 2018 
11. 
Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus 
chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib 
(IMPRESS): a phase 3 randomised trial. Lancet Oncol 16:990-8, 2015 
12. 
Naumov GN, Nilsson MB, Cascone T, et al: Combined vascular endothelial growth factor 
receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of 
EGFR inhibitor resistance. Clin Cancer Res 15:3484-94, 2009 
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Ichihara E, Ohashi K, Takigawa N, et al: Effects of vandetanib on lung adenocarcinoma 
cells harboring epidermal growth factor receptor T790M mutation in vivo. Cancer Res 69:5091-8, 2009 
14. 
Seto T, Kato T, Nishio M, et al: Erlotinib alone or with bevacizumab as first-line therapy in 
patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an 
open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15:1236-44, 2014 
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Furuya N, Fukuhara T, Saito H, et al: Phase III study comparing bevacizumab plus erlotinib 
to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. Journal of 
Clinical Oncology 36:abstract 9006, 2018 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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16. 
Manegold C, Dingemans AC, Gray JE, et al: The Potential of Combined Immunotherapy 
and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol 12:194-207, 2017 
17. 
Tao L, Huang G, Shi S, et al: Bevacizumab improves the antitumor efficacy of adoptive 
cytokine-induced killer cells therapy in non-small cell lung cancer models. Med Oncol 31:777, 2014 
18. 
Shi S, Wang R, Chen Y, et al: Combining antiangiogenic therapy with adoptive cell 
immunotherapy exerts better antitumor effects in non-small cell lung cancer models. PLoS One 8:e65757, 2013 
19. 
Kowanetz M, Socinski MA, Zou W, et al: IMpower150: Efficacy of atezolizumab plus 
bevacizumab and chemotherapy in 1L metastatic nonsquamous  NSCLC across key subgroups. Presented at: 
2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois Abstract CT076, 2018 
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Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for First-Line Treatment 
of Metastatic Nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018 
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Cappuzzo F, McCleod M, Hussein M, et al: Progression-free survival (PFS) and safety 
analysis from a randomized phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab 
(atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. . Abstract presented at: the ESMO 2018 
Congress; Munich, Germany: October 19-23, 2018. Abstract LBA53. 
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Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for patients with 
previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled 
trial. Lancet 387:1837-46, 2016 
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Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909-20, 2016 
24. 
Fridman WH, Pages F, Sautes-Fridman C, et al: The immune contexture in human tumours: 
impact on clinical outcome. Nat Rev Cancer 12:298-306, 2012 
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Angell H, Galon J: From the immune contexture to the Immunoscore: the role of prognostic and 
predictive immune markers in cancer. Curr Opin Immunol 25:261-7, 2013 
26. 
Tarhini AA, Edington H, Butterfield LH, et al: Immune monitoring of the circulation and 
the tumor microenvironme nt in patients with regionally advanced melanoma receiving neoadjuvant 
ipilimumab. PLoS One 9:e87705, 2014 
27. 
Frelinger J, Ottinger J, Gouttefangeas C, et al: Modeling flow cytometry data for cancer vaccine 
immune monitoring. Cancer Immunol Immunother 59:1435-41, 2010 
28. 
Chan C, Feng F, Ottinger J, et al: Statistical mixture modeling for cell subtype identification 
in flow cytometry. Cytometry A 73:693-701, 2008 
29. 
Sarzotti-Kelsoe M, Cox J, Cleland N, et al: Evaluation and recommendations on good clinical 
laboratory practice guidelines for phase I-III clinical trials. PLoS Med 6:e1000067, 2009 
30. 
Nair SK, De Leon G, Boczkowski D, et al: Recognition and killing of autologous, 
primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic  T cells. 
Clin Cancer Res 20:2684-94, 2014 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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31. 
Murdoch DM, Suchard MS, Venter WD, et al: Polychromatic 
immunophenotypic characterization of T cell profiles among HIV-infected patients 
experiencing immune reconstitution inflammatory syndrome (IRIS). AIDS Res Ther 6:16, 2009 
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Murdoch DM, Staats JS, Weinhold KJ: OMIP-006: phenotypic subset analysis of human T 
regulatory cells via polychromatic flow cytometry. Cytometry A 81:281-3, 2012 
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Nixon AB, Pang H, Starr MD, et al: Prognostic and predictive blood-based biomarkers in 
patients with advanced pancreatic cancer: results from CALGB80303 (Alliance). Clin Cancer Res 19:6957-66, 
2013 
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Liu Y, Starr MD, Brady JC, et al: Biomarker signatures correlate with clinical outcome in 
refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus. Mol Cancer Ther 
14:1048-56, 2015 
35. 
Nixon AB, Sibley A, Hatch AJ, et al: Blood-based biomarkers  in  patients  (pts) with metastatic 
colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI plus bevacizumab (Bev), cetuximab (Cetux), or 
bev plus Cetux: Results from CALGB 80405 (Alliance). Journal of Clinical Oncology 34:abstract 3597, 2016 
36. 
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 
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Jung SH, Kim KM: On the estimation of the binomial probability in multistage clinical trials. 
Stat Med 23:881-96, 2004 
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2008 


CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
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15.0 APPENDICES 
 
Appendix 1: Performance status criteria 
Appendix 2: Measurement of effect 
Appendix 3: Cockcroft‐Gault equation 
APPENDIX 1: PERFORMANCE STATUS CRITERIA: ECOG 
Grade 
Description 
0 
Fully active, able to carryon all predisease activities 
without restriction 
(Karnofsky 90‐100). 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carryout work of a light or 
sedentary nature, e.g., light housework, office work 
(Karnofsky 70‐80). 
2 
Ambulatory andcapable of all self‐care, but unable to 
carry out any workactivities. Up and about more than 
50 percent of waking hours 
(Karnofsky 50‐60). 
3 
Capable of only limited self‐care, confined to bed or 
chair 50 percent or more of waking hours 
(Karnofsky 30‐40). 
4 
Completely disabled. Cannot carryon anyself‐care. 
Totallyconfined to bed or chair 
(Karnofsky 10‐20) 
5 
Dead 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
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APPENDIX 2: MEASUREMENT OF EFFECT 
 
Although response is the primary endpoint of this trial, participants with measurable disease will be assessed by 
standard criteria. For the purposes of this study, participants should be re‐evaluated every as per time and events 
table in section 10. 
 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).1. Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest  diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for Target Disease response. Only those participants who have measurable disease present at 
baseline, have received at least one dose of study therapy, and have had their disease re‐evaluated will be 
considered evaluable for target disease response. These participants will have their response classified 
according to the definitions stated below 
 
Evaluable Non‐Target Disease Response. Participants who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease, have received at least one dose of study therapy, and 
have had their disease re‐evaluated will be considered evaluable for non‐target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions. 
 
Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accuratelymeasured in at least 
one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x‐ray or ≥10 mm with CT scan, MRI, 
or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are considered measurable if the lesion 
is not in bone. 
 
Malignant lymph nodes. To be considered pathologically enlargedand measurable, a lymph node must be 
≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow‐up, only the short axis will be measured and followed. 


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Non‐measurable disease. All other lesions (or sites of disease), including small lesions  (longest diameter <10 
mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non‐ measurable disease. 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
considered non‐measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 


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considered as malignant lesions (neither measurable nor non‐measurable) since they are, by definition, 
simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions,  if they meet 
the definition of measurability described above. However, if non‐cystic lesions are present in the same 
participant, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non‐ nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. 
 
Non‐target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non‐target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow up. 
 
Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital 
measurement tool. All baseline evaluations should be performed as closely as possible to  the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow‐up. Imaging‐based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers (e.g., skin nodules). In the case 
of skin lesions, documentation by color photography, including a  ruler  to estimate the size of the lesion, is 
recommended. 
 


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Chest x‐ray. Lesions on chest x‐ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung; however, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size of a measurable lesion should be twice the slice thickness. MRI is also acceptable in 


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The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
Protocol TOP 1901 
  
112 
certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an 
MRI is performed, the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow‐up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. 
It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath‐hold scanning techniques, if possible. 
 
FDG‐PET. While FDG‐PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG‐PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of FDG‐PET imaging can be identified 
according to the following algorithm: 
(a) Negative FDG‐PET at baseline, with a positive FDG‐PET at follow‐up is a sign of PD based on 
a new lesion. 
(b) No FDG‐PET at baseline and a positive FDG‐PET at follow‐up: If the positive FDG‐PET at 
follow‐up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG‐ 
PET at follow‐up is not confirmed as a new site of disease on CT, additional follow‐up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG‐PET scan). If the positive FDG‐PET at follow‐up 
corresponds to a pre‐existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
(c) FDG‐PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG‐PET in this circumstance should be prospectively  described  in the protocol and 
supported by disease‐specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG‐ 
PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG‐PET scan lesion means one which is FDG avid with an uptake greater than twice that 
of the surrounding tissue on the attenuation corrected image. 
 
PET‐CT. At present, the low dose or attenuation correction CT portion of a combined PET‐CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the 
CT performed as part of a PET‐CT is of identical diagnostic quality to a  diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET‐CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
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Protocol TOP 1901 
  
113 
the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or 
serially performed. 
 
Response Criteria 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
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Protocol TOP 1901 
  
114 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non‐
target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non‐Target Lesions 
 
Complete Response (CR): Disappearance of all non‐target lesions and normalization of tumor marker 
level. All lymph nodes must be non‐pathological in size (<10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for  a patient to be 
considered in complete clinical response. 
 
Non‐CR/Non‐PD: Persistence of one or more non‐target lesion(s) and/or maintenance  of  tumor marker level 
above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing 
non‐target lesions. Unequivocal progression should not  normally  trump target lesion  status. It must be 
representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non‐target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a later 
time by the review panel (or PI). 
 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
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Protocol TOP 1901 
  
115 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor (for example, some ‘new’ bone lesions 
may be simply healing or flare of pre‐existing lesions). However, a lesion identified on a follow‐up scan in an 
anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion 
is equivocal (because of small size etc.), follow‐up evaluation will clarify if it truly represents new disease and 
if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was 
discovered. 


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required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written 
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Protocol TOP 1901 
  
116 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). The patient's best response assignment will depend on the achievement of 
both measurement and confirmationcriteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non‐Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non‐CR/Non‐PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non‐CR/Non‐ 
PD/not evaluated 
No 
PR 
SD 
Non‐CR/Non‐ 
PD/not evaluated 
No 
SD 
Documented at least once >4 wks 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non‐randomized trials with response as primary endpoint. 
*** 
 In exceptional circumstances, unequivocal progression in non‐target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Participants with Non‐Measurable Disease (i.e., Non‐Target Disease) 
 
Non‐Target Lesions 
New Lesions 
Overall Response 


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Protocol TOP 1901 
  
117 
CR 
No 
CR 
Non‐CR/non‐PD 
No 
Non‐CR/non‐PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non‐CR/non‐PD’ is preferred over ‘stable disease’ for non‐target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assignthis 
category when no lesions can be measured is not advised 
 
Duration of Response 


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Protocol TOP 1901 
  
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Duration of overall response: The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for  progressive disease the smallest measurements 
recorded since the treatment started, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively documented, or death 
due to any cause. Participants without eventsreportedare censored at the last disease evaluation. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 


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Protocol TOP 1901 
  
119 
 
Appendix 3: 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
 
Creatinine clearance for females = 
 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL)