Conditions: Non-Small Cell Lung Cancer (NSCLC)
Keywords: Non-Small Cell Lung Cancer (NSCLC) Anaplastic lymphoma kinase ALK Brain metastases
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This research study is evaluating two drugs, alectinib and bevacizumab, as possible treatments for Advanced Non-Small Cell Lung Cancer (NSCLC).

Detailed description:
This is a Phase I/II clinical trial.

* A Phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose(s) of the investigational intervention to use for further studies.
* Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease.
* "Investigational" means that the intervention is being studied.

  * In this research study, the investigators are investigating the combination of two study drugs: alectinib and bevacizumab. The FDA (the U.S. Food and Drug Administration) has not approved alectinib as a treatment for any disease.

It has been found that some people with NSCLC have a change (mutation) in a certain gene called the anaplastic lymphoma receptor tyrosine kinase (ALK) gene. This mutated gene helps cancer cells grow.

\-- Alectinib belongs to a class of drugs designed to inhibit ALK. This drug has been used in other research studies. Information from those other research studies suggests that alectinib may be effective in killing cancer cells that have changes in ALK. Only participants with changes in the ALK gene will be allowed to participate in this study.

In this research study, Alectinib will be combined with Bevacizumab. -- Bevacizumab (also called Avastin) works by slowing or stopping the growth of cells in cancer tumors by decreasing the blood supply of the tumors. If blood supply is decreased, oxygen and nutrients that are needed for tumor growth are decreased. The FDA has approved Bevacizumab as a treatment option for your disease

The purpose of this study is to test the safety of Alectinib and Bevacizumab. The investigators will also determine how effective this combination is in participants with advanced, ALK-positive NSCLC with a focus on participants with brain metastases.

In the phase I portion of the study, a 3 + 3 dose de-escalation design was to determine the recommended phase II dose (RP2D) of alectinib and bevacizumab. Three patients will be treated per cohort for one cycle (21 days per cycle) beginning with dose level 1 cohort.

* Dose level 1 (starting dose) = Alectinib 600mg twice daily orally (PO), and Bevacizumab 15 mg/kg administered intravenously (IV) every 3 weeks.

  \-- Dose level 1 was selected based on the individual RP2Ds for each medication and anticipation for minimal overlapping toxicities.
* Dose level -1 = Alectinib 600mg twice daily orally (PO),and Bevacizumab 7.5 mg/kg administered intravenously (IV) every 3 weeks.
* Dose level -2 = Alectinib 450mg twice daily orally (PO), and Bevacizumab 7.5 mg/kg administered intravenously (IV) every 3 weeks.

DLTs were defined as adverse events (AEs) occurring within the first cycle of treatment (21 days) attributed to the study drugs, and grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. If no DLTs are observed with dose level 1 cohort, we will enroll an additional 3 participants (6 total) to the same cohort and proceed with the phase II portion of the study if one or less experience a DLT. In any other dose level cohort, if one of three patients experiences a DLT, another 3 patients will be treated at the same dose level for one cycle. If no additional DLTs are observed, we will proceed with the phase II portion of the trial. If more than one of 3 patients develops a DLT in any cohort, another 3 patients will be treated in the next lowest dose cohort.

The RP2D for the combination of alectinib and bevacizumab was defined as either (i) the highest dosage cohort in which less than a third of patients experienced a DLT, or (ii) alectinib at the previously defined RP2D as a single agent (600 mg twice daily) plus bevacizumab at the highest tolerated dose investigated for the indication (15 mg/kg every 21 days), whichever was the lower dose.

In the phase II portion of the study, all patients received alectinib plus bevacizumab at the RP2D determined in the phase I portion. Cycles were 21 days long. Treatment was continued until there was evidence of progressive disease, death, or unacceptable toxicity. Patients were allowed to continue study drugs beyond progression if deemed clinically beneficial at the investigator's discretion. Intra-patient dose modification of bevacizumab was not permitted.

Arms:
arm 1: Participants were administered Alectinib 600 mg twice daily by mouth, and Bevacizumab 15 mg/kg intravenously once every 3 weeks. DLTs will be monitored and evaluated throughout the first cycle (21 days). arm 2: Participants were administered Alectinib 600 mg twice daily by mouth, and Bevacizumab 7.5 mg/kg intravenously once every 3 weeks. DLTs will be monitored and evaluated throughout the first cycle (21 days). arm 3: Participants were administered Alectinib 450 mg twice daily by mouth, and Bevacizumab 7.5 mg/kg intravenously once every 3 weeks. DLTs will be monitored and evaluated throughout the first cycle (21 days). arm 4: In the phase II portion of the study, all patients received alectinib plus bevacizumab at the RP2D determined in the phase I portion.

Interventions: intervention 1: Alectinib intervention 2: Bevacizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
ICF_002.pdf: 
Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 1 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
Protocol Title:  A Phase I/II Trial to Evaluate the Safety and Tolerability of Alectinib 
and Bevacizumab in Patients with Advanced, ALK-Positive, Non-small Cell Lung 
Cancer
DF/HCC Principal Research Doctor / Institution: 
Justin Gainor, MD / Massachusetts General Hospital
Phase II Consent
A. INTRODUCTION
You are invited to take part in a clinical trial, a type of research study, because 
you have advanced non-small cell lung cancer (NSCLC). For purposes of this 
research, you will be referred to as a “participant.” This research study is 
evaluating two drugs, alectinib and bevacizumab, as possible treatments for 
NSCLC. 
It is expected that approximately 20 patients will take part in the Phase II portion 
of the study
Genentech/F. Hoffmann- La Roche, Ltd., a pharmaceutical company, is 
supporting this research study by providing funding for the research study as well 
as the study drugs.   
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor. 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future.
NCT02521051
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Dana-Farber/ Harvard Cancer Center
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
B. WHY IS THIS RESEARCH STUDY BEING DONE? 
This is a Phase I/II clinical trial.  You are being asked to participate in the Phase 
II portion of the study. A Phase II clinical trial tests the safety and effectiveness of 
an investigational intervention to learn whether the intervention works in treating 
a specific disease. “Investigational” means that the intervention is being studied. 
In this research study, we are investigating the combination of two study drugs: 
alectinib and bevacizumab. The FDA (the U.S. Food and Drug Administration) 
has not approved alectinib as a treatment for any disease.
It has been found that some people with NSCLC have a change (mutation) in a 
certain gene called the anaplastic lymphoma receptor tyrosine kinase (ALK) 
gene. This mutated gene helps cancer cells grow. Alectinib belongs to a class of 
drugs designed to inhibit ALK. This drug has been used in other research 
studies. Information from those other research studies suggests that alectinib 
may be effective in killing cancer cells that have changes in ALK. Only 
participants with changes in the ALK gene will be allowed to participate in this 
study. 
In this research study, alectinib will be combined with bevacizumab. 
Bevacizumab (also called Avastin) works by slowing or stopping the growth of
cells in cancer tumors by decreasing the blood supply of the tumors. If blood
supply is decreased, oxygen and nutrients that are needed for tumor growth are
decreased. The FDA has approved bevacizumab as a treatment option for your 
disease
The purpose of this study is to test the safety of alectinib and bevacizumab. We 
will also determine how effective this combination is in participants with 
advanced, ALK-positive NSCLC.
C. WHAT OTHER OPTIONS ARE THERE?
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 

Receive standard treatment including crizotinib (XALKORI) or ceritinib 
(Zykadia). 

Receive standard chemotherapy
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 3 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Receive radiation therapy to brain metastases. 

Take part in another research study. 

Receive no therapy specific to your cancer.

Comfort care, also called palliative care.  This type of care may help to 
reduce pain, tiredness, appetite problems and other problems caused 
by the cancer.  It does not treat the cancer directly, but instead tries to 
treat the symptoms.  
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study.
D. WHAT IS INVOLVED IN THE RESEARCH STUDY?
Since we are looking for the highest dose of the study drug that can be 
administered safely without severe or unmanageable side effects in participants 
that have ALK-positive lung cancer, not everyone who participates in this 
research study will receive the same dose of the study drug.  The dose you get 
will depend on the number of participants who have been enrolled in the study 
before you and how well they have tolerated their doses. 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study.  We will describe them in this consent form and you can 
refer to this at any time during the research study.
If you take part in this research study you will be given a drug diary.  You will be 
asked to document information in the drug diary about the study treatment you 
are being asked to take.
Before the research starts (screening):  
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  Many of these 
tests and procedures are likely to be part of regular cancer care and may be 
done even if it turns out that you do not take part in the research study.  If you 
have had some of these tests or procedures recently, they may or may not have 
to be repeated.  

A medical history, which includes questions about your health, current 
medications, and any allergies.
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for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Performance status, which evaluates how you are able to carry on with 
your usual activities. 

Physical exam, including measurement of height, weight and vital signs 
(temperature, breathing rate, blood pressure and pulse).

An assessment of your tumor by one or more of the following standard 
assessment tools: CT (Computerized Tomography) scan and  MRI 
(Magnetic Resonance Imaging) 

Blood tests, for standard laboratory tests (about 2 tablespoons), a 
pregnancy test (if you can become pregnant), and tests to check how 
quickly your blood clots. 

Urine test.

EKG, a test that measures the electrical activity and rhythm of the heart.

Patient questionnaires, which include questions about your health
If these tests show that you are eligible to participate in the research study, you 
will begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study.
After the screening procedures confirm that you are eligible to participate 
in the research study:
Each treatment cycle last 21 days (3 weeks). 
Alectinib is a capsule that you take by mouth. You will be given a drug diary to 
record the dose of alectinib you take each day. The diary will also include special 
instructions for taking alectinib. 
You will be given Bevacizumab via IV, which is called an infusion.
You will receive an infusion of bevacizumab on the first day of each treatment 
cycle (once every 21 days). 
During the COVID19 pandemic, your doctor may hold or discontinue 
Bevacizumab infusions. If Bevacizumab is held or discontinued, your visits and 
assessments may be every 42 days (6 weeks). 
Study Treatment Period
A schedule of clinic visits for the study is summarized below. At every visit, you 
should tell the study staff how you are feeling and whether your health has 
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Research Consent Form
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
changed. You may have other lab tests done as part of your cancer care in 
addition to those listed below. 
Cycle 1 Day 1:

Performance status. 

Physical exam.

Routine blood tests (about 2 tablespoons of blood). 

Urine test.

EKG.

Patient questionnaires.
Cycle 1 Day 15: 

Performance status. 

Physical exam.

Routine blood tests (about 2 tablespoons of blood).
Cycles 2-10
Day 1 of Each Cycle

Performance status. 

Physical exam.

Routine blood tests (about 2 tablespoons of blood). 

Urine test.

EKG only be performed on Day 1 of Cycle 2 and Cycle 8. 

Patient questionnaires.

An assessment of your tumor. You will only have brain MRIs performed 
if abnormalities were detected on the initial screening MRI.  
Cycles 11 and Beyond
Day 1 of Each Cycle

Performance status. 

Physical exam.

Routine blood tests (about 2 tablespoons of blood). 

Urine test.

EKG only be performed on Day 1 of Cycle 18.  

Patient questionnaires.

An assessment of your tumor. 
End of Study Treatment Visit
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
When you stop alectinib and bevacizumab permanently, you will return to the 
study clinic. The following procedures will be done at this visit: 

Performance status. 

Physical exam.

Routine blood tests (about 2 tablespoons of blood). 

Urine test.

EKG. 

Patient questionnaires.

An assessment of your tumor. 
30 Day Follow-up Visit
You will also visit the clinic 30 days after you stop taking study drugs. The 
following tests and procedures will be done: 

Review of medical history and medications

Patient questionnaires
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY?
You will be in this research study for up to a year. 
The research doctor may decide to take you off the research study for many 
reasons including if:

It is considered to be in your best interest

The study treatment or procedures are found to be unsafe or ineffective

There is any problem with following study treatments and procedures

Your condition worsens

A decision is made to close the study

Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study
If you are removed from the research study, the research doctor will explain to 
you why you were removed.  
In addition, you can stop participating in the research study at any time. 
However, the FDA requires that any information collected up to the point of your 
withdrawal cannot be removed from the study.  If you decide to stop participating 
in this research study, we encourage you to talk to the research doctor and your 
primary doctor first.
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY?
There are risks to taking part in any research study. One risk is that you may get 
a study drug or study dose of a drug that does not help treat your disease or that 
makes your condition or disease worse.  Another risk is that there may be side 
effects.  
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects. 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal. 
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you.
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study.
Risks Associated with Alectinib:
Common (occurs in greater than 10% of patients)

Loss of taste
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 8 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Abnormally high levels of bilirubin in the blood. (Bilirubin is a bile pigment 
produced by the liver which is normally and continually excreted from the 
body). This may indicate that too many red blood cells are being 
destroyed, or that the liver or gallbladder is not functioning properly.

Constipation

Increase in liver enzyme, indicating possible liver damage (AST/ALT 
increase)

Nose and throat inflammation (nasopharyngitis)

Rash

Abnormal kidney test which may indicate possible kidney damage (blood 
creatinine increase)

Low white blood cell count which may increase your risk for infection, such 
as pneumonia and/or severe blood infection (neutrophil count decrease)

Increased blood level of enzyme from muscle which may indicate possible 
muscle damage (Blood CPK increase) 

Muscle pain (myalgia)

White blood cell decrease (which may increase your risk of infection)

Blood alkaline phosphatase increase (which may indicate possible liver
damage)

Oral inflammation (stomatitis)

Nausea

Weight increase

Diarrhea

Feeling of bodily discomfort (malaise)

Bradycardia (slow heart rate)
Alectinib also contains a substance called sodium lauryl sulfate that is known to 
sometimes cause gastrointestinal problems, such as nausea, vomiting and 
diarrhea. 
Rare but serious:

Interstitial lung disease (ILD; lung scarring) which could cause breathing 
difficulty, cough, and fever. ILD can be life threatening.

Low blood pressure and slower blood clotting.
Eye disorders, such as blurred vision.
Risks Associated with Bevacizumab: 
Frequent (Chance of 10-50% that this will happen):
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 9 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Nausea and vomiting

Headaches

High blood pressure, with increased risk of heart problems, headache, and 
stroke.

Pain

Abdominal pain

Shortness of breath

Mouth sores

Weakness

Upper respiratory infection

Chills

Loss of appetite

Bleeding (including in stomach or intestines)

Runny nose or increase in tears in your eyes

Kidney damage, found by testing your urine

Loss of function of the ovaries, which can lead to menopause
Occasional (Chance of 5-10% that this will happen):

Hoarseness

Nosebleeds

Low levels of potassium in the blood which can cause an irregular heart 
beat 

Hair loss

Dry skin

Hole in your intestine may occur which may require hospitalization and/or 
surgery which could be serious or life threatening. 

Blood clots in your veins and arteries. These can cause chest pain, heart 
attack, or stroke. A blood clot in your eye might cause vision loss. Clots 
can be serious and life threatening.

Allergic reaction when the infusion is given. A serious allergic reaction 
may result in death.

Slowed growth and development (based on laboratory studies)
Rare (Less than 5% chance this will happen):

Inability of heart to pump blood properly, which can cause weakness and 
tiredness, fluid retention, and fluid build-up in the lungs, which can cause 
shortness of breath (congestive heart failure)
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 10 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Decreased ability of your wounds to heal. This can lead to infections, 
hospitalization, or could possibly be fatal.

A very rare problem in your brain that may cause confusion, blindness, 
and coma. This is associated with very high blood pressure and is not 
thought to be a permanent condition.

Confusion

Abdominal abscess or infection in your abdomen

Fistula or hole in your bowel. This is an abnormal connection between two 
different organs and may lead to life threatening complications including 
serious infections, bleeding, or dysfunction of the organs

Dehydration

Abnormal bleeding from in your body or from the tumorwhich could be 
serious of life threatening
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research. 
Radiation Risks Associated with Scans and X-Rays: 
While you are in this research study, CT scans may be used to evaluate your 
disease.  The frequency of these exams is slightly greater than what you would 
receive as standard care. In the long term, over many years, there is a very low 
risk of developing a new cancer as a result of the radiological evaluation and 
treatment for your cancer.  
Risks Associated with MRI Scans: 
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a 
table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. If you feel uncomfortable in confined spaces, please tell your 
research doctor. Your doctor may give you a medication to make you feel more 
comfortable. As images are taken, a loud banging noise will be produced.  
Earplugs or headphones will be available if needed. The MRI can be stopped at 
any time at your request, but the scan may not be complete.
Risks Associated with Contrast Agents Used During Scans:
There is a small risk with using a contrast agent that is injected into a vein during 
CT scans and MRIs. The contrast agent is a special dye that highlights organs, 
blood vessels or tissue to make them more visible.  Depending on the type of 
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
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DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
contrast agent that is used, it may cause decreased kidney function or worsen 
kidney function in people who already have decreased kidney function.  
Therefore, we will monitor your kidney function closely while you participate in 
this study.  If there is any change in your kidney function, we may have to 
remove you from the study.
Uncommonly, some people have allergic reactions (such as hives and itching) to 
the contrast agent.  Serious reactions (for example, drop in blood pressure, 
difficulty breathing or severe allergic reaction and death) are rare.  
Reproductive Risks: 
The drugs used in this research study may affect a fetus.  While participating in 
this research study, you should not become pregnant or father a baby, and 
should not nurse a baby.  We can provide counseling about preventing 
pregnancy for either male or female study participants. Let your doctor know 
immediately if you become pregnant or find out that you are going to be the 
father of a child.
If a female becomes pregnant while on this study or within 90 days after the last 
dose of the study drug, a report should be completed and provided to the 
sponsor. We would also like to follow-up with you to obtain the outcome of the 
pregnancy if this occurs. 
Non-Physical Risks: 
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities. 
The questionnaires used in this study may be upsetting. If you find the 
questionnaires upsetting, you may speak with the research doctor or ask to be 
referred for additional emotional support.
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY?
This study may or may not help you. Taking part in this research study may help 
us learn more about alectinib and bevacizumab as treatments for ALK-positive 
lung cancer that may help people in the future.
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H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS?
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study. 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.  
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled. 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the study drugs. 
Another reason to tell your research doctor that you are thinking about stopping 
is to discuss what follow-up care and testing could be most helpful for you.
I.
WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY?
You will not be paid for participation in this study. 
We may use your samples and information to develop a new product or medical 
test to be sold.  The hospital, Genentech/F. Hoffmann- La Roche, Ltd., and 
researchers may benefit if this happens. There are no plans to pay you if your 
samples are used for this purpose. 
J. WHAT ARE THE COSTS?
Taking part in this research study might lead to added costs to you or your 
insurance company.
You will not be charged for alectinib and bevacizumab.
You or your insurance company will be charged for portions of your care during 
this research study that are considered standard care. You may be responsible 
for co-payments and deductibles that are typical for your insurance coverage.
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 13 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are:  

Massachusetts General Hospital: (617) 726-2191
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team:
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237)
K. WHAT HAPPENS IF I AM INJURED OR SICK BECAUSE I TOOK PART IN THIS 
RESEARCH STUDY?
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form.
The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  The treating hospital may bill your 
insurance company or other third parties, if appropriate, for the costs of the care 
you get for the injury, but you may also be responsible for some of them.
There are no plans for Dana-Farber/Partners CancerCare (DF/PCC) on behalf of 
the Dana-Farber/Harvard Cancer Center (DF/HCC) to pay you or give you other 
compensation for the injury. You do not give up your legal rights by signing this 
form.
L. WHAT ABOUT CONFIDENTIALITY?
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data. 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file. It may also become part of a DF/HCC research database.  
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 14 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
The results of this research study may be published. You will not be identified in 
publications without your permission.
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.
M. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY?
If you have questions about the study, please contact the research doctor or 
study staff as listed below:
Massachusetts General Hospital (MGH)
Justin Gainor, MD: 617-724-4000
24 hour Contact: Call Dr. Gainor at 617-724-4000 and ask the doctor to be 
paged. 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at DFCI (617) 632-
3029. This can include questions about your participation in the study, concerns 
about the study, a research related injury, or if you feel/felt under pressure to 
enroll in this research study or to continue to participate in this research study. 
N. PRIVACY OF PROTECTED HEALTH INFORMATION
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below.
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 15 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
1. What protected health information about me will be used or shared with 
others during this research?

Existing medical records, including mental health records.

New health information created from study-related tests, procedures, 
visits, and/or questionnaires
2. Why will protected information about me be used or shared with others?
The main reasons include the following:

To conduct and oversee the research described earlier in this form;

To ensure the research meets legal, institutional, and accreditation 
requirements; 

To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and

To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug for the 
purpose of this or other research relating the study drug and its use in 
cancer; and,

Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.)
3. Who will use or share protected health information about me?

DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information.
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 16 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
4. With whom outside of DF/HCC may my protected health information be 
shared?
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities:

Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors).

The supporters of the study, its subcontractors, and its agent(s): 
Genentech/F. Hoffmann- La Roche, Ltd.

Other research doctors and medical centers participating in this research, 
if applicable

Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
other domestic or foreign government bodies if required by law and/or 
necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records.

Hospital accrediting agencies

A data safety monitoring board organized to oversee this research, if 
applicable
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission. 
5. For how long will protected health information about me be used or 
shared with others?

There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.  
6. Statement of privacy rights:

You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 17 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?”

You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?”
O. OPTIONAL RESEARCH STUDIES: 
One goal of this study is to learn more about who may best respond to the study 
drugs alectinib and bevacizumab. During this study, if feasible and if you 
consent, fresh tumor biopsies will be performed during screening and/or after you 
stop receiving the study drugs. These samples, along with stored tissue samples, 
will be used to learn how cancer cells respond to alectinib and bevacizumab. The 
samples will also be used to sequence the ALK gene and other genes thought to 
be important in cancer. This information may help us understand which patients 
will respond best to alectinib and bevacizumab, and why other ALK inhibitors 
stop working. The research tests performed on your tissue will not benefit you 
directly, but could help other patients in the future. 
If you agree, fresh tumor biopsies will be done at the screening visit and/or at the 
time of disease progression, if your study doctor thinks the biopsies will be 
feasible and safe. Tests done on the tissue collected at these biopsies will be 
done to help us learn more about who may or may not respond to the study 
drugs alectinib and bevacizumab. You will have a chance to agree or not agree 
to have fresh biopsies collected below. 
Risks associated with biopsies:
Biopsies are normally performed under the guidance of an imaging technique. 
Each procedure requires a separate consent prior to the biopsy. The risks may 
include: 

Pain and discomfort. The amount of pain and discomfort will vary, 
depending on the location of the biopsy site. These risks can be discussed 
with the study doctor.
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 18 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 

Minor bleeding at the biopsy site.

Tenderness at the biopsy site.

Scarring at the biopsy site.

Rarely, an infection at the biopsy site.
Additional risks of a lung biopsy may include:

Collapse of your lung during or following the biopsy.

Severe bleeding.

Infection such as pneumonia. Usually this type of infection can be treated 
with antibiotics.

Spasms of the breathing (bronchial) tubes, which can cause breathing 
difficulties right after the biopsy.

Irregular heart beat (rhythm).
Uncommonly, complications from biopsies can be life-threatening. As with any 
interventional procedure, other potentially serious complications from bleeding or 
organ damage may occur. These might require additional surgical intervention.
Permission for biopsy to collect fresh tumor tissue during this study
Please indicate whether or not your wish to undergo a biopsy or biopsies to 
provide additional tumor tissue for research tests by choosing one of the options 
below and writing your initials in the space provided.
 Yes      
 Initials                       Date
 No       
 Initials                       Date
3/10/2023 9:56 PM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 19 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
P. DOCUMENTATION OF CONSENT
My signature below indicates:

I have had enough time to read the consent and think about 
participating in this study;

I have had all of my questions answered to my satisfaction;

I am willing to participate in this study;

I have been told that my participation is voluntary and I can withdraw at 
any time
Signature of Participant
Date
or Legally Authorized Representative  
Relationship of Legally Authorized Representative to Participant  
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 10.03.14
Page 20 of 20
DFCI Protocol Number: 15-055 
Approved Date (DFCI IRB Approval): 12/28/2020 
Date Posted for Use: 01/06/2021 
Adult Participants
To be completed by person obtaining consent:
The consent discussion was initiated on  
 (date).
Signature of individual obtaining consent: 
Printed name of above: 
Date: 
A copy of this signed consent form will be given to the participant or legally authorized 
representative, or, where the participant is a minor, the participant’s parent or legal guardian.
For Adult Participants
 1)  The participant is an adult and provided consent to participate.
1a)  Participant (or legally authorized representative) is a non-English speaker and
signed the translated Short Form in lieu of English consent document:
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation 
of the English consent form.  The participant was given the opportunity to ask questions. 
Signature of Interpreter/Witness: 
Printed Name of Interpreter/Witness: 
Date: 
1b)  Participant is illiterate
The consent form was read to the participant who was given the opportunity 
to ask questions. 
Signature of Witness: 
Printed Name of Witness: 
Date: 
2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative:
2a) gave permission for the adult participant to participate 
2b) did not give permission for the adult participant to participate 
3/10/2023 9:56 PM

Prot_SAP_000.pdf: 
1
A Phase I/II Trial to Evaluate the Safety and Tolerability of 
Alectinib and Bevacizumab in Patients with Advanced, ALK-
Positive, Non-Small Cell Lung Cancer
Protocol 15-055
Version Date:  October 7, 2020
NCT02521051


Protocol #:15-055
Version Date:  October 7, 2020 
2
NCI Protocol #:
N/A
Local Protocol #:
15-055
TITLE:  A Phase I/II Trial to Evaluate the Safety and Tolerability of Alectinib and 
Bevacizumab in Patients with Advanced, ALK-Positive, Non-Small Cell Lung Cancer
Principal Investigator (PI):
Justin Gainor, MD
Massachusetts General Hospital
32 Fruit Street, Yawkey 7B
Boston, MA 02114
Phone: 617-724-4000
Fax: 617-726-0453
Email: Jgainor@partners.org
Statistician:
Alona Muzikansky
Massachusetts General Hospital
Amuzikansky@partners.org
Responsible Data Manager: 
Beth Kennedy
Massachusetts General Hospital
Eakennedy@partners.org
Agent(s):  
Alectinib (IND pending), Supplier – Genentech, a member of the Roche Group
Bevacizumab (IND pending), Supplier – Genentech, a member of the Roche Group
IND #: 125774
Sponsor: Dr. Justin Gainor
NCT02521051


Protocol #:15-055
Version Date:  October 7, 2020 
3
Schema


Protocol #:15-055
Version Date:  October 7, 2020 
4
TABLE OF CONTENTS
1.
OBJECTIVES
8
1.1
Study Design
8
1.2
Primary Objectives
9
1.3
Secondary Endpoints
9
2.
BACKGROUND
9
2.1
ALK-Positive Lung Cancer
9
2.2
Overview of Alectinib
10
2.3
Overview of Bevacizumab
14
2.4
Rationale
15
2.5
Correlative Studies Background
17
3.
PARTICIPANT SELECTION
18
3.1
Eligibility Criteria
18
3.2
Exclusion Criteria
19
4.
REGISTRATION PROCEDURES
22
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
22
4.2
Registration Process for DF/HCC and DF/PCC Institutions
22
4.3
General Guidelines for Other Investigative Sites
23
4.4
Registration Process for Other Investigative Sites
23
5.
TREATMENT PLAN
23
5.1
Treatment Regimen
23
5.2
Agent Administration
24
5.3
Definition of Dose-Limiting Toxicity (DLT)
25
5.4
General Concomitant Medication and Supportive Care Guidelines
26
5.5
Criteria for Taking a Participant Off Protocol Therapy
27
5.6
Duration of Follow Up
28
5.7
Criteria for Taking a Participant Off Study
28
5.8
Replacement Policy
29
6.
DOSING DELAYS/DOSE MODIFICATIONS
29
6.1
Toxicity Related to Bevacizumab
29
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
35
7.1
Adverse Events
35
7.2
Safety Reporting of Adverse Events
42
Adverse Events
42


Protocol #:15-055
Version Date:  October 7, 2020 
5
7.3
Expedited Adverse Event Reporting
46
7.4
Expedited Adverse Event Reporting – Genentech
46
7.5
Expedited Reporting to the Food and Drug Administration (FDA)
48
7.6
Reporting to the Institutional Review Board (IRB)
50
7.7
Expedited Reporting to Hospital Risk Management
50
7.8
Routine Adverse Event Reporting
50
8.
PHARMACEUTICAL INFORMATION
50
8.1
Alectinib
50
8.2
Bevacizumab
52
9.
STUDY CALENDAR AND ASSESSMENTS
54
9.1
Study Assessments
57
●
Informed consent:  Informed consent, documented by a signed consent form, must be 
obtained prior to any screening activities not otherwise part of the participant’s care. A note 
documenting the informed consent procedure should be included in the participant’s medical 
record. Signed, informed consent should be obtained with 28 days of treatment start.
57
●
Demographics: Demographic information consists of the participant’s age, gender, race, 
and ethnicity (as allowed by local law and regulations).
57
●
Diagnosis and Extent of Cancer: The initial cancer diagnosis and the current cancer 
diagnosis at the time of screening (if different), along with dates of diagnosis need to be 
recorded.
57
●
Documentation of an ALK Rearrangement: ALK status to be determined using ALK 
FISH, IHC or next-generation sequencing (NGS). For ALK FISH, positivity is defined as 
>15% positive tumor cells. Local ALK testing is acceptable, provided that archival tissue is 
available for patients deemed ALK positive on the basis of IHC or NGS.
57
●
Concomitant Medications: Concomitant medications for all ongoing medical history 
conditions or AEs must be reported from the date the informed consent is signed until at 
least 30 Days After the End of Treatment, and for all concomitant medications related to 
serious or study drug-related toxicities until the medication is no longer taken or until patient 
contact discontinues. Special focus will be placed on use and dose of corticosteroids over 
time.
57
●
Vital Signs: Vital signs include temperature, pulse, respiratory rate, and blood pressure 
(when patient is seated). In addition, the screening assessment should include height and 
weight.
57
●
ECOG Performance Status: The participant’s performance status must be assessed 
using the ECOG performance scale (Appendix A).
57
●
Physical Exam: A physical examination will be performed, the extent of which should 
be consistent with the medical history and the participant’s underlying disease.
57
●
Hematology: Hematology assessments of the parameters listed in Table 9-1 will be 
tested as per the schedule of assessments (Table 9-1).
57


Protocol #:15-055
Version Date:  October 7, 2020 
6
Table 9-2: Local Clinical Laboratory Parameters Collection Plan
58
●
Chemistry: Clinical chemistry assessments of the parameters listed in Table 9-2 will be 
tested as per the schedule of assessments (Table 9-1).
58
●
Coagulation: Coagulation assessments of the parameters listed in Table 9-2 will be 
tested as per the schedule of assessments (Table 9-1).
58
●
Urinalysis: measurements will be performed as per Table 9-2 and according to the 
schedule of assessments (Table 9-1). Pregnancy Test: During screening, a serum pregnancy 
test will be completed.
58
●
Disease Assessments: At screening, disease assessment must include imaging of the 
chest and abdomen. A CT of the pelvis should also be performed if clinically indicated. A 
gadolinium-enhanced brain MRI is also required at entry and as part of serial assessments 
(Note: Phase I participants with a brain MRI that is negative for intracranial metastases at 
baseline do not require serial brain MRIs as part of their disease assessments). MRI slices 
should be 1 mm for brain metastases measuring 5-10 mm in size. MRI slices of 1-5 mm are 
permitted for brain metastases measuring between 10 and 40 mm.
58
Target and non-target lesions must be selected at study start and followed throughout the 
course of treatment for response assessment according to RECIST version 1.1 guidelines 
(See Section 10) and a modified RECIST for CNS response (Long 2012; Section 10).  
Imaging assessment is also required to be performed at the End of Treatment.
58
●
Tumor Biopsies (Optional): An optional baseline biopsy will be performed on 
participants at the time of study entry (i.e., prior to treatment with alectinib and 
bevacizumab). When possible, a core biopsy is preferred, though not required, over a fine-
needle aspiration or cytology specimen. Among participants previously treated with other 
ALK inhibitors (e.g. crizotinib), tissue will be analyzed for molecular mechanisms of 
resistance. For example, specimens will be assessed for ALK gene amplification, secondary 
mutations in the ALK tyrosine kinase domain, and bypass tract activation.
59
In addition, participants will undergo an optional biopsy at the time of disease progression 
on alectinib/bevacizumab. This will be evaluated for molecular mechanisms of resistance to 
alectinib/bevacizumab (e.g. secondary mutations in the ALK tyrosine kinase domain). Due 
to the evolving nature of the field, not all of the proteins or genes of interest leading to 
response or resistance can be pre-specified in this document.
59
●
Adverse Events: Participants must be followed for all adverse events (AEs) from the 
start of study treatment until at least 30 Days After the End of Treatment, and for all serious 
or study drug-related toxicities until the AEs are resolved or are considered chronic or stable 
or until patient contact discontinues. Serious adverse events (SAEs) should be monitored 
and reported as described in Section 7.
59
10.
MEASUREMENT OF EFFECT
59
10.1
Antitumor Effect – Solid Tumors
59
Complete Response (CR):
61
Disappearance of all target lesions. Any pathological lymph node must have reduction in 
short axis to < 10 mm.
61


Protocol #:15-055
Version Date:  October 7, 2020 
7
Partial Response (PR):
62
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference 
the baseline sum diameters.
62
11.
DATA REPORTING / REGULATORY REQUIREMENTS
64
11.1
Data Reporting
64
11.2
Data Safety Monitoring
64
11.3
Multicenter Guidelines
64
12.
STATISTICAL CONSIDERATIONS
65
12.1
Study Design/Endpoints
65
12.2
Sample Size, Accrual Rate and Study Duration
66
ALK rearrangements are identified in approximately 4-6% of patients with NSCLC. At MGH 
alone, approximately 500 patients with NSCLC undergo genotyping annually. Additionally, 
MGH is a referral center for patients with ALK-positive NSCLC. Recently, data from the 
phase III global ALEX study has established the superiority of alectinib over crizotinib, 
establishing alectinib as a new standard of care. With this new data, we expect to enroll 1-2 
patients per month.
66
12.3
Interim Monitoring Plan
66
12.4
Analysis of Primary Endpoints
67
12.5
Analysis of Secondary Endpoints
67
13.
PUBLICATION PLAN
67
REFERENCES
69
APPENDIX A
PERFORMANCE STATUS CRITERIA
72


Protocol #:15-055
Version Date:  October 7, 2020 
8
1.
OBJECTIVES
Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small 
cell lung cancer that is associated with marked sensitivity to the ALK tyrosine kinase inhibitor (TKI) 
crizotinib.1 Despite the efficacy of crizotinib, however, the majority of ALK-positive patients relapse 
within one to two years. Therapeutic strategies to overcome crizotinib resistance have centered upon 
using structurally-distinct and more potent, second-generation ALK inhibitors, such as alectinib. Alectinib 
is a novel, orally-available next-generation ALK TKI that has shown promising anti-tumor activity in 
preclinical models.2 In a preliminary report of an ongoing phase I/II study in patients who had previously 
failed crizotinib alectinib also appeared effective, with responses seen in ~55% of patients.3 Importantly, 
responses were also seen in the central nervous system (CNS), which has emerged as a frequent site of 
relapse for ALK-positive patients treated with crizotinib. 
Bevacizumab is a recombinant, humanized monocolonal antibody directed against vascular endothelial 
growth factor (VEGF). Although initial clinical trials of bevacizumab excluded patients with known brain 
metastases, more recent data has emerged demonstrating the safety of bevacizumab in NSCLC patients 
with both treated and untreated brain metastases. Moreover, data has emerged combining bevacizumab 
with TKIs in molecularly-defined patient populations with encouraging preliminary results.4 We therefore 
hypothesize that the combination of alectinib and bevacizumab will be safe and tolerable in ALK-positive 
patients. Furthermore, we hypothesize that bevacizumab may normalize tumor vasculature, leading to 
improved drug delivery and increased efficacy of alectinib in the CNS. 
1.1
Study Design
This is a phase I/II trial evaluating the safety and tolerability of alectinib and bevacizumab in patients 
with advanced NSCLC harboring ALK rearrangements. In part I of this study, eligible participants with 
ALK-positive NSCLC will be treated with the combination of alectinib and bevacizumab in order to 
identify the recommended phase II doses of this combination. Participants will be treated using a 3+3 
design. As we expect minimal overlapping toxicities between bevacizumab and alectinib, dose level 1 
will consist of the individual recommended phase II doses of alectinib and bevacizumab. The 
recommended phase II doses for the combination of alectinib and bevacizumab will be defined as either 
a) the highest dosage cohort in which less than 1/3 of patients experience a DLT or b) alectinib at the 
previously defined recommended phase II dose (600 mg twice daily PO) as a single agent plus 
bevacizumab at the highest tolerated dose (15 mg/kg IV every 21 days) investigated in this indication – 
whichever is the lower dose.
In the phase II portion of this study, we will further evaluate the combination of alectinib plus 
bevacizumab in a cohort (N=20) of ALK-positive patients. Eligible participants will receive alectinib plus 
bevacizumab at the recommended phase II doses determined in the phase I portion of the study. Our 
primary objective will be to evaluate the safety and tolerability of alectinib and bevacizumab in this 
patient population. Secondary objectives will be to assess the systemic efficacy of this combination, with 
particular focus on control of brain metastases. Secondary endpoints will include CNS objective response 
rate (ORR), CNS disease control rate (DCR), CNS progression-free survival, overall ORR, overall DCR, 
and progression-free survival. Exploratory endpoints will include molecular profiling of pre- and post-
alectinib/bevacizumab biopsy tissues to evaluate for potential mechanisms of resistance to therapy. Post-
treatment biopsies will be optional. Efficacy assessments (CT chest/abdomen and brain MRI) will be 
performed every 2 cycles for the first 10 cycles, after which assessments will be performed every 3 
cycles. For patients with baseline brain metastases, CNS efficacy will be measured using a modified 
RECIST criteria.5 Treatment will continue until disease progression, unacceptable toxicity, patient 
withdrawal, death or discontinuation from the study for any other reason. Of note, participants who are 
clinically benefitting may continue on treatment post-progression. 


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1.2
Primary Objectives
Phase I:
●
To determine the recommended phase II doses (RP2Ds) of the combination of alectinib and 
bevacizumab
Phase II:
●
To evaluate the safety and tolerability of alectinib and bevacizumab at the RP2Ds as assessed by 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
1.3
Secondary Endpoints
Phase I: 
●
Safety, tolerability and dose-limited toxicities
Phase II:
●
CNS Objective Response Rate 
●
CNS Disease Control Rate
●
Time to CNS progression
●
Overall (Intra- and Extra-CNS) Objective Response Rate
●
Overall (Intra- and Extra-CNS) Disease Control Rate
●
Progression-free survival (PFS)
●
Patient Reported Functioning and Impact on Disease/Treatment-Related Symptoms of Brain 
Metastases and Global QOL 
●
Select tumor genotyping of pre- and post-alectinib/bevacizumab biopsies (optional)
2.
BACKGROUND
2.1
ALK-Positive Lung Cancer
Lung cancer is the leading cause of cancer-related mortality in the United States. The disease is 
traditionally divided into non-small-cell and small-cell variants, with non-small-cell lung cancer 
(NSCLC) accounting for approximately 85% of cases.6 Despite improved therapies, patients with NSCLC 
often present with an advanced stage, portending a poor long term prognosis. 
Recently, it has been recognized that NSCLC can be further divided into molecularly-defined subsets. 
This, in turn, has translated into effective new targeted therapies. In 2007, Soda et al. identified the 
echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion 


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oncogene in NSCLC.7 This novel oncogene is formed by an inversion in the short arm of chromosome 2, 
which results in the fusion of the EML4 gene and exons 20-29 of ALK. Multiple variants of EML4-ALK 
have since been reported. Although the variants preserve the same cytoplasmic portion of ALK, they 
possess different truncations of EML4.8 Subsequent work has demonstrated that EML4 is not the sole 
fusion partner for ALK, though it is the most common in NSCLC.9 These fusion partners facilitate ligand-
independent dimerization of ALK leading to constitutive kinase activation.10 ALK rearrangements have 
since been recognized to possess potent transforming activity in cell lines and transgenic mouse models.11 
Rearrangements in ALK are identified in approximately 3-5% of patients with NSCLC.10 Patients 
harboring ALK rearrangements typically possess unique clinicopathologic features, including younger 
age, never- or light-smoking history, and adenocarcinoma histology.12 Consistent with preclinical studies, 
this subset of patients is uniquely sensitive to targeted tyrosine kinase inhibition. In a phase I trial of the 
ALK tyrosine kinase inhibitor (TKI) crizotinib, patients with ALK-rearranged, metastatic NSCLC 
experienced an overall response rate of approximately 60% and a median progression free survival of 10 
months.1,13 Based upon impressive disease activity from this and another early phase clinical trial, 
crizotinib was granted accelerated approval by the US Food and Drug Administration in August, 2011, 
followed by full regulatory approval in November 2013. In more recent phase III trials, crizotinib has 
been shown to produce significant improvements in response rate and PFS compared to first- and second-
line cytotoxic chemotherapy.14,15 In retrospective analyses, crizotinib has also been associated with 
improved overall survival compared to ALK-positive, crizotinib-naïve controls.16   
Despite the efficacy of crizotinib in ALK-positive NSCLC, patients invariably relapse - typically within 
1-2 years. To date, several different mechanisms of acquired resistance have been identified among ALK-
positive patients.17 Secondary mutations in the ALK tyrosine kinase domain have been found in 
approximately 30% of patients.17-19 These resistance mutations are distributed throughout the ALK 
tyrosine kinase domain and confer differential sensitivities to next-generation ALK inhibitors in vitro. 
The most common ALK secondary mutations are G1269A and the gatekeeper mutation L1196M.20 In 
addition to these ALK resistance mutations, ALK gene amplification has been identified in approximately 
10% of crizotinib-resistant patients.17 It is now appreciated that acquired resistance to crizotinib can also 
occur as a result of up-regulation of bypass signaling tracts. Specifically, in crizotinib-resistant biopsy 
specimens, ligand-dependent EGFR activation (~40%) and c-KIT gene amplification (15%) have been 
observed.17 Still, approximately one-third of crizotinib-resistant patients have no known mechanisms of 
resistance identified to date. To date, therapeutic strategies to overcome crizotinib resistance have 
centered on using more potent and structurally-distinct, second-generation ALK inhibitors. 
2.2
Overview of Alectinib
Alectinib (also RO5424802 or CH5424802) is a newly developed small molecule, highly selective, and 
potent oral next-generation ALK inhibitor with a benzo[b]carbazole scaffold. In enzyme inhibition assays 
performed in vitro, this compound has been shown to selectively inhibit ALK. The compound also shows 
high antitumor activity both in vitro and in vivo against tumor cell lines with ALK gene alterations, 
including NSCLC and anaplastic large cell lymphoma lines harboring ALK rearrangements and a 
neuroblastoma line harboring ALK amplification. 
Nonclinical pharmacology studies have demonstrated that alectinib is efficacious in a model of tumors 
expressing an ALK fusion bearing the L1196M mutation, which is associated with resistance to 
crizotinib. Alectinib is also effective in mouse NCI H2228 NSCLC xenografts that are already maximally 
suppressed by crizotinib. Alectinib also prolongs survival in an intracerebral NCI H2228 implantation 
model, and it reduces tumor growth in an intracranial model monitored using bioluminescence.


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The clinical development program for alectinib, to date, comprises three ongoing Phase I/II studies in 
patients with ALK-positive NSCLC. The ongoing Phase I/II studies are as follows: Study AF-001JP, 
which is being conducted in Japan; Study NP28761/AF-002JG, which is being conducted in North 
America; and Study NP28673, which is being conducted globally.
The first-in-human study AF-001JP is an open-label Phase I/II study being conducted in
Japan. This study is assessing the pharmacokinetics, safety, and efficacy of alectinib in patients with 
ALK-positive NSCLC who are crizotinib-naïve and have disease progression after at least one line of 
chemotherapy. This study has completed enrollment, but it is still ongoing. A total of 70 patients were 
included (24 patients in the Phase I portion and 46 patients in the Phase II portion of the study). In the 
Phase I portion of the study, at the data cutoff date of 31 July 2012, 24 patients were treated at doses of 
20−300 mg twice daily (BID). No dose-limiting toxicities (DLTs) or adverse events of Grade 4 were 
noted up to the highest dose; thus, 300 mg BID was evaluated in the Phase II portion of the study without 
further escalating the dose. In the Phase II portion of the study, 46 patients were treated with the highest 
evaluated dose of 300 mg
BID, of whom 43 achieved an objective response (93.5%; 95% CI: 82.1%, 98.6%) and
7 patients had a complete response (CR) on the basis of an independent radiological review in the 12-
month follow-up analysis (data cutoff for response data: 18 April 2013). The median duration of 
treatment (DOT) in the study has not been achieved at that date because 86% of patients were still on 
treatment in the study, but the projected median DOT is more than 14 months as data mature.
Figure 2.1 shows the waterfall plot of the best change from baseline in the size of target lesions by an 
independent radiological review. The majority (86%) of patients had a time to response of within 6 weeks 
after administration of the first dose.
FIGURE 2.1: Change in Size of Target Lesions by the Independent Review Committee in Part 2 of 
Study AF-001JP (Data Cutoff Date: 18 April 2013)


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Two of 7 patients who were assessed as having a CR had lymph nodes as the target lesions. Per Response 
Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), the percent change from baseline for 
patients with CR can be less than 100% when lymph nodes are identified as the target lesions. Therefore, 
they were assessed as having CR, although their tumor change from baseline was less than 100%. 
In Study NP28761/AF-002JG (crizotinib-failed ALK-positive NSCLC patients), the Phase I portion has 
completed enrollment. Two ‘bridging’ cohorts of patients receiving alectinib using the 150-mg capsule at 
600 and 900 mg BID were included in Study NP28761/AF-002JG to transition/facilitate the planned 
formulation for the Phase II trials. A total of 47 patients were enrolled in Phase I (Part 1). There does not 
appear to be any substantial difference in pharmacokinetics between the two formulations (20/40-mg 
capsule and the 150-mg capsule) at the 600-mg dose on the basis of available data.
The radiological imaging analysis performed in 44 evaluable patients who had a baseline scan and at least 
one follow-up scan (data cutoff date: 12 September 2013) has shown that 2 of 7 patients in the 300-mg 
BID dosage cohort, 5 of 7 patients in the 460-mg BID dosage cohort, 4 of 10 patients in the 600-mg BID 
dosage cohort, and 4 of 13 patients (including 1 patient with CR) in the 900-mg BID dosage cohort have 
achieved a confirmed partial response (PR), as assessed by the investigator. Three of 10 patients in the 
600-mg BID dosage cohort, 2 of 7 patients in the 760-mg BID dosage cohort, and 4 of 13 patients in the 
900-mg BID dosage cohort have achieved a PR, as assessed by the investigator, which is still to be 
confirmed. Three patients (all in the 600-mg BID dosage cohort) were not evaluable. The ORR was 
54.5% (i.e., 24 of 44 evaluable patients who had a baseline scan and at least one post-treatment scan 
available to determine overall response, or who had a best overall response of progressive disease [PD] 
determined by the investigator, on the basis of symptomatic progression [3 patients]), including 
unconfirmed responses across all dose cohorts. Thirty-three of the 47 (70%) treated patients were still 
receiving study treatment. 
The waterfall plot for the 42 patients, with a post-baseline radiological tumor assessment, is shown in 
Figure 2.2. On the basis of the data analyzed at that date, 27 patients experienced tumor shrinkage of > 
30%, of whom 23 patients were assessed as experiencing PR (9 of which are still to be confirmed by a 
second tumor assessment).
Figure 2.2: Best Percent Change in Size of Target Lesions from Baseline as Assessed by the 
Investigator in Part 1 of Study NP28761/AF-002JG


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Study NP28673 started enrollment on 20 June 2013 and has since completed enrollment. No data are 
available to report at this time.
The first Phase I dose-escalation study of alectinib conducted only in Japan (Study AF001-JP), with a 
dose schedule of 20, 40, 80, 160, 240, and 300 mg BID orally, showed that alectinib was generally well 
tolerated without major toxicities. Of the 58 patients who received treatment with 300 mg BID alectinib 
in Study AF-001JP, 27 experienced Grade 3 adverse events and 9 experienced serious adverse events. No 
deaths were reported during this study and up to 28 days after treatment discontinuation. There were 5 
adverse events leading to treatment discontinuation in Part 2 (brain edema, sclerosing cholangitis, 
interstitial lung disease [ILD], ALT increased, and tumor hemorrhage). Alectinib was well tolerated at all 
doses investigated in this study. Its adverse event profile was consistent with other ALK TKIs.
In the Phase II Study NP28761/AF-002JG, alectinib was well tolerated, with no DLTs or treatment-
related dose modifications up to 600 mg BID. Two DLTs were reported at 900 mg BID. The 
recommended alectinib Phase II dosage of 600 mg BID was chosen as having the best balance between 
clinical safety, efficacy, and pharmacokinetic (PK) data as observed in the Phase I/II studies. 
More recently, two randomized trials have evaluated the role of alectinib in newly-diagnosed, ALK-
positive NSCLC. J-ALEX was a randomized phase III trial exclusively conducted in Japan (Hida T, et al. 
Lancet 2017). Eligible patients had ALK inhibitor naïve NSCLC and were randomized to receive either 
crizotinib or alectinib (300 mg twice daily). Among 207 patients, alectinib produced a significant 
improvement in PFS (median not reached versus 10.2 months, respectively; HR 0.34, p<0.0001). In a 
subsequent global, randomized phase III trial (ALEX), similar findings were observed (Peters S, et al. 
NEJM 2017). Among 303 previously treated, ALK-positive NSCLC patients, alectinib produced 
significant improvements in PFS (HR 0.47) compared to crizotinib. Based upon these findings, alectinib 
has become a new standard of care for newly diagnosed, ALK+ NSCLC patients.   


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2.3
Overview of Bevacizumab
Bevacizumab is a recombinant monoclonal antibody targeting vascular endothelial growth factor (VEGF), 
a predominant factor in tumour angiogenesis.21 Bevacizumab has been evaluated in more than 3700 
patients over multiple Phase I, II and III studies in various types of tumours (colorectal, breast, lung and 
kidney cancer) and in >3000 patients during post-marketing studies on metastatic colorectal cancer.
In 1st line treatment of NSCLC, bevacizumab administered in combination with carboplatin and paclitaxel 
has shown encouraging results in a randomised Phase II study.22 During this study, 99 patients presenting 
with NSCLC, relapsed or stage IIIb or IV, were randomised to receive paclitaxel/carboplatin (PC) alone 
or paclitaxel/carboplatin plus bevacizumab (at 7.5 mg/kg or 15 mg/kg every 21 days). The best confirmed 
response rate was greater in the arm treated at the higher dose of bevacizumab as compared to that of the 
control arm (investigator’s evaluation: 32% vs. 19%). Furthermore, the time to progression of the disease 
was greater for the arm at 15 mg/kg (investigator’s evaluation: median of 225 days vs. 129 days for the 
control arm).
Two pivotal phase III studies on bevacizumab combined with chemotherapy have been conducted in 
NSCLC:
-
The phase III study of the Eastern Cooperative Oncology Group (E4599), which evaluated 
bevacizumab combined with first-line carboplatin/paclitaxel chemotherapy in patients with non-
squamous, locally advanced or metastatic NSCLC.23 
-
The AVAIL study (BO17704), an international, phase III, randomised, double-blind, controlled, 
multicentre study evaluated the efficacy and safety of two doses of bevacizumab (7.5 and 15 mg/kg) 
in combination with cisplatin/gemcitabin.24
In study E4599, the addition of bevacizumab to first-line carboplatin/paclitaxel chemotherapy in patients 
with non-squamous, locally advanced or metastatic NSCLC demonstrated an improvement in overall 
survival and progression-free survival (PFS) as compared to chemotherapy alone. Median survival 
increased from 10.3 months for chemotherapy alone to 12.3 months for carboplatin, paclitaxel and 
bevacizumab (HR 0.79, p = 0.003). Median progression-free survival went from 4.5 months for 
chemotherapy to 6.2 months for Bev/CP (HR 0.66, p < 0.001).23
In the AVAIL study, both bevacizumab doses significantly improved progression-free survival and the 
response rate. The results are presented in Table 2.3.
Table 2.3: Efficacy results – Studies E4599 and AVAIL (BO17704)
 Overall survival 
(months)
 Progression-free 
survival
 (months)
Overall 
response rate 
Study E4599
Carboplatin/paclitaxel
(n = 444)
10.3
4.8
12.9%
Carboplatin/paclitaxel + 
bevacizumab 15 
mg/kg/every 3 weeks 
(n = 434)
12.3
HR = 0.80 (p = 0.003)
95% CI (0.69 – 0.93)
6.4
HR = 0.65 (p < 
0.0001)
95% CI (0.56 – 0.76)
29.0%
(p < 0.0001)


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AVAIL Study 
Cisplatin/gemcitabin/ 
placebo
(n = 347)
-
6.1
20.1%*
Cisplatin/gemcitabin/ 
bevacizumab 7.5 mg/kg/ 
every 3 weeks
(n = 345)
-
6.7
HR = 0.75 (p = 
0.0026)
95% CI (0.62 – 0.91)
34.1%*
(p< 0.0001)
Cisplatin/gemcitabin/ 
bevacizumab 15 mg/kg/ 
every 3 weeks
(n = 351)
-
6.5
HR = 0.82 (p = 
0.0301)
95% CI (0.68 – 0.98)
30.4%*
(p = 0.0023)
*Patients for whom the disease was measurable upon entry into the study 
Marketing authorisation of bevacizumab in combination with carboplatin and paclitaxel, in first-line 
treatment of non-squamous, non-resectable, locally advanced, relapsed or metastatic NSCLC, was granted 
in the United States by the FDA in October 2006 and in Europe in August 2007 following the results of 
these trials.
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety signals were 
identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. Additional completed 
Phase II and Phase III studies of bevacizumab as well as spontaneous reports have further defined the 
safety profile of this agent. Bevacizumab-associated adverse events identified in Phase III trials include 
congestive heart failure (CHF) (primarily in metastatic breast cancer), gastrointestinal perforations, 
wound healing complications, and arterial thromboembolic events (ATE). These and other safety signals 
are described in further detail in Section 7 and in the bevacizumab Investigator Brochure. 
2.4
Rationale
Despite the significant activity of ALK inhibitors, such as crizotinib and alectinib, in ALK-positive 
NSCLC, patients invariably develop resistance to therapy. Thus, additional strategies are needed to 
further improve outcomes. Beyond strategies aimed at developing increasingly potent and select ALK 
inhibitors, an alternative therapeutic approach is to explore combination therapy. To date, combination 
partners have included PD-1 inhibitors, MEK inhibitors and heat-shock protein 90 inhibitors, but few 
outcomes have been reported. 
In this study, we aim to explore the combination of alectinib and bevacizumab. This has been, in part, 
informed by the experience of a similar combination in EGFR-mutant NSCLC. At the 2014 ASCO 
Annual Meeting.4 Kato and colleagues presented data from an open-label, randomized study comparing 
the combination of erlotinib and bevacizumab versus erlotinib alone in EGFR-mutant NSCLC without 
CNS metastases. A total of 154 patients were enrolled. Median PFS was 16.0 months for the combination 
arm and only 9.7 months for the erlotinib alone arm (HR 0.54, 95% CI, 0.36-0.79; log rank p = 0.0015), 
suggesting that the addition of bevacizumab to EGFR TKIs results in improved systemic efficacy in a 
molecularly-defined population. As bevacizumab has also been shown to improve overall survival when 
combined with platinum-based chemotherapy in a general NSCLC patient population (ECOG 4599), we 
hypothesize that the combination of alectinib and bevacizumab will improve outcomes in ALK-positive 
patients. As part of this study, we will be focusing on ALK-positive NSCLC with brain metastases; 


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however, the study has been modified to eliminate brainetastases as an eligibility criterion. 
Metastatic involvement of the CNS is a frequent complication in patients with lung cancer.25 Up to 40% 
of patients with NSCLC ultimately develop brain metastases during the course of their disease.26 In recent 
years, CNS metastases have also been recognized as an emerging complication in patients with ALK-
positive NSCLC. In the PROFILE 1007 trial, for example, approximately 35% of ALK-positive patients 
had brain metastases at the time of study entry.14 Moreover, among patients treated with crizotinib, the 
CNS is among the most common sites of relapse on therapy.13 Of note, such relapses often occur despite 
continued systemic disease control. Costa and colleagues recently demonstrated that treatment with 
crizotinib results in low CSF-to-plasma ratios, indicative of poor blood brain barrier penetration.27 In turn, 
this may result in a primary pharmacokinetic failure of crizotinib therapy in the CNS. At present, 
management of progressive CNS metastases in these patients typically consists of radiation therapy and 
occasionally surgical resection, but both modalities have the potential for significant morbidity. 
Alectinib is a lipophilic drug and not a P-glycoprotein (P-gp) substrate; thus, it has the potential to 
penetrate the blood-brain barrier and achieve higher concentrations in brain as compared to substrates of 
P-gp, such as crizotinib. This has been shown in the pre-clinical setting on the basis of the prolongation of 
survival in a mouse model with implanted CNS lesions and in a tissue distribution study with a single oral 
dose of [14C]-alectinib at 1 mg/kg to albino rats.28 
In a phase I/II trial conducted in Japan (Study AF-001JP), which enrolled crizotinib-naïve patients, 
alectinib was generally well tolerated and safe.29 In this trial, alectinib was associated with an objective 
response rate of nearly 94%. In a preliminary report of an ongoing phase I/II study in crizotinib-resistant 
patients, alectinib also appeared effective, with responses seen in ~55% of patients.3 Importantly, alectinib 
has also demonstrated activity in patients with CNS metastases, including patients with leptomeningeal 
disease.28 
Preliminary assessments of the CNS activity of alectinib have come from two active studies: Study AF-
001JP in Japan and Study NP28761/AF-002JG in North America. In Phase II of Study AF-001JP, 14 of 
the 46 (30%) crizotinib-naïve patients had documented CNS lesions before enrollment into the trial. 
Three of these 14 patients were asymptomatic and had not received prior CNS radiation. At the clinical 
cutoff date of 18 March 2013, 5 of the 14 patients were off-study because of systemic disease progression 
or an adverse event. Nine patients remain in the study with duration of treatment ranging from 10 to 18 
months (none of these patients presented signs or evidence of systemic disease or CNS progression).
Similarly, in Study NP28761/AF-002JG, among the 47 patients enrolled (data cutoff date: 12 September 
2013), 21 patients (45%) were known to have brain metastases at baseline. Of these 21 patients, 11 (52%) 
achieved an ORR as determined by Independent Review Committee (IRC; data cutoff date: 12 September 
2013).30 Moreover, of these 21 patients, 17 remained on active study treatment and 4 discontinued study 
treatment because of systemic PD (1 patient had both systemic disease and CNS progression). No patient 
discontinued because of CNS progression alone. In addition, 2 patients with leptomeningeal 
carcinomatosis received benefit from alectinib treatment. One patient with leptomeningeal spread in 
Study NP28761/AF-002JG achieved PR after 6 weeks of treatment. Another patient with leptomeningeal 
carcinomatosis but without systemic lesions was treated under a single-patient Investigational New Drug 
(IND) application because of an inability to enter either of the two Phase II alectinib studies (because of 
the high intake of dexamethasone for symptom control). After 6 weeks of treatment, this patient achieved 
a CR as demonstrated by complete disappearance of gadolinium enhancement on magnetic resonance 
imaging (MRI) and clearance of the CSF on cytology. This patient has been able to reduce corticosteroids 
to physiological replacement dosing only.
Bevacizumab is a recombinant, humanized monoclonal antibody directed against vascular endothelial 


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growth factor (VEGF), a key factor in tumor-associated angiogenesis. Although bevacizumab has 
received FDA approval in several tumor types, including NSCLC (Sattler et al, 2006), early concerns 
related to the risk of intracranial hemorrhage initially limited its use to patients with no evidence of brain 
metastases. More recently, however, bevacizumab was shown to be safe and effective in patients with 
recurrent glioblastoma, a primary brain tumor.31 Several retrospective and prospective studies have also 
suggested that the risk of intracranial hemorrhage following treatment with angiogenesis inhibitors is 
relatively similar in patients with and without brain metastases.32-34
In NSCLC, the safety of bevacizumab in patients with treated CNS metastases was demonstrated in the 
phase II PASSPORT trial.34 In this trial, patients with advanced, non-squamous NSCLC received 
bevacizumab in combination with first-line or second-line chemotherapy. Among 106 evaluable patients, 
there were no episodes of grade ≥ 2 CNS hemorrhage. More recently, preliminary data from a phase II, 
non-comparative study of bevacizumab in NSCLC patients with untreated brain metastases were 
presented.35 In this two-arm trial, patients were treated with first-line carboplatin/paclitaxel/bevacizumab 
or second-line erlotinib/bevacizumab. Among patients receiving first-line 
carboplatin/paclitaxel/bevacizumab (n=67), approximately 60% experienced intracranial objective 
responses, while an additional 28% experienced stable disease in the CNS. Among those patients 
receiving erlotinib/bevacizumab (n=24), the intracranial disease control rate was nearly 70% (objective 
response rate 20%; stable disease 50%). Importantly, only 1 (1.1%) patient developed an intracranial 
hemorrhage across the entire study population. 
2.5
Correlative Studies Background
Patient-derived biopsies have emerged as powerful 
tools for elucidating molecular mechanisms of 
resistance to crizotinib and other next-generation 
ALK TKIs (e.g., ceritinib, alectinib). To date, 
several different mechanisms of acquired resistance 
have been identified among ALK-positive patients 
(Figure 3). For example, secondary mutations in the 
ALK tyrosine kinase domain have been found in 
approximately 30% of patients.17-19 These 
resistance mutations are distributed throughout the 
ALK tyrosine kinase domain and confer differential 
sensitivities to next-generation ALK inhibitors in 
vitro. The most common ALK secondary mutations 
following treatment with crizotinib are G1269A 
and the gatekeeper mutation L1196M.20 In addition 
to these ALK resistance mutations, ALK gene 
amplification has been identified in approximately 10% of crizotinib-resistant patients.17
It is now appreciated that acquired resistance to crizotinib can also occur as a result of up-regulation of 
bypass signaling pathways. Specifically, in crizotinib-resistant biopsy specimens, ligand-dependent 
EGFR activation (~40%) and c-KIT gene amplification (15%) have been observed.17 Moreover, multiple 
different mechanisms of resistance have been identified in the same patient. Still, approximately one-third 
of crizotinib-resistant patients have no known mechanisms of resistance identified to date. 
Notably, molecular mechanisms of resistance may vary in response to different ALK inhibitors. For 
example, nearly 50% of ALK-positive patients who acquired resistance to the second-generation ALK 
inhibitor ceritinib were found to have ALK resistance mutations at two residues, G1202 and F1174 


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(Friboulet). Notably, the G1202R resistance mutation was also observed in a case report of an ALK-
positive patient with resistance to alectinib (Ou, JTO).
As part of this study, we aim to collect optional pre- and post-treatment biopsies from participants. These 
biopsies will be evaluated for molecular mechanisms of resistance. Specifically, we will evaluate for ALK 
resistance mutations, ALK amplification, and activation of bypass signaling pathways. Due to the 
evolving nature of the field, not all of the proteins or genes of interest leading to resistance can be pre-
specified in this document. Molecular techniques may include but will not necessarily be limited to: 
targeted next-generation sequencing, FISH studies, and whole-exome sequencing. 
3.
PARTICIPANT SELECTION
Participants must meet the following eligibility criteria for study entry: 
3.1
Eligibility Criteria 
●
Histologically or cytologically confirmed advanced (stage IIIB or IV) non-squamous, non-small cell 
lung cancer.
●
Molecular confirmation of an ALK rearrangement using ALK FISH, IHC or next-generation 
sequencing (NGS). For ALK FISH, rearrangements must be detected in >15% of tumor cells. If an 
ALK rearrangement has been detected by IHC or NGS, archival tissue must be available to confirm 
ALK positivity by FISH.
●
Age ≥ 18 years old. 
●
Life expectancy > 12 weeks.
●
ECOG performance status 0-2. 
●
Adequate hematologic function:
o
ANC ≥ 1500 cells/μL
o
Platelet count ≥ 100 x 1009/L
o
Hemoglobin ≥ 8 g/dL
●
Adequate renal function:
o
An estimated Glomerular Filtration Rate (eGFR) calculated using the Modification of 
Diet in Renal Disease (MDRD) equation of at least 45 mL/min/1.73 m2
●
Coagulation
o
International normalized ratio (INR) ≤ 1.5, and
o
PTT ≤ 1.5 x ULN
●
For all females of childbearing potential, a negative pregnancy test must be obtained within 3 
days before starting study treatment.
●
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or 
combined contraceptive methods that result in a failure rate of < 1% per year during the treatment 
period and for at least 3 months after the last dose of study drug. Abstinence is only acceptable if it is 


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in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of 
contraception. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year 
include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods 
(e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure 
rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
●
For men: agreement to remain abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of < 1% per year during the treatment period and for at least 3 months 
after the last dose of study drug. Abstinence is only acceptable if it is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
●
Able and willing to provide written informed consent prior to performing any study-related 
procedures and to comply with the study protocol, including patients must be willing and able to use 
the electronic patient-reported outcome (ePRO) device.
●
At least one measurable lesion based upon RECIST version 1.1.
3.2
Exclusion Criteria
Participants who meet any of the following criteria will be excluded from study entry: 
●
Squamous cell histology or mixed, predominantly squamous adenosquamous carcinoma
●
Previous history of haemoptysis (expectoration of more than 2.5 mL of blood), within three months 
prior to enrolment.
●
Tumour infiltrating into large vessels or infiltrating into the proximal tracheobronchial network, 
visible on medical imaging. The investigator or radiologist must rule out tumours that conjoin, 
surround or extend into the immediate area of a large vessel (e.g.: pulmonary artery, superior vena 
cava).
●
Unstable, symptomatic brain metastases. Asymptomatic CNS metastasis noted on baseline scans 
are acceptable after discussion and approval from the Overall PI of the study.   
●
History of hemorrhagic CNS metastases
●
History of intracranial hemorrhage (either by clinical history or neuroimaging)
●
History of or genetic predisposition to a bleeding diathesis or coagulopathy
●
Therapeutic anticoagulation, including but not limited to: low-molecular weight heparin (LMWH), 
heparin, or warfarin. Anticoagulants must be discontinued 10 days prior to the first administration 
of bevacizumab. Prophylactic use of anticoagulants is allowed. 


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●
Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or 
other  nonsteroidal anti-inflammatories known to inhibit platelet function. Prophylactic use of 
anticoagulants is allowed. 
●
Clinically significant heart disease (i.e., active), stroke or myocardial infarction within 6 months 
prior to enrolment, unstable angina pectoris, congestive heart failure of grade > II according to 
the New York Heart Association (NYHA), or cardiac arrhythmia requiring specific treatment 
during the study and that may interfere with the follow-up of the study treatment or poorly 
controlled by treatment.
●
Arterial or venous thromboembolic events within 6 months of study enrolment. 
●
Poorly controlled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg), 
with or without antihypertensive medication. Patients presenting with high blood pressure are 
eligible if the dose or adjustment of anti-hypertensives lowers blood pressure to meet the 
inclusion criteria of the study.
●
Invasive surgical intervention (including biopsy by surgical route), major traumatic injury during 
the 28 days prior to the start of treatment, or scheduled invasive surgical intervention during the 
study treatment. 
●
Minor surgical intervention, including placement of a permanent catheter within 24 hours prior to 
the first infusion of bevacizumab.  
●
Non-healing wound, active peptic ulcer or bone fracture.
●
Previous history of abdominal fistula, tracheoesophageal fistula or other fistula with grade 4 
severity, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to 
enrolment.
●
Proteinuria at baseline. Subjects unexpectedly found to have ≥2+ proteinuria on a urine dipstick 
at baseline should undergo a 24-hour urine which must be an adequate collection and must 
demonstrate <2 g of protein/24 hr to allow participation in the study. 
●
Patients who have received previous anti-angiogenic treatment (experimental or marketed: 
bevacizumab, thalidomide, CP-547632, sunitinib, sorafenib or others). 
●
Patients previously treated with alectinib 
●
Radical radiotherapy to the thorax with curative intent within 28 days of initiation of study drug 
treatment; palliative radiotherapy for bone lesions outside of the thorax or brain within 14 days of 
the first dose of study treatment; palliative radiotherapy to the brain or thorax within 28 days of the 
first dose of study drug treatment. 


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●
Cytotoxic chemotherapy within 21 days prior to enrolment. 
●
Treatment with crizotinib within 7 days prior to enrolment. For all other ALK TKIs, the washout 
period should 3 days prior to enrolment.  A shorter washout period may be considered after 
discussion with the Overall Investigator. 
●
Any GI disorder that may affect absorption of oral medications, such as mal-absorption syndrome 
or status post major bowel resection. 
●
Liver disease characterized by: ALT or AST > 3 × ULN (≥ 5 × ULN for patients with concurrent 
liver metastasis) 
OR
Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or other        
conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, 
hypoalbuminemia, ascites, and bleeding from esophageal varices
OR
Acute viral or active autoimmune, alcoholic, or other types of hepatitis
●
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
(version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g. radiotherapy) (excluding 
alopecia), which have not shown improvement and are strictly considered to interfere with current 
study medication.
●
History of organ transplant. 
●
Co-administration of anti-cancer therapies other than those administered in this study.
●
Patients with baseline QTc > 470 ms or patients with symptomatic bradycardia.
●
History of hypersensitivity to any of the additives in the alectinib drug formulation (lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, 
sodium lauryl sulfate [SLS], magnesium stearate).
●
Documented allergy or hypersensitivity to monoclonal antibodies (bevacizumab), to Chinese 
hamster ovarian cells of the or to any other humanised or recombinant antibodies.
●
A history of drug-induced pneumonitis or hypersensitivity pneumonitis from prior ALK TKI 
therapy. 
●
Pregnant or lactating women.
●
Known HIV positivity or AIDS-related illness.
●
Any clinically significant concomitant disease or condition that could interfere with, or for which 
the treatment might interfere with, the conduct of the study or the absorption of oral medications 
or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient 
in this study.


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4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for Clinical 
Trials (QACT) central registration system. Registrations must occur prior to the initiation of protocol 
therapy. Any participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the QACT 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause treatment delays 
should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study must be canceled. Notify the 
QACT Registrar of registration cancellations as soon as possible. 
4.2
Registration Process for DF/HCC and DF/PCC Institutions
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin protocol therapy during off-hours 
or holidays, call the QACT registration line at 617-632-3761 and follow the instructions for registering 
participants after hours.
The registration procedures are as follows:
●
Obtain written informed consent from the participant prior to the performance of any protocol 
specific procedures or assessments. 
●
Complete the QACT protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for 
registration to the protocol, the participant must meet all inclusion and exclusion criterion 
as described in the protocol and reflected on the eligibility checklist.
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a treatment 
protocol. Registration to both treatment and ancillary protocols will not be completed if eligibility 
requirements are not met for all studies. 
●
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-632-2295. 
For Phase I protocols, attach participant dose level assignment confirmation from the sponsor.
●
The QACT Registrar will (a) review the eligibility checklist, (b) register the participant on the 
protocol, and (c) randomize the participant when applicable.
●
An email confirmation of the registration and/or randomization will be sent to the Overall PI, 
study coordinator(s) from the Lead Site, treating investigator and registering person immediately 
following the registration and/or randomization.


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4.3
General Guidelines for Other Investigative Sites
N/A
4.4
Registration Process for Other Investigative Sites
N/A
5.
TREATMENT PLAN
For this study, the terms “study drug(s)” will refer to the combination of alectinib and bevacizumab. 
In the phase I portion of this study, eligible participants with ALK-positive NSCLC will be treated with 
the combination of alectinib and bevacizumab in order to identify the recommended phase II doses of this 
combination. As we expect minimal overlapping toxicities between alectinib and bevacizumab, dose 
cohort 1 will be the combination of alectinib at its recommended phase II dose (600 mg twice daily) and 
bevacizumab at it’s highest tolerated dose (15 mg/kg IV every 21 days) investigated in this indication.22 
This dose of bevacizumab has been used in combination with other TKIs (e.g., erlotinib) and standard 
platinum-based chemotherapy doublets (e.g, carboplatin and paclitaxel) with acceptable side effect 
profiles.23,35,36 Participants will be treated using a 3+3 design. Three patients will be treated per cohort for 
one cycle (21 days per cycle) beginning with dose cohort 1. If no DLTs are observed with dose cohort 1, 
we will enroll an additional 3 participants (6 total) and proceed with the phase II portion of the trial if one 
or less experience a DLT. In subsequent dose cohorts, if one of three patients experiences a DLT, another 
3 patients will be treated at the same dose level for one cycle. If no additional DLTs are observed, we will 
proceed with the phase II portion of the trial. If more than one of 3 patients develops a DLT in any cohort, 
another 3 patients will be treated in the next lowest lower dose cohort. We will continue until 
identification of the recommended phase II doses for the combination of alectinib and bevacizumab. The 
recommended phase II doses for the combination of alectinib and bevacizumab will be defined as either 
a) the highest dosage cohort in which less than 1/3 of patients experience a DLT or b) alectinib at the 
previously defined recommended phase II dose (600 mg twice daily PO) as a single agent plus 
bevacizumab at the highest tolerated dose (15 mg/kg IV every 21 days) investigated in this indication – 
whichever is the lower dose.
In the phase II portion of this study, we will evaluate the combination of alectinib plus bevacizumab in 
ALK-positive patients with untreated or progressive, asymptomatic brain metastases. Eligible participants 
will receive alectinib plus bevacizumab at the recommended phase II doses determined in the phase I 
portion of the study. 
5.1
Treatment Regimen
One treatment cycle will consist of 21 consecutive days. A 3-day window period will be authorized 
throughout the study period. 
Alectinib will be administered twice daily on an outpatient basis. Bevacizumab will be administered as an 
infusion every 3 weeks. 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose modifications 
are described in Section 6.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy.


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Please see Table 5.1 and Table 5.2 for the Dose Escalation Schedule and Regimen Description, 
respectively.  
Table 5.1
Dose De-escalation Schedule
Dose
Dose Level
Alectinib
Bevacizumab
Level 1: Starting Dose
600 mg BID
15 mg/kg IV every 3 weeks
Level minus 1
600 mg BID
7.5 mg/kg IV every 3 weeks
Level minus 2
450 mg BID
7.5 mg/kg IV every 3 weeks
Table 5.2
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Alectinib
Should be taken 
within 30 minutes of a 
meal
Dose as 
appropriate for 
assigned dose 
level 
Oral
Days 1-21
Bevacizumab
Do NOT administer or 
mix with glycolated 
solutions.
Dose as 
appropriate for 
assigned dose 
level
IV infusion 
lasting 30-90 
minutes*
Day 1
* The initial dose of bevacizumab will be administered in 90 (± 15) minutes. If the first 
infusion is tolerated well and there are no associated adverse events (fever or shivering), the 
second infusion may be administered in 60 (± 10) minutes. If the infusion is tolerated well 
in 60 minutes, all subsequent administrations may be performed in 30 (± 10) minutes.
21 days 
(3 weeks)
5.2
Agent Administration
5.2.1
Alectinib
Alectinib comes in a capsule dosage form containing the following active ingredient:
[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11- dihydro-5H-
benzo[b]carbazole-3-carbonitrile hydrochloride


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Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, carmellose 
calcium, hydroxypropyl cellulose, SLS, and magnesium stearate. Alectinib capsules should be stored in 
accordance with the storage instructions on the label.
Alectinib capsules should be administered orally BID with food (within 30 minutes after a meal, in the 
morning and evening).
If a patient misses a dose, it can be taken within 6 hours of the scheduled time. If the time is greater than 6 
hours, or if the patient vomits the dose, the patient should wait until the next scheduled time and take the 
next scheduled dose. Patients should not take two doses at the same time to make up for a missed dose.
Guidelines for dosage modifications and treatment interruptions or discontinuation due to specified 
adverse events are provided in Section 6. 
For further details, see the alectinib Investigator's Brochure.
5.2.2
Bevacizumab
Bevacizumab will be administered on day 1 of each cycle. The bevacizumab dose will be per the assigned 
dose cohort level (Phase I) or the recommended phase II dose (Phase II).  
The initial dose of bevacizumab will be administered in 90 (± 15) minutes. If the first infusion is tolerated 
well and there are no associated adverse events (fever or shivering), the second infusion may be 
administered in 60 (± 10) minutes. If the infusion is tolerated well in 60 minutes, all subsequent 
administrations may be performed in 30 (± 10) minutes. 
Do not administer by direct intravenous or bolus injection
In case of extravasation of the study treatment, the following procedures will be followed:
-
Stop the infusion
-
If the volume of the remaining product is significant, restart the infusion at another site on the 
same arm.
Treat the infiltration according to the guidelines of the centre for infiltration of a non-caustic product.
**Note: During the COVID-19 pandemic, bevacizumab infusions may be held in the absence of toxicity 
at the discretion of the investigation in order to minimize patient exposures in the clinic. 
5.3
 Definition of Dose-Limiting Toxicity (DLT) 
Safety will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Select Adverse Events will be closely monitored, including intracranial hemorrhage, bleeding, 
arterial/venous thrombotic events, hypertension, interstitial lung disease (ILD), hepatobiliary tests 
elevations, hematologic abnormalities, GI disorders, skin disorders, vision disorders, abnormal renal 
function, proteinuria, muscular adverse events and CPK increases. 
For the purposes of this protocol, the DLT determination period will be 21 days (1 cycle). DLTs are 
defined as drug-related toxicities that meet any one of the following criteria:
Non-hematologic toxicities: 
●
Grade ≥ 2 intracranial hemorrhage


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●
Any grade ≥ 3 non-hematologic toxicity (except for the following):
o
Alopecia;
o
Grade 3 or 4 hypophosphatemia;
o
Grade 3 or 4 hyperuricemia without signs or symptoms of gout;
o
Transient electrolyte abnormalities that resolve to ≤ grade 1 in less than 2 days
o
Diarrhea, nausea, vomiting, and hypertension that recovers to grade 2 or lower with 
appropriate treatment; 
o
Grade 3 AST or ALT elevations when grade 2 AST or ALT elevations were present at 
baseline (unless grade 3 AST or ALT elevations are present for 7 days or grade 4 AST or 
ALT elevations are observed)
●
Adverse events that require interruption of treatment for a total of ≥ 7 days
Hematologic toxicities:
●
Febrile neutropenia not related to the underlying study disease (fever, >101 ºF; absolute 
neutrophil count <500);
●
Prolonged grade 4 neutropenia (>7 days);
●
Grade 3 neutropenia with grade ≥ 3 infection; 
●
Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days
Management and dose modifications associated with the above adverse events are outlined in Section 6.
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
Permitted Therapy
Concomitant medication includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal 
or homeopathic remedies, nutritional supplements) used by a patient from 28 days prior to screening to 
the study completion/discontinuation visit. All concomitant medications should be reported to the 
investigator and recorded on the CRFs. 
Caution should be exercised when the following are co-administered with alectinib:
●
For medications that are substrates of P-gp transporter or breast cancer resistance protein 
transporter, the investigator should use caution and monitoring when considering concomitant use 
of alectinib. Alectinib has been shown to have potential for inhibition of these transporters. 
Substrates with a narrow therapeutic index (e.g., methotrexate, digoxin) should be avoided. If co-
administration cannot be avoided, it is recommended that drug levels and/or signs for toxicity are 
carefully monitored (see Appendix B).
Caution should be exercised when the following are administered with bevacizumab:
●
Aspirin and NSAIDS: Since the most serious toxicities observed with bevacizumab to date are 
hemorrhages, thromboses, and gastrointestinal perforations, the use of aspirin and NSAIDs must 
be limited. 
o
Participants who require long-term administration of aspirin (>325 mg/day) or non-
steroidal anti-inflammatory drugs that inhibit platelet function at doses used to treat 
chronic inflammatory diseases will not be included in the study (see inclusion and 
exclusion criteria). 
o
Administration of low doses of aspirin (≤ 325 mg/day), occasional administration of 
nonsteroidal anti-inflammatory drugs or nonsteroidal anti-inflammatory drugs inhibiting 
platelet function is authorised. Patients presenting with a venous thromboembolic 


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accident during the trial will be withdrawn from bevacizumab treatment as described in 
section 6.
5.4.2
Prohibited Therapy
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) is prohibited during the study and for at least 14 days prior to initiation 
of study treatment, unless otherwise specified below. Exceptions to the below listed concomitant 
therapies restrictions (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) may be made if the rationale is discussed and documented between the 
investigator and the Sponsor/Principal Investigator. 
●
Anticoagulants (e.g., LMWH, Coumadin) are prohibited within 10 days of the first administration 
of bevacizumab and for the entire duration of treatment. 
●
Anti-platelet agents (e.g., ticlopidine, clopidogrel) 
The above lists of medications are not necessarily comprehensive. Thus, the investigator should consult 
the prescribing information for any concomitant medication as well as the Internet references provided 
below when determining whether a certain medication can be given. In addition, the investigator should 
contact the Sponsor/Principal Investigator if questions arise regarding medications not listed above.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf
5.4.3
Supportive Care Guidelines
Patients should receive full supportive care including transfusions of blood and blood products, antibiotics, 
analgesia etc, according to local practice/institutional guidelines where appropriate. Anti-emetic medication 
should be prescribed according to local practice
Treatments received prior to the study entry and that are not prohibited by the protocol will be continued 
by the patients during the study, depending on their doctor’s recommendations. All concomitant 
medication(s) must be reported in the case report form. 
Palliative radiation therapy will be permitted for participants with symptomatic bone metastases provided 
that the participant continues to derive clinical benefit from study drugs in the opinion of the Investigator. 
Alectinib should be held for at least 72 hours before the initiation of radiation and resumed no sooner than 
72 hours after the completion of radiation. 
In the event of progression of disease in the CNS, cerebral radiotherapy is permitted where 
appropriate.  Bevacizumab should be held for 14 days following completion of radiation. Alectinib 
should be held for at least 72 hours before cranial radiation and resumed no sooner than 72 hours after the 
completion of cranial radiation. 
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In 
the absence of treatment delays due to adverse event(s), treatment may continue until one of the following 


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criteria applies:
●
Disease progression. Note: In some cases, despite disease progression by RECIST criteria, 
participants may be continued on study drugs if deemed beneficial by the participant and 
investigators. Depending on the participant’s prior tolerance of therapy, he/she may continue 
alectinib/bevacizumab or single-agent alectinib or bevacizumab at the same doses/schedules 
following disease progression (if determined appropriate by the investigator).  
●
Intercurrent illness that prevents further administration of treatment
●
Unacceptable adverse event(s)
●
Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements
●
Participant decides to withdraw from the protocol therapy
●
General or specific changes in the participant's condition render the participant unacceptable 
for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the case 
report form (CRF). Alternative care options will be discussed with the participant.
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol 
therapy. This form can be found on the QACT website or obtained from the QACT registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately notify 
the Overall PI, Justin Gainor, MD at 617-724-4000 or pager 16567. 
5.6
Duration of Follow Up
The follow-up period for a participant begins after the last completed assessment during the active study 
period. Any participant who discontinued study treatment for any reason other than disease progression, 
death or withdrawal of consent will continue to have tumor assessments every 12 weeks (±14 days). 
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:
●
Lost to follow-up
●
Withdrawal of consent for data submission
●
Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. This 
form can be found on the QACT website or obtained from the QACT registration staff. 


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5.8
Replacement Policy
Subjects who receive bevacizumab and at least 75% of planned alectinib doses in Cycle 1 will be 
considered to have had sufficient study drug exposure to support dose determination. Patients who did not 
receive bevacizumab and/or 75% of planned alectinib doses in Cycle 1 may be replaced, unless the reason 
for the early withdrawal is drug toxicity or drug-related death. Enrollment of a new patient to the current 
cohort will be considered if there is less than the required number of evaluable patients or if the Sponsor 
deems it necessary to add patients for determination of the recommended phase II doses. Enrollment of 
new patients may be considered until at least the minimum number (3) or at most the maximum number 
(6) of evaluable patients is achieved within the cohort. All patients who receive at least part of one dose 
will be included in the safety analysis. Any patient who either completed one cycle of study treatment or 
experienced a DLT during the first treatment cycle is evaluable for MTD. 
6.
DOSING DELAYS/DOSE MODIFICATIONS
6.1
Toxicity Related to Bevacizumab
●
No intra-patient dose modification of bevacizumab is permitted during this study. In the Phase I 
portion of the study, however, DLTs may result in subsequent patient cohorts receiving a lower 
dose level of bevacizumab as outlined in Section 5 
●
In general, the occurrence of toxicity related to bevacizumab (haemorrhage, thromboembolic 
accidents, arterial hypertension, proteinuria, gastrointestinal perforation, complication of the 
healing of wounds, fistula or intra-abdominal abscess, congestive heart failure or allergic 
reaction), will require temporary discontinuation of treatment with bevacizumab. 
●
Treatment with bevacizumab must be permanently discontinued in case of treatment-related 
intracerebral hemorrhage, arterial thromboembolic accident, gastrointestinal perforation and 
grade 4 proteinuria (nephrotic syndrome).
●
In the case of permanent discontinuation of alectinib for toxicity reasons, bevacizumab can be 
administered until progression of the disease at the discretion of the treating investigator, except in 
case of unacceptable toxicity or the decision of the patient or the investigator. 
Allergic reaction related to the administration of bevacizumab/hypersensitivity (e.g. fever, rash, 
urticaria, bronchospasm)
Grades 1, 2 
●
In case of occurrence of reactions related to the infusion, premedication will be administered with 
the subsequent infusion, but the infusion time will not be reduced for the subsequent infusion. If 
the subsequent infusion that is preceded by premedication is tolerated well, the next administration 
can be reduced to 30 ± 10 minutes as long as the premedication is still used. If AEs related to the 
infusion occur with the infusion over 60 minutes, all subsequent infusions will be administered 
over 90 ± 15 minutes (with premedication). Similarly, if AEs related to the infusion appear with 
the infusion over 30 minutes, all subsequent infusions will be administered over 60 ± 10 minutes 


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(with premedication). 
Grade 3:
●
In patients that had a grade 3 reaction, the infusion of bevacizumab will be discontinued and not 
resumed that same day. The permanent discontinuation of bevacizumab or another administration 
with premedication and infusion over 90 ± 15 minutes will be left to the discretion of the 
investigator. If the reaction reappears again during the 90-minute infusion, the investigator may 
test an infusion with a longer flow and gradually increase the flow to achieve an infusion time of 
90 minutes. Upon resuming bevacizumab, the patient must be monitored according to the usual 
routine of the centre, for a duration at least equal to the duration of the reaction.
Grade 4: 
●
Permanent discontinuation of bevacizumab.
**Note: During the COVID-19 pandemic, bevacizumab infusions may be held in the absence of toxicity at 
the discretion of the investigation in order to minimize patient exposures in the clinic
Table 6.1. Modifications of the administration of bevacizumab in case of adverse events
CTCAE Grade
Conduct to follow
Hypertension
Grade 1 or 2
No treatments modifications with bevacizumab
Grade 3
If not controlled at ≤ 150 mmHg with antihypertensive treatment, do not administer 
bevacizumab.
Grade 4
Discontinue bevacizumab.
Signs of Posterior Reversible Leukoencephalopathy Syndrome (PRLS)
Any grade (confirmed on 
an MRI)
Discontinue bevacizumab
Haemorrhaging of the CNS
Any grade
Discontinue bevacizumab
Pulmonary haemorrhage
Any grade
Discontinue bevacizumab
Non-pulmonary, non-CNS haemorrhage
Grade 1
No dose modifications. 


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Grade ≥ 2
Discontinue bevacizumab
Venous thrombosis
Any grade
Discontinue bevacizumab. 
Arterial thromboembolic event (angina pectoris, myocardial infarction, ischemic heart attack, arterial 
thromboembolic attack or any other arterial thromboembolic event) 
Any grade 
Discontinue bevacizumab
Proteinuria
Grade 1 or 2
No dose modifications
Grade 3
Suspend bevacizumab until resolution of grade to ≤ 2 
Grade 4 (nephrotic 
syndrome)
Discontinue bevacizumab
GI Perforation
Grade ≥ 2
(Requiring medical or 
surgical intervention)
Discontinue bevacizumab
Intestinal obstruction
Grade 1 
Keep the patient in the study for partial obstruction NOT requiring medical/surgical 
intervention. 
Grade 2
Suspend bevacizumab  for partial obstruction requiring medical/clinical intervention. 
The administration of treatment will resume after full resolution.
Grade 3 or 4
Discontinue bevacizumab for total obstruction. If surgical intervention is needed, the 
patient will resume treatment after wounds are healed and the assessment of 
investigator.
Dehiscence of wounds requiring medical or surgical treatment (if the wound comes from incision of a 
cavity)
Any grade 
Discontinue bevacizumab
Left ventricular systolic dysfunction
Grade 1 or 2
No dose modifications
Grade 3
Suspend bevacizumab until resolution of grade ≤ 1
Grade 4
Discontinue bevacizumab
Fistula
TE Fistule 
Discontinue bevacizumab


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Any Grade
Any other events  of Grade 3/ 4 that may be related to bevacizumab according to the investigator
Grade 3
Discontinue bevacizumab until resolution of grade ≤ 1.
Grade 4
Discontinue bevacizumab
6.2 Adverse Events Relating to ALK Inhibitors and/or the Tyrosine Kinase Inhibitor Class and 
Alectinib Data
See Table 6.2 for an overview of the management of AEs related to alectinib. 
Of note, participants may remain on alectinib despite discontinuation of bevacizumab, provided they do 
not meet criteria for discontinuation of alectinib as well. 
Table 6.2: Modification of the administration of alectinib in case of adverse events
Event
Action to be Taken
Interstitial lung disease
●
Patients should be monitored for pulmonary symptoms 
indicative of pneumontis
●
Alectinib should be permanently discontinued in patients 
diagnosed with interstitial lung disease
Hepatotoxicity 
●
If ALT or AST > 3 x baseline, repeat testing of ALT, 
AST, ALP and total bilirubin within 48-72 hours, w/ 
inquiry about symptoms.  If upon repeat testing the 
transaminases remain  > 3 × baseline, but are 
not  > 5 × baseline or not accompanied with bilirubin 
increases or do not match any other rule for permanent 
discontinuation, then monitoring can continue as per 
investigator judgment, and dose modification is not 
necessary.
●
At any time during study treatment, if symptoms 
compatible with liver injury are observed, liver enzymes 
should be measured as soon as possible. 
●
Alectinib should be permanently discontinued if any of 
the following occurs: 
- First observation of ALT or AST > 8 x ULN
- ALT or AST > 5 x ULN for > 2 weeks
-
First observation of ALT or AST > 3 x ULN and 
total bilirubin > 2 x ULN
-
First observation of ALT or AST >3 x ULN and the 


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appearance of jaundice or signs of hepatic 
dysfunction or other symptoms (such as fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia [>5%]). 
●
Following alectinib discontinuation, weekly monitoring of 
laboratory values should continue until the abnormal 
values have normalized to pre-treatment levels and/or an 
adequate explanation of the abnormal value is found. 
●
Resumption of alectinib is not allowed in patients 
discontinuing because of any of the above criteria. 
Event
Action to be Taken
Gastrointestinal tract AEs (e.g., 
nausea, vomiting, diarrhea, 
stomatitis)
●
The events are expected to be minimized by taking alectinib 
with meals. In case GI events occur, appropriate measures 
should be taken in accordance with local clinical practice 
guidelines. If GI toxicities are observed and are not 
tolerable, treatment with alectinib should be temporarily 
interrupted until recovery to Grade 1 or lower. 
Skin disorder AEs (e.g., 
photosensitivity, rash)
●
Participants should be advised to avoid prolonged sun 
exposure while taking alectinib and for at least 5 days after 
discontinuation. Participants should also be advised to use a 
broad-spectrum sun screen and lip balm of at least SPF > 50 
to help protect against potential sunburn. 
Vision disorders
●
Investigators should consider referring participants for an 
ophthalmological evaluation according to local clinical 
practice guidelines, particularly if vision disorders persist or 
worsen in severity. Investigators should also advise patients 
to exercise caution when driving or operating machinery 
due to the risk of developing a vision disorder. 
Edema
●
Physical examinations will be performed routinely in 
clinical trials. In case edema events occur, appropriate 
measures should be taken in accordance with local clinical 
practice guidelines. 
Event
Action to be Taken
Abnormal kidney function AEs
●
If, at any time during study treatment, eGFR decreases more 
than 50% of the baseline visit value, the patient has to be 
carefully monitored. All of the underlying factors that may 
have acutely impacted serum creatinine levels need to be 
evaluated and corrected (e.g., dehydration, recent exposure 
to contrast media, increased amount of cooked meat in diet, 


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concomitant medications affecting renal function as 
appropriate, etc). 
●
Any eGFR decrease of more than 50% of the baseline visit 
value requires repeat testing.  If, at the repeat test, the eGFR 
decrease is still more than 50% over the baseline visit value, 
the treatment with alectinib should be interrupted.
●
Alectinib treatment may be resumed with caution if the 
eGFR value has increased to approximately the baseline 
visit value. 
Event
Action to be Taken
Severe myalgia and/or CPK 
Elevations
●
Myopathy should be considered in any patient with diffuse 
myalgia, muscle tenderness or weakness, and/or marked 
elevation of CPK levels. Patients should promptly report 
unexplained muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise or fever. CPK levels 
should be assessed in patients reporting these symptoms. 
●
At the first occurrence of any asymptomatic CPK values (> 
10 x ULN, symptomatic CPK > 5 x ULN, or in the presence 
of severe muscular symptoms with CPK > ULN but ≤ 5 x 
ULN) at any time during study treatment, the patient requires 
monitoring of the CPK values until they are normalized to 
pre-treatment levels or a reasonable explanation for the CPK 
elevation and the symptoms is established. 
Event
Action to be Taken
Other AEs (including bradycardia, 
anemia, ALP increases, dysgeusia) 
or laboratory abnormalities
●
Grade 3 or 4: 
-
Temporarily interrupt alectinib for a maximum of 3 week
-
If improvement to Grade ≤ 1 or baseline does not occur 
within 3 weeks, permanently discontinue alectinib. 
-
First episode: If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 150 
mg BID. 
-
Second episode: If improvement to Grade ≤ 1 or baseline 
within 21 days, decrease the current dose of alectinib by 
another 150 mg BID. 
-
Third episode: permanently discontinue alectinib.
●
Grade 2 (except any symptoms and signs that can be 
corrected with supportive care)
-
Temporarily interrupt alectinib and resume if recovering to 
Grade ≤ 1 or baseline if clinically indicated.
-
First episode: If improvement to Grade ≤ 1 or baseline 
within 10 days, continue same dose of alectinib. If 
improvement occurs after 10 days, decrease the current dose 
of alectinib by 150 mg BID when resuming treatment. 
-
Second episode: If improvement to Grade ≤ 1 or baseline 
within 10 days, decrease the current dose of alectinib by 150 
mg BID. If improvement occurs after 10 days, decrease the 
current dose of alectinib by 300 mg BID when resuming 


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treatment. 
-
Third episode: permanently discontinue alectinib. 
●
Grade 1: no action required
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of 
reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting.
7.1
Adverse Events
7.1.1
Adverse Events Lists
Adverse Events Relating to ALK Inhibitors and/or the Tyrosine Kinase Inhibitor Class and 
Alectinib Data
AEs associated with alectinib or ALK inhibitors as a class are outlined below. A more detailed safety 
profile of alectinib is provided in the alectinib Investigator's Brochure.
Interstitial Lung Disease
Interstitial lung disease cases, some of which have been associated with fatal outcomes, have been 
reported with other ALK inhibitors, such as ceritinib and crizotinib.  
See section 6.2 for management and follow-up.
Hepatotoxicity 
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity studies with 
alectinib, and findings in the 13-week studies were similar to those of the 4-week studies. The findings 
were at or close to clinically relevant exposures. Hepatobiliary effects included increased hepatic ALP, 
direct bilirubin, GGT and liver weight, vacuolation/degeneration/necrosis of bile duct epithelium, 
inflammatory cell infiltration in Glisson’s sheath, enlargement/focal necrosis of hepatocytes, and 
enlargement of Kupffer cells.
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin levels, have been 
observed after alectinib administration. AST, ALT, and total bilirubin levels temporarily increased in the 
initial stages of treatment and then improved. In
patients with Grade 3−4 AST/ALT elevations, documented drug-induced liver injury
by liver biopsy was reported with uncommon frequency in alectinib pivotal clinical trials. Concurrent 
elevations in ALT or AST greater than or equal to three times the
ULN and total bilirubin greater than or equal to two times the ULN, with normal
alkaline phosphatase, occurred with uncommon frequency in patients treated in
alectinib clinical trials.
In patients treated with other ALK inhibitors, abnormal liver function tests and drug-induced 
hepatotoxicity, including cases with fatal outcome, have been reported.
See section 6.2 for management and follow-up.


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Anemia 
Hematologic findings were observed in both the rat and monkey 4- and 13-week toxicity studies with 
alectinib, and findings in the 13-week studies were similar to those of the 4-week studies. Findings were 
at or close to clinically relevant exposures. Hematologic adverse effects such as anemia, 
thrombocytopenia, bleeding, and neutropenia have been observed with most TKIs, including crizotinib 
and ceritinib. 
Cases of anemia have been reported in patients treated with alectinib; the majority of
the events were Grade 1 or 2.
See section 6.2 for management and follow-up.
Gastrointestinal Disorders
GI disorders such as nausea, vomiting, constipation, diarrhea and stomatitis have been reported with 
alectinib. Similar GI disorders have been observed with other ALK inhibitors, including crizotinib and 
ceritinib. SLS (syn. sodium dodecyl sulfate)) is a surfactant excipient in the clinical formulation at a 
concentration of 50% (w/w SLS to active pharmaceutical ingredient). This excipient is a known GI 
irritant and may be associated with GI AEs including nausea, vomiting, diarrhea, and abdominal pain. Of 
note, GI tract toxicity as the safety determinant of SLS is not because of systemic toxicity, but a 
consequence of local irritation to the GI tract. In general, when mixed with diet, higher levels of SLS--a 
known GI tract mucosal irritant--are tolerated versus gavage administrations.
See section 6.2 for management and follow-up.
Skin Disorders
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic potential.
Skin rash has been reported with a majority of TKIs including those targeting the ALK receptor 
(Hartmann et al. 2009). Cases of skin rash and photosensitivity have been reported with alectinib and 
were generally Grade 1 or 2.
See section 6.2 for management and follow-up.
Vision Disorders
In the rat quantitative whole body autoradiography study, tissue radioactivity disappeared over time, 
following a time course comparable to that of plasma radioactivity, except for melanin-containing tissues 
such as uveal tract of eyes, which had much higher and more sustained exposure in pigmented rats. This 
is consistent with what is commonly observed for lipophilic basic drugs.
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and vitreous floaters, 
have been reported with several TKIs, including crizotinib. Vision disorders, such as dry eye, blepharitis, 
conjunctivitis, blurred vision, and vision impaired, have been reported with alectinib and were generally 
Grades 1 and 2.
See section 6.2 for management and follow-up.
Edema
Crizotinib is associated with the development of lower extremity edema. Events of edema have been 
reported with alectinib, mostly Grade 1 or 2.


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Bradycardia
In the monkey telemetry study, there were no effects on the ECG, any of the other cardiovascular 
parameters or body temperature at doses up to 15 mg/kg (mean maximum concentration [Cmax]: 279 
ng/mL).
In a preliminary non- Good Laboratory Practice telemetry study in conscious cynomolgus monkeys, a 
slight hypotensive effect (approximately 10 mmHg) was seen when alectinib was administered at 20 and 
60 mg/kg orally with no effects on ECG or heart rate. The hypotensive effect of alectinib observed in 
monkeys was considered to likely be caused by vasodilatation induced by L-type Ca2+ channel 
inhibition. Events of bradycardia have been reported with alectinib.
Events of bradycardia have been reported with alectinib. Data based on ECG and pulse measurements 
from the ongoing alectinib clinical trials show a decrease in heart rate during alectinib treatment, which is 
mainly asymptomatic. In patients treated with other ALK inhibitors (crizotinib and ceritinib), bradycardia 
adverse events, as well as decreases in heart rate based on ECG and pulse measurements, have also been 
reported (XALKORI® U.S. Package Insert; ZYKADIA™ U.S. Package Insert).
In case of bradycardia, concomitant medications must be evaluated to identify those that are known to 
cause bradycardia, as well as anti-hypertensive medications; and discontinuation or dose reduction of 
these concomitant medications must be considered.
See section 6.2 for management and follow-up.
Abnormal Renal Function (Serum Creatinine increased, Acute Kidney Injury)
In the 2-week non-human primate study at 60 mg/kg, an increase in creatinine was observed but no 
changes were observed in histopathology. In all other non-human primate studies, no changes in 
creatinine were observed. Serum creatinine increases have been reported with alectinib treatment. Serum 
creatinine increases and acute kidney injury with fatal outcome has been observed with uncommon 
frequency in patients treated in alectinib clinical trials.
Serum creatinine increases and/or decreases in GFR, renal failure and/or renal impairment have been 
reported for other ALK inhibitors (crizotinib, ceritinib).
Serum creatinine increases and/or decreases in GFR, renal failure and/or renal impairment have been 
reported for other ALK inhibitors (crizotinib, ceritinib).
See section 6.2 for management and follow-up.
Severe myalgia and CPK Elevations 
Postmarketing experience with some TKIs includes reports of myopathy and rhabdomyolysis. Blood CPK 
increases, generally Grades 1 and 2, and muscular AEs have been reported with alectinib treatment. Grade 
3 myalgia and CPK elevations have been reported with
alectinib treatment and were reversible upon dose reduction and interruption.
See section 6.2 for management and follow-up.
Dysgeusia
Events of dysgeusia have been reported in clinical trials with alectinib, and were generally of Grade 1 and 
2 severity. All patients who experienced dysgeusia, continued alectinib treatment without any 
modification. In patients treated with other ALK inhibitors, such as crizotinib and ceritinib, dysgeusia has 
been reported.


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See section 6.2 for management and follow-up.
Alkaline Phosphatase (ALP) Increase 
Cases of increased blood ALP have been observed after alectinib administration. The majority of the 
cases were of Grade 1 and Grade 2 severity. In patients treated with other ALK inhibitors, increased 
blood ALP has been reported.
See section 6.2 for management and follow-up.
7.1.1.1
Adverse Event List for Bevacizumab
Hypertension: An increased incidence of hypertension has been observed in patients treated with 
bevacizumab. Grade 4 and 5 hypertensive events are rare. Clinical sequelae of hypertension are rare but 
have included hypertensive crisis, hypertensive encephalopathy, and reversible posterior 
leukoencephalopathy syndrome (RPLS). There is no information on the effect of bevacizumab in patients 
with uncontrolled hypertension at the time of initiating bevacizumab therapy. Therefore, caution should 
be exercised before initiating bevacizumab therapy in these patients. Monitoring of blood pressure is 
recommended during bevacizumab therapy. Optimal control of blood pressure according to standard 
public health guidelines is recommended for patients on treatment with or without bevacizumab. 
Temporary interruption of bevacizumab therapy is recommended in patients with hypertension requiring 
medical therapy until adequate control is achieved. If hypertension cannot be controlled with medical 
therapy, bevacizumab therapy should be permanently discontinued. Bevacizumab should be permanently 
discontinued in patients who develop hypertensive crisis or hypertensive encephalopathy.
Proteinuria: An increased incidence of proteinuria has been observed in patients treated with 
bevacizumab compared with control arm patients. In the bevacizumab-containing treatment arms of 
clinical trials (across all indications), the incidence of proteinuria (reported as an adverse event) was up to 
38% (metastatic CRC Study AVF2192g). The severity of proteinuria has ranged from asymptomatic and 
transient events detected on routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria 
events have been grade 1. NCI-CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab-
treated patients, and Grade 4 in up to 1.4% of bevacizumab-treated patients. The proteinuria seen in 
bevacizumab clinical trials was not associated with renal impairment and rarely required permanent 
discontinuation of bevacizumab therapy. Bevacizumab should be discontinued in patients who develop 
Grade 4 proteinuria (nephrotic syndrome). Patients with a history of hypertension may be at increased risk 
for the development of proteinuria when treated with bevacizumab. There is evidence from the dose-
finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that
Grade 1 proteinuria may be related to bevacizumab dose. 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in severity 
from catheter-associated phlebitis to fatal events, have been reported in patients treated with bevacizumab 
in the colorectal cancer trials and, to a lesser extent, in patients treated with bevacizumab in NSCLC and 
breast cancer trials.
Venous thromboembolism (including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis): In the pivotal Phase III trial in metastatic CRC, there was a slightly higher rate of 
venous TE events in patients treated with bevacizumab plus chemotherapy compared with chemotherapy 
alone (19% vs. 16%). In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, 
including deep venous thrombosis, pulmonary embolism, and thrombophlebitis, occurred in 15.2% of 
patients receiving chemotherapy alone and 16.6% of patients receiving chemotherapy andbevacizumab.


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The incidence of NCI-CTC Grade ≥3 venous VTE events in one NSCLC trial (E4599) was higher in the 
bevacizumab-containing arm compared to the chemotherapy control arm (5.6% vs. 3.2%). One event 
(0.2%) was fatal in the bevacizumab-containing arm; no fatal events were reported in the 
carboplatin/paclitaxel arm (see bevacizumab Investigator Brochure). 
In metastatic CRC clinical trials, the incidence of VTE events was similar in patients receiving 
chemotherapy plus bevacizumab and those receiving the control chemotherapy alone. In clinical trials 
across all indications the overall incidence of VTE events was 2.8 - 17.3% in the bevacizumab-containing 
arms compared with 3.2 - 15.6% in the chemotherapy control arms. The use of bevacizumab with 
chemotherapy does not substantially increase the risk of VTE event compared with chemotherapy alone. 
However, patients with metastatic CRC who receive bevacizumab and experienced a VTE event may be 
at higher risk for recurrence of VTE event.
Arterial Thromboembolic Events: An increased incidence of ATE events was observed in patients 
treated with bevacizumab compared with those receiving control treatment. ATE events include 
cerebrovascular accidents, myocardial infarction, transient ischemic attacks (TIAs), and other ATE 
events. In a pooled analysis of data from five randomized Phase II and III trials (mCRC [AVF2107g, 
AVF2192g, AVF0780g]; locally advanced or metastatic NSCLC [AVF0757g]; and metastatic breast 
cancer [AVF2119g]), the incidence of ATE events was 3.8% (37 of 963) in patients who received 
chemotherapy and bevacizumab compared with 1.7% (13 of 782) in patients treated with chemotherapy 
alone. ATE events led to a fatal outcome in 0.8% (8 of 963) of patients treated with chemotherapy and 
bevacizumab and 0.5% (4 of 782) of patients treated with chemotherapy alone. Cerebrovascular accidents 
(including TIAs) occurred in 2.3% of patients treated with chemotherapy andbevacizumab and 0.5% of 
patients treated with chemotherapy alone. Myocardial infarction occurred in 1.4% of patients treated with 
chemotherapy plusbevacizumab compared with 0.7% of patients treated with chemotherapy alone 
(see the bevacizumab Investigator Brochure for additional details).
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial thromboembolic events in 
patients at high risk of such events, and the use of aspirin ≤ 325 mg daily was allowed in the five 
randomized studies discussed above. Use of aspirin was assessed routinely as a baseline or concomitant 
medication in these trials, though safety analyses specifically regarding aspirin use were not preplanned. 
Due to the relatively small numbers of aspirin users and arterial thromboembolic events, retrospective 
analyses of the ability of aspirin to affect the risk of such events were inconclusive. However, similarly 
retrospective analyses suggested that the use of up to 325 mg of aspirin daily does not increase the risk of 
grade 1-2 or grade 3-4 bleeding events, and similar data with respect to metastatic colorectal cancer 
patients were presented at ASCO 2005 (Hambleton et al., 2005). Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor types are ongoing.
Gastrointestinal perforation: Patients with metastatic carcinoma may be at increased risk for the 
development of gastrointestinal perforation and fistula when treated with bevacizumab and chemotherapy. 
Bevacizumab should be permanently discontinued in patients who develop gastrointestinal perforation. A 
causal association of intra-abdominal inflammatory processes and gastrointestinal perforation to 
bevacizumab treatment has not been established. Nevertheless, caution should be exercised when treating 
patients with intra-abdominal inflammatory processes with bevacizumab. Gastrointestinal perforation has 
been reported in other trials in non-colorectal cancer populations (e.g., ovarian, renal cell, pancreas, 
breast, and NSCLC) and may be higher in incidence in some tumor types.
Fistula: Bevacizumab use has been associated with serious cases of fistulae including events resulting in 
death. Fistulae in the GI tract are common (1%–10% incidence) in patients with metastatic CRC, but 
uncommon (0.1 - 1%) or rare (0.01%–0.1%) in other indications. In addition, fistulae that involve areas of 
the body other than the GI tract (e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been 


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reported uncommonly (0.1%–1%) in patients receiving bevacizumab in clinical studies and postmarketing 
reports. Events were reported at various timepoints during treatment, ranging from 1 week to >1 year 
following initiation of bevacizumab, with most events occurring within the first 6 months of therapy. 
Bevacizumab should be permanently discontinued in patients with tracheoesophageal fistulae or any 
Grade 4 fistula. 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: Wound healing complications such as wound dehiscence have been 
reported in patients receiving bevacizumab. In an analysis of pooled data from two trials in metastatic 
colorectal cancer, patients undergoing surgery 28-60 days before study treatment with 5-FU/LV plus 
bevacizumab did not appear to have an increased risk of wound healing complications compared to those 
treated with chemotherapy alone.37 Surgery in patients currently receiving bevacizumab is not 
recommended. No definitive data are available to define a safe interval after bevacizumab exposure with 
respect to wound healing risk in patients receiving elective surgery; however, the estimated half life of 
bevacizumab is 21 days. Bevacizumab should be discontinued in patients with severe wound healing 
complications.
If patients receiving 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 or 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 weeks and
bevacizumab no earlier than 8 weeks after surgery).
Hemorrhage: Overall, Grade 3 and 4 bleeding events were observed in 4.0% of 1132 patients treated 
with bevacizumab in a pooled database from eight Phase I, II, and III clinical trials in multiple tumor 
types (bevacizumab Investigator Brochure). The hemorrhagic events that have been observed in 
bevacizumab clinical studies were predominantly tumor-associated hemorrhage (see below) and minor 
mucocutaneous hemorrhage.
Tumor-Associated Hemorrhage: Major or massive pulmonary hemorrhage or hemoptysis has been 
observed primarily in patients with NSCLC. Life-threatening and fatal hemoptysis was identified as a 
bevacizumab-related adverse event in NSCLC trials. These events occurred suddenly and presented as 
major or massive hemoptysis. Among the possible risk factors evaluated (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 during therapy), the only variables that showed statistically significant 
correlations with bleeding were bevacizumab therapy and squamous cell histology. 
Of patients experiencing pulmonary hemorrhages requiring medical intervention, many had cavitation 
and/or 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. 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 plusbevacizumab arm.23
GI hemorrhages, including rectal bleeding and melena have been reported in patients with CRC, and have 
been assessed as tumor-associated hemorrhages.


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Tumor-associated hemorrhages were also seen rarely in other tumor types and locations, including a case 
of CNS bleeding in a patient with hepatoma with occult CNS metastases and a patient who developed 
continuous oozing of blood from a thigh sarcoma with necrosis. A recent review examined the risk of 
CNS hemorrhage in association with anti-VEGF therapy. Among 669 patients treated on Phase I and II 
studies of bevacizumab that excluded brain metastases, only 1 case (0.2%) of CNS bleeding was 
reported.38 
Mucocutaneus Hemorrhage: Across all bevacizumab clinical trials, mucocutaneous hemorrhage has 
been seen in 20%-40% of patients treated with bevacizumab. These were most commonly NCI-CTC 
Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not 
require any changes in bevacizumab treatment regimen. There have also been less common events of 
minor mucocutaneous hemorrhage in other locations, such as gingival bleeding and vaginal bleeding.
Reversible Posterior Leukoencephalopathy Syndrome: There have been rare reports of bevacizumab-
treated patients developing signs and symptoms that are consistent with RPLS, a rare neurological 
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 RPLS. In patients who develop RPLS, 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 RPLS is 
not known.39
Congestive heart failure: In clinical trials, CHF was observed in all cancer indications studied to date, 
but predominantly in patients with metastatic breast cancer. In the Phase III clinical trial of metastatic 
breast cancer (AVF2119g), 7 (3%) bevacizumab-treated patients experienced CHF, compared with two 
(1%) control arm patients. These events varied in severity from asymptomatic declines in left ventricular 
ejection fraction (LVEF) to symptomatic CHF requiring hospitalization and treatment. All the patients 
treated with bevacizumab were previously treated with anthracyclines (doxorubicin cumulative dose of 
240-360 mg/m2). Many of these patients also had prior radiotherapy to the left chest wall. Most of these 
patients showed improved symptoms and/or left ventricular function following appropriate medical 
therapy.
In a randomized, Phase III trial of patients with previously untreated metastatic breast cancer (E2100), the 
incidence of LVEF decrease (defined as NCI-CTC Grade 3 or 4) in the paclitaxel bevacizumab arm 
was 0.3% versus 0% for the paclitaxel alone arm. No information is available on patients with preexisting 
CHF of New York Heart Association (NYHA) Class IIIV at the time of initiating bevacizumab therapy, 
as these patients were excluded from clinical trials. Prior anthracyclines exposure and/or prior 
radiotherapy to the chest wall may be possible risk factors for the development of CHF. Caution should 
be exercised before initiating bevacizumab therapy in patients with these risk factors. A Phase II trial in 
patients with refractory acute myelogenous leukemia reported 5 cases of cardiac dysfunction (CHF or 
LVEF decrease to <40%) among
48 patients treated with sequential cytarabine, mitoxantrone, and bevacizumab. All but 1 of these patients 
had significant prior exposure to anthracyclines as well.40
Two additional studies investigated concurrent administration of anthracyclines and bevacizumab. In 21 
patients with inflammatory breast cancer treated with neoadjuvant docetaxel, doxorubicin, and 
bevacizumab, no patients developed clinically apparent CHF; however, patients had asymptomatic 
decreases in LVEF to < 40%.41 In a small Phase II study in patients with soft tissue sarcoma, 2 of the 17 
patients treated with bevacizumab and high-dose doxorubicin (75 mg/m2) developed CHF (one Grade 3 
event after a cumulative doxorubicin dose of 591 mg/m2, one Grade 4 event after a cumulative 
doxorubicin dose of 420 mg/m2); an additional 4 patients had asymptomatic decreases in LVEF.42 Other 


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studies in patients with various tumor types and either a history of anthracycline exposure or concomitant 
use with bevacizumab are ongoing. Patients receiving concomitant anthracyclines or with prior exposure 
to anthracyclines should have a baseline MUGA scans or echocardiograms (Echo’s) with a normal LVEF.
Neutropenia: Increased rates of severe neutropenia, febrile neutropenia, or infection with severe 
neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic 
chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone.
Additional Adverse Events: See the bevacizumab Investigator Brochure for additional details regarding 
the safety experience with bevacizumab.
7.2
Safety Reporting of Adverse Events
Specifications of Safety Variables
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse 
events (SAEs) that are considered related to alectinib and/or bevacizumab, all events of death, and any 
study specific issue of concern.
●
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of 
attribution.
This includes the following:
●
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with NSCLC that were not 
present prior to the AE reporting period.
●
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations).
If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, 
no treatment run-in, or other protocol-mandated intervention.
Preexisting medical conditions (other than the condition being studied) judged by the investigator to have 
worsened in severity or frequency or changed in character during the protocol-specified AE reporting 
period.
Serious Adverse Events
An AE should be classified as an SAE if the following criteria are met:
●
It results in death (i.e., the AE actually causes or leads to death).
●
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.).
●
It requires or prolongs inpatient hospitalization.


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●
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions).
●
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP.
●
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above).
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).
Adverse Event Reporting Period
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 30 days following the last administration of study 
treatment or study discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment.
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 study drugs (see following guidance), and 
actions taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply the following 
general guideline:
Yes
There is a plausible temporal relationship between the onset of the AE and administration of the study 
drugs, 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 study drugs; and/or the 
AE abates or resolves upon discontinuation of the study drugs or dose reduction and, if applicable, 
reappears upon re-challenge.
No
Evidence exists that the AE has an etiology other than the study drugs (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no 
plausible temporal relationship to study drug 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 or 
current Investigator Brochure. 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator 
Brochure (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.


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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 ok 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, regardless of 
attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or 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:
o
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions
o
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or
o
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study.
e.
Pregnancy


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If a female subject or a female partner of a male subject, becomes pregnant while receiving 
investigational therapy or within 90 days after the last dose of study drug, a report should be 
completed and expeditiously submitted to the 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 drugs should be reported as an SAE.
f.
Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a subject has completed 
or discontinued study participation if attributed to prior study drug exposure. If the 
investigator should become aware of the development of cancer or a congenital anomaly in a 
subsequently conceived offspring of a female subject who participated in the study, this 
should be reported as an SAE. 
g.
Reconciliation/Case Transmission Verification of Single Case Reports
The Sponsor agrees to conduct reconciliation to ensure that all single case reports have been 
adequately received by Genentech. Genentech and the Sponsor will agree to the 
reconciliation periodicity and format, but agree at minimum to exchange quarterly line 
listings of cases received by the other party. 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.
Following Case Transmission Verification, single case reports which have not been received 
by Genentech/Roche shall be forwarded by the Sponsor to Genentech/Roche within five (5) 
calendar days from request by Genentech/Roche.
At the end of the study, a final cumulative Case Transmission Verification report will be sent 
to Genentech/Roche.
Case transmission verification/ queries on CTV should be sent to:
ctvist_drugsafety@gene.com
h.  AEs of Special Interest (AESIs)
AEs of Special Interest are defined as a potential safety problem, identified as a result of 
safety monitoring of the Product.
Adverse events of special interest for this study include the following:
▪
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:
o Treatment-emergent ALT or AST > 3 x ULN in combination with 
total bilirubin > 2 x ULN
o Treatment-emergent ALT or AST > 3 x ULN in combination with 
clinical jaundice


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▪
Suspected transmission of an infectious agent by the study drug, as defined 
below:
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 the study drug is suspected
7.3
Expedited Adverse Event Reporting 
7.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after 
the initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form. 
7.3.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
7.4
Expedited Adverse Event Reporting – Genentech
Investigators must report all SAEs, AESIs,Special Situation Reports (including pregnancy reports) and 
Product Complaints with an AE should be sent to Genentech within the timelines described below. The 
completed Medwatch/case report should be sent immediately upon completion to Genentech Drug Safety 
at:
Fax: 650-238-6067
Email: usds_aereporting-d@gene.com
●
Fax Cover Sheets are available in Appendix C.
●
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as 
it becomes available.
●
Serious AE reports that are related to the study drugs will be transmitted to Genentech 
within fifteen (15) calendar days of the Awareness Date.
●
Serious AE reports that are unrelated to the study drugs will be transmitted to Genentech 
within thirty (30) calendar days of the Awareness Date.
●
AESIs will be transmitted to Genentech within fifteen (15) calendar days of the 
Awareness Date.
●
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.


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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.
●
In addition to all SAEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to 
Genentech/Roche within thirty (30) calendar days:
o
· Data related to the Product usage during pregnancy or breastfeeding
o
· Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without association 
with an AE/SAE unless otherwise specified in the protocol
In addition, reasonable attempts should 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.
All Product Complaints without an AE or special situation should be reported to:  
Product Complaints Hotline Number: (800) 334-0290
Note: Investigators should also report events to their IRB as required (see Section 7.6).
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description of the MedWatch 3500A form:
●
Protocol description (and number, if assigned)
●
Description of event, severity, treatment, and outcome if known
●
Supportive laboratory results and diagnostics
●
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication
Follow-up Information
Additional information may be added to a previously submitted report by any of the following methods:
●
Adding to the original MedWatch 3500A report and submitting it as follow-up
●
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 


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●
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the new 
information is added to the correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom an adverse event was reported. For questions regarding SAE reporting, you 
may contact the Genentech Drug Safety representative noted above or the MSL assigned to the study. 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it becomes 
available and/or upon request.
MedWatch 3500A (Mandatory Reporting) form is available at
http://www.fda.gov/medwatch/getforms.html 
7.5
Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall 
PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria for expedited reporting following the reporting requirements and timelines in accordance 
with the guidance set forth in 21 CFR § 600.80.
Events meeting the following criteria need to be submitted to the Food and Drug Administration (FDA) 
as expedited IND Safety Reports according to the following guidance and timelines:
7 Calendar Day Telephone or Fax Report:
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of the study drug(s). An 
unexpected adverse event is one that is not already described in the study drug’s Investigator Brochure. 
Such reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first 
learning of the event.
15 Calendar Day Written Report
The Investigator is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use 
of the study drug. An unexpected adverse event is one that is not already described in the study drug 
investigator brochure.
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 
21 CFR § 312.32. All safety reports previously filed by the investigator with the IND concerning similar 
events should be analyzed and the significance of the new report in light of the previous, similar reports 
commented on.
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Genentech, 
and all participating investigators within 15 calendar days of first learning of the event. The FDA prefers 
these reports on a Medwatch 3500 form, but alternative formats are acceptable (e.g., summary letter).
FDA fax number for IND Safety Reports:
Fax: 1 (800) FDA 0178


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All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety:
Fax: (650) 225-4682 or (650) 225-4630
For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
IND Annual Reports
Copies to Genentech:
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail box: 
ctvist_drugsafety@gene.com
Aggregate Reports
The Sponsor will forward a copy of the Final Study Report to Genentech/Roche upon completion of the 
Study. Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail box: 
ctvist_drugsafety@gene.com
The Sponsor 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. The Sponsor agrees to share a copy of 
their own DSUR with Genentech/Roche as soon as reasonably possible after completion. 
Genentech/Roche agrees to forward to the Sponsor an executive summary of the Genentech/Roche DSUR 
upon request. Furthermore, Genentech/Roche agrees that the Sponsor may cross-reference the executive 
summary of the Genentech/Roche DSUR, as applicable.
Note: Investigators should also report events to their IRB as required.
Study Close-Out
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. 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. Copies of such reports should 
be emailed to Genentech at:  Genentech Drug Safety CTV mail box: ctvist_drugsafety@gene.com
Queries
Queries related to the Study will be answered by the 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. The 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/Roche.


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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. The 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/Roche.
7.6
Reporting to the Institutional Review Board (IRB)
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI Office for 
Human Research Studies (OHRS).
7.7
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety reports 
or sentinel events that require reporting according to institutional policy. 
7.8
Routine Adverse Event Reporting
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 to the IRB, FDA, etc.) 
must also be reported in routine study data submissions.
7.9 Overall PI/Sponsor of the Study, will be responsible for the expedited reporting of safety reports 
originating from the study to the EMA through Eudravigilance Clinical Trial Module (EVCTM), where 
applicable. Overall PI/Sponsor of the Study will be responsible for the distribution of safety information 
to its own investigators, where relevant, in accordance with local regulations.
8.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the study agents can be found in Section 
7.1.
8.1
Alectinib
8.1.1
Description
Alectinib is a second-generation ALK tyrosine kinase inhibitor. 


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[Chemical name] 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-6,11 dihydro-
5H-benzo[b]carbazole-3-carbonitrile hydrochloride
8.1.2
Form
Each capsule contains 150 mg of alectinib (as free base) along with lactose monohydrate, carmellose 
calcium, hydroxypropyl cellulose, SLS, and magnesium stearate.
8.1.3
Storage and Stability
Alectinib capsules should be stored in accordance with the storage instructions on the label.
8.1.4
Compatibility
N/A
8.1.5
Handling
Procedures for proper handling and disposal of anticancer drugs should be considered.
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper number of each 
strength capsule to the participant to satisfy dosing requirements for the study. The containers provided 
to the participant should be labeled with proper instructions for use. The lot numbers, dosing start dates 
and the number of capsules for each dosage strength must be recorded on the drug accountability pages 
of record for the site. The participant must be instructed to return all unused alectinib in the provided 
packaging at each subsequent visit.
8.1.6
Availability
Alectinib will be provided by Genentech/Roche. 
8.1.7
Preparation
N/A 
8.1.8
Administration
See Section 5.2.1
8.1.9
Ordering
Investigative site(s) will order alectinib directly through Genentech/Roche. Shipments will be at 
appropriate intervals, depending on patient accrual. The site(s) must use an appropriate dispensing 
log/accountability form provided by the Sponsor, or an acceptable substitute approved by the 
Sponsor. Each time study medication is dispensed for a participant, the following information must be 
recorded: the patient’s initials, the patient’s study number, the number of capsules dispensed with the 
corresponding lot number, and the initials of the person dispensing the drug. These logs are to be 
maintained by the study pharmacist in the pharmacy throughout the duration of the study. The 
Investigator is responsible for ensuring that the patient diary card(s) and study drug provided to the 


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participant and returned from the participant are accounted for and noted in source documentation.
8.1.10 Accountability
The investigator will ensure that a current record of disposition of investigational product is maintained 
at each study site where the investigational product is inventoried and disposed.
Alectinib dispensing record/inventory logs and copies of signed packing lists must be maintained at the 
investigational site. Batch numbers for alectinib must be recorded in the drug accountability records.
8.1.11 Destruction and Return
If the investigational product is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. Appropriate 
records of the disposal must be maintained.
Consult with the Principal Investigator for instructions on disposal of unused alectinib capsules.
8.2
Bevacizumab
8.2.1
Description
Bevacizumab is a recombinant monoclonal antibody targeting vascular endothelial growth factor 
(VEGF)
8.2.2
Form
Pharmaceutical form: solution for dilution for infusion 
Bevacizumab 25 mg per mL
Trehalose dihydrate 
Sodium phosphate
Polysorbate 20
Water for injection
Clear to slightly opalescent liquid, colourless to pale brown 
8.2.3
Storage and Stability
Chemical and physical stability during use has been demonstrated for 48 hours between 2°C and 30°C 
in an injectable solution of sodium chloride at 9 mg/mL (0.9%). From a microbiological point of view, 
immediate use is recommended. If the product is not used immediately after reconstitution, the storage 
period and conditions are the responsibility of the user and must not normally exceed 24 hours in the 
refrigerator between 2°C and 8°C, unless the dilution has been performed in controlled, aseptic 
conditions. 
Do not freeze. 
Store the vial in the outer packaging away from light. 


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8.2.4
Compatibility
No incompatibility between bevacizumab and infusion bags or devices made of polyvinyl chloride or 
polyolefin has been observed.
8.2.5
Handling/Preparation
Procedures for proper handling and disposal of anticancer drugs should be considered.
Bevacizumab must be prepared by a health professional observing aseptic precautions. Take the volume 
of bevacizumab needed for the preparation of one dose of 15 mg/kg of body weight every 3 weeks and 
dilute it with an injectable solution of sodium chloride at 9 mg/mL (0.9%) up to a total volume of 100 
mL. Dispose of any unused amount remaining in the vial, since the product does not contain a 
preservative. Medicinal products intended for parenteral route must be visually examined, looking for 
particles and colour deviations, before their administration.
No incompatibility between bevacizumab and infusion bags or devices made of polyvinyl chloride or 
polyolefin has been observed.
When bevacizumab has been mixed with a sterile saline solution bag, the solution must be administered 
within 8 hours.
Bevacizumab must not be administered or mixed with glycated solutions (see investigator’s brochure).
A mechanism regulating the speed of the infusions will be used for all infusions. When the bag is empty, 
a volume of 50 mL of sodium at 0.9% will be added or another bag will be added, and the infusion will 
be continued for a volume equal to that of the tube in order to ensure the complete administration of 
bevacizumab. Saline solution, which will then be injected to empty the tube, will not influence the 
infusion time of the study treatment. 
8.2.6
Availability
Bevacizumab will be provided by Genentech/Roche. 
8.2.7
Administration
See Section 5.2.2
8.2.8
Ordering
Investigative site(s) will order bevacizumab directly through Genentech/Roche. Shipments will be at 
appropriate intervals, depending on patient accrual. The site(s) must use an appropriate dispensing 
log/accountability form provided by the Sponsor, or an acceptable substitute approved by the 
Sponsor. 
8.2.9
Accountability
The investigator will ensure that a current record of disposition of investigational product is maintained 
at each study site where the investigational product is inventoried and disposed.
Bevacizumab dispensing record/inventory logs and copies of signed packing lists must be maintained 


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at the investigational site. Batch numbers for bevacizumab must be recorded in the drug accountability 
records.
8.2.10 Destruction and Return
If the investigational product is to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have been 
established accordingto applicable regulations, guidelines, and institutional procedures. Appropriate 
records of the disposal must be maintained.
Consult with the Principal Investigator for instructions on disposal of unused bevicizumab. 
9.
STUDY CALENDAR AND ASSESSMENTS
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans must be 
done <4 weeks prior to the start of therapy.  In the event that the participant’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments and agents 
should be administered within + 3 days of the protocol-specified date, unless otherwise noted.


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Table 9-1: Study Calendar
Assessment
Base
line
Cycle 
1
Day 1
Cycle 
1
Day 
15
Cycle 
2-10
Day 1
Subsequ
ent 
Cycles 
Day 1
End of 
Treat
ment
30 Day 
Safety 
Follow-up
Informed Consent
X
Demographics
X
Inclusion/Exclusion Criteria
X
Relevant Medical History & 
Current Medical Conditions
X
Diagnosis & Extent of 
Cancer
X
Prior Antineoplastic 
Therapy
X
Documentation of ALK 
status
X
Concomitant Medications
X
Continuous
X
Vital signs
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Hematology/Chemistry1
X
X
X
X
X
X
Coagulation
X
X
ECG
X
X
X2
X2
X
Urinalysis
X
X
X
X
X
Pregnancy Test
X
Disease Assessments
X3
X3, 7
X4,7
X
Patient Reported Outcomes5
X
X
X
X
X
X
Tumor Biopsies (Optional)6
X
X
Adverse Events7
X
Continuous
X


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1.
ALT, AST and total bilirubin should also be obtained on cycle 1, day 15. 
2.
ECGS will be performed at baseline, cycle 1 day 1, cycle 2 day 1, cycle 8 day 1 (week 24), 
cycle 18 day 1 (week 56), end of treatment visit, and as clinically indicated throughout the 
study. 
3.
Baseline disease assessments will include CTs of the chest and abdomen (if clinically 
indicated, a CT of the pelvis should also be performed) and a brain MRI. Please see 
Section 9.1 for specifics on MRI slice thickness.  Repeat disease assessments (including a 
brain MRI) should take place every 2 cycles for the first 10 cycles of study treatment. 
Note: Participants in the phase I portion of the study will not be required to have brain 
MRIs performed beyond screening, provided that the baseline brain MRI is negative for 
intracranial metastases. 
4.
After cycle 10, disease assessments will take place every 4 cycles. 
5.
Patient reported outcome (PROs) questionnaires will include: EORTC QLQ-C30 and 
QLQ-BN20. 
6.
Optional biopsies will be performed at baseline and upon disease progression on 
alectinib/bevacizumab. When possible, a core biopsy is preferred, though not required, 
over a fine-needle aspiration or cytology specimen. 
7.
For patients who are holding bevacizumab or who have permanently discontinued 
bevacizumab, study assessments (vitals, exam, and laboratories) can be performed every 6 
weeks. Virtual visits are permitted during the COVID-19 pandemic. 


57
9.1
Study Assessments
●
Informed consent:  Informed consent, documented by a signed consent form, must be 
obtained prior to any screening activities not otherwise part of the participant’s care. A note 
documenting the informed consent procedure should be included in the participant’s 
medical record. Signed, informed consent should be obtained with 28 days of treatment 
start.  
●
Demographics: Demographic information consists of the participant’s age, gender, race, 
and ethnicity (as allowed by local law and regulations).
●
Relevant Medical History & Current Medical Conditions: Medical and surgical 
history includes diagnoses, therapies, and medical/surgical treatments. 
●
Diagnosis and Extent of Cancer: The initial cancer diagnosis and the current cancer 
diagnosis at the time of screening (if different), along with dates of diagnosis need to be 
recorded. 
●
Prior Antineoplastic Therapy: Prior cancer therapy history consists of the specific 
oncologic regimens a patient has received, the dates of the regimen and the best response 
to the regimen, and the reason for failure or intolerance to each regimen. Stem cell 
transplant or experimental or investigational therapy history must also be recorded. In 
particular, focus will be placed on prior CNS-directed therapies, such as radiation or 
surgical procedures. 
●
Documentation of an ALK Rearrangement: ALK status to be determined using ALK 
FISH, IHC or next-generation sequencing (NGS). For ALK FISH, positivity is defined as 
>15% positive tumor cells. Local ALK testing is acceptable, provided that archival tissue 
is available for patients deemed ALK positive on the basis of IHC or NGS.
●
Concomitant Medications: Concomitant medications for all ongoing medical history 
conditions or AEs must be reported from the date the informed consent is signed until at 
least 30 Days After the End of Treatment, and for all concomitant medications related to 
serious or study drug-related toxicities until the medication is no longer taken or until 
patient contact discontinues. Special focus will be placed on use and dose of 
corticosteroids over time. 
●
Vital Signs: Vital signs include temperature, pulse, respiratory rate, and blood pressure 
(when patient is seated). In addition, the screening assessment should include height and 
weight.
●
ECOG Performance Status: The participant’s performance status must be assessed 
using the ECOG performance scale (Appendix A). 
●
Physical Exam: A physical examination will be performed, the extent of which should 
be consistent with the medical history and the participant’s underlying disease.  
●
Hematology: Hematology assessments of the parameters listed in Table 9-1 will be 
tested as per the schedule of assessments (Table 9-1).


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Table 9-2: Local Clinical Laboratory Parameters Collection Plan 
Test 
Category
Test Name
Hematology
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), 
differential [basophils, eosinophils, lymphocytes, monocytes, 
neutrophils (% or absolute)]
Chemistry
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct 
bilirubin (only if total bilirubin is ≥ grade 2), blood urea nitrogen 
(BUN) or urea, magnesium, potassium, sodium, glucose, phosphate 
(inorganic phosphorus), alkaline phosphatase, and creatine 
phosphokinase (CPK)
Coagulation
International normalized ration (INR) and PTT. 
Urinalysis
Macroscopic panel ()(color, total bilirubin, blood, glucose, ketones, 
leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen)
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial 
cells)
Pregnancy test
At screening visit, serum pregnancy test will be performed
●
Chemistry: Clinical chemistry assessments of the parameters listed in Table 9-2 will be 
tested as per the schedule of assessments (Table 9-1).
●
Coagulation: Coagulation assessments of the parameters listed in Table 9-2 will be 
tested as per the schedule of assessments (Table 9-1).
●
Electrocardiogram: 12-lead ECGs will be performed at baseline, cycle 1 day 1, cycle 2 day 
1, cycle 8 day 1, cycle 18 day 1 and at end of treatment. ECGs will also be performed as 
clinically indicated throughout the study. 
●
Urinalysis: measurements will be performed as per Table 9-2 and according to the 
schedule of assessments (Table 9-1). Pregnancy Test: During screening, a serum 
pregnancy test will be completed. 
●
Disease Assessments: At screening, disease assessment must include imaging of the chest 
and abdomen. A CT of the pelvis should also be performed if clinically indicated. A 
gadolinium-enhanced brain MRI is also required at entry and as part of serial assessments 
(Note: Phase I participants with a brain MRI that is negative for intracranial metastases at 
baseline do not require serial brain MRIs as part of their disease assessments). MRI slices 
should be 1 mm for brain metastases measuring 5-10 mm in size. MRI slices of 1-5 mm are 
permitted for brain metastases measuring between 10 and 40 mm. 
Target and non-target lesions must be selected at study start and followed 
throughout the course of treatment for response assessment according to RECIST version 
1.1 guidelines (See Section 10) and a modified RECIST for CNS response (Long 2012; 
Section 10).  Imaging assessment is also required to be performed at the End of 
Treatment. 
●
Patient-reported outcomes (PROs): PROs (EORTC QLQ-C30 and QLQ-BN20) will be 


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collected to more fully characterize the clinical profile of alectinib/bevacizumab. The 
instruments will be translated as required into the local language. To ensure instrument 
validity, the PROs scheduled for administration during a clinic visit should be completed 
prior to the performance of non-PRO assessments and the administration of study drugs. 
●
Tumor Biopsies (Optional): An optional baseline biopsy will be performed on 
participants at the time of study entry (i.e., prior to treatment with alectinib and 
bevacizumab). When possible, a core biopsy is preferred, though not required, over a 
fine-needle aspiration or cytology specimen. Among participants previously treated with 
other ALK inhibitors (e.g. crizotinib), tissue will be analyzed for molecular mechanisms 
of resistance. For example, specimens will be assessed for ALK gene amplification, 
secondary mutations in the ALK tyrosine kinase domain, and bypass tract activation. 
In addition, participants will undergo an optional biopsy at the time of disease 
progression on alectinib/bevacizumab. This will be evaluated for molecular mechanisms 
of resistance to alectinib/bevacizumab (e.g. secondary mutations in the ALK tyrosine 
kinase domain). Due to the evolving nature of the field, not all of the proteins or genes of 
interest leading to response or resistance can be pre-specified in this document.
●
Adverse Events: Participants must be followed for all adverse events (AEs) from the 
start of study treatment until at least 30 Days After the End of Treatment, and for all 
serious or study drug-related toxicities until the AEs are resolved or are considered 
chronic or stable or until patient contact discontinues. Serious adverse events (SAEs) 
should be monitored and reported as described in Section 7.
Type, incidence, severity (graded in accordance with the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0) timing, 
seriousness and relatedness, outcome, action taken with study drug, and treatment will be 
assessed and documented by the investigator throughout the study.
Malignancy-related signs and symptoms noted at study entry will be recorded as AEs 
during the trial if they worsen in severity or increase in frequency.
10. MEASUREMENT OF EFFECT
Although response is not the primary endpoint of this trial, participants with measurable disease will be 
assessed by RECIST version 1.1 as well as a modified version of RECIST to include assessment of CNS 
responses (Long 2012). For the purposes of this study, participants should be reevaluated every 6 weeks 
(After cycle 10, this will be changed to every 9 weeks). In addition to a baseline scan, confirmatory scans 
should also be obtained ≥ 4 weeks following initial documentation of an objective response.
10.1
Antitumor Effect – Solid Tumors
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be evaluable 
for toxicity from the time of their first treatment.


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Evaluable for objective response. Only those participants who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression or die prior to the 
end of cycle 1 will also be considered evaluable.
10.1.1 Disease Parameters
Measurable disease. Measurable disease is the presence of at least one (1) lesion that can 
be accurately measured in at least one dimension with longest diameter >10 mm with 
spiral CT scan (excluding lymph nodes). Measurable lesions must be at least 2 times the 
slice thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters).
Measurable CNS disease. Measurable CNS lesions with a minimum size of  > 5 mm if 
performed with a gadolinium-enhanced MRI with contingent slices of 1 mm. 
Note: A lesion in a previously irradiated area is not eligible for measurable disease 
unless there is objective evidence of progression of the lesion prior to study enrollment. 
Lesions in previously irradiated areas must be clearly identified as such.
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease. 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with > 10 to < 15mm short axis, are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques, 
and cystic lesions are all considered non-measurable.
      Target lesions. 
Extra-CNS 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. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered target lesions if the soft tissue component meets the definition of 
measurability as defined above. Cystic lesions thought to represent cystic metastases can 


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be considered as target lesions. However, if non-cystic lesions are present, these are 
preferred for selection as target lesions. Lesions in previously irradiated areas or areas 
subject to other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression of that lesion. 
CNS Target Lesions
CNS metastases ≥ 5 mm in diameter will be considered measurable CNS targets, 
provided assessments were performed using gadolinium-enhanced MRIs with 
contingent slices of 1 mm. Up to 5 CNS lesions will be permitted as target lesions in 
addition to 5 extracranial lesions previously noted (Long 2012).  Target lesions 
should be selected on the basis of their size, be representative of all the involved organs, 
and should be lesions that can be followed with reproducible repeated measurements. 
Non-target lesions. 
All other lesions, including small lesions < 10 mm (excluding CNS metastases described 
above) or pathological lymph nodes measuring > 10 mm to < 15 mm in short axis, as 
well as truly non-measurable lesions, which include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
10.1.2 Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or 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 when both methods have 
been used to assess the anti-tumor effect of a treatment.
10.1.3 Response Criteria 
10.1.3.1
Evaluation of Target Lesions
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph node must have 
reduction in short axis to < 10 mm.


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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 with at least a 5 
mm absolute increase in the sum of all lesions. The appearance of one or more 
new lesions* denotes disease progression. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given.
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in an 
overall assessment of PD. However, if there is missing or unevaluable data for 
non-target lesions, but data is available for all target lesions, the overall 
response for that time point will be assigned based on the sum LD of all target 
lesions. Additionally, the assessment of CR cannot be made if there is missing 
or unevaluable data for non-target lesions. In this case, the overall assessment 
would be PR.
*Definition of New Lesion: 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 (ex: new bone lesions may be 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. 
10.1.3.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and
normalization of tumor marker level. All lymph nodes must be non-
pathological in size ( < 10 mm short axis). 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesions and/or maintenance of tumor marker level above the 
normal limits.
Progressive Disease (PD): Appearance of one or more new lesions* (new 
lesions must be > slice thickness) and/or unequivocal progression of 


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existing non-target lesions.
Overall level of substantial worsening that merits discontinuation of 
therapy. A useful test that can be applied when assessing non-targets for 
unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for 
measurable disease.
Unknown (UN): Assessment of non-target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given.
*Definition of New Lesion: 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 (ex: new bone lesions may be 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. 
10.1.3.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target
Lesions
New
Lesions
Overall 
Response
Best Overall Response for 
when Confirmation is 
Required:
CR
CR
No
CR
>4 wks confirmation
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/Not 
evaluated
No
PR
>4 wks confirmation
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


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Any
PD*
Yes or No
PD
Any
Any
Yes
PD
*
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression.
Note:   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.
11. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements).
11.1
Data Reporting
11.1.1 Method
 The QACT will collect, manage, and perform quality checks on the data for this study.
11.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the QACT according to the schedule set by the QACT.
11.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Overall PI and study team.
The DSMC will review each protocol up to four times a year or more often if required to review toxicity 
and accrual data. Information to be provided to the committee may include: up-to-date participant accrual; 
current dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring with 30 days of intervention for Phase I or II 
protocols; for gene therapy protocols, summary of all deaths while being treated and during active follow-
up; any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
11.3
Multicenter Guidelines
N/A


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12. STATISTICAL CONSIDERATIONS
12.1
Study Design/Endpoints
This is a phase I/II trial evaluating the safety and tolerability of alectinib and bevacizumab in patients 
with advanced NSCLC harboring ALK rearrangements. In the phase I portion of this study, eligible 
participants with ALK-positive NSCLC will be treated with the combination of alectinib and 
bevacizumab. The primary objective is to identify the recommended phase II doses of this combination. 
Participants will be treated using a 3+3 design. As dose level 1 consists of the individual recommended 
phase II doses of alectinib and bevacizumab, we will follow a dose de-escalation protocol in the setting of 
DLTs (as outlined below). Three patients will be treated per cohort for one cycle (21 days per cycle) 
beginning with dose cohort 1. If no DLTs are observed with dose cohort 1, we will enroll an additional 3 
patients (6 total) proceed with the phase II portion of the trial if one or less experience a DLT. In any 
other dose cohort, if one of three patients experiences a DLT, another 3 patients will be treated at the 
same dose level for one cycle. If no additional DLTs are observed, we will proceed with the phase II 
portion of the trial. If more than one of 3 patients develops a DLT in any cohort, another 3 patients will be 
treated in the next lowest dose cohort. We will continue until identification of the recommended phase II 
doses for the combination of alectinib and bevacizumab. The recommended phase II doses for the 
combination of alectinib and bevacizumab will be defined as either a) the highest dosage cohort in which 
less than 1/3 of patients experience a DLT or b) alectinib at the previously defined recommended phase II 
dose (600 mg twice daily PO) as a single agent plus bevacizumab at the highest tolerated dose (15 mg/kg 
IV every 21 days) investigated in this indication – whichever is the lower dose.
Table 12.1 Dose De-Escalation Probabilities
True 
DLT 
prob
De-
escalation 
Probability
0.1
0.09
0.2
0.29
0.3
0.50
0.4
0.69
0.5
0.82
0.6
0.91
Additional secondary endpoints for the phase I portion of the study include safety, tolerability and dose-
limiting toxicities of alectinib/bevacizumab. Toxicity will be assessed using CTCAE v4.0 criteria. All 
participants who receive any study drug will be evaluable for toxicity. Summary tables of adverse events 
and serious adverse events will be created. 
In the phase II portion of this study, we will evaluate the combination of alectinib plus bevacizumab in 
ALK-positive patients with untreated or progressive, asymptomatic brain metastases. Eligible participants 


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will receive alectinib plus bevacizumab at the recommended phase II doses determined in the phase I 
portion of the study. Our primary objective will be to evaluate the safety and tolerability of alectinib and 
bevacizumab in this patient population. Toxicity will be assessed using CTCAE v4.0. All participants 
who receive any study drug will be evaluable for toxicity. Summary tables of adverse events and serious 
adverse events will be created. The focus of AE summaries will be on treatment emergent AEs – those 
with initial onset of increasing in severity after the first dose of study medicine. The number and 
percentage of participants who experience any AE, SAE, treatment-related AE, and treatment-related 
SAE will be summarized according to worst toxicity grades. These will be presented for the entire study 
period and potentially by cycle. The incidence and reasons for dose reductions, interruptions and 
discontinuations will be recorded for both the Phase I and II portions of the study. 
Secondary objectives will be to assess the efficacy of this combination, with particular focus on control of 
brain metastases. Secondary endpoints will include CNS objective response rate (ORR), CNS disease 
control rate (DCR), extra-CNS ORR, extra-CNS DCR, and progression-free survival. Exploratory 
endpoints will include molecular profiling of pre- and post-alectinib/bevacizumab biopsy tissues to 
evaluate for potential mechanisms of resistance to therapy. Post-treatment biopsies will be optional. 
12.2
Sample Size, Accrual Rate and Study Duration
For the phase I portion of the study, at least 3 participants will be treated at each dose level. However, not 
every dose level listed will be studied; thus, the exact sample size for this portion of the study cannot be 
clearly defined. It is expected that roughly 6-12 participants will enroll in the phase I portion of the study. 
In the phase II portion of the study, we aim to further investigate the safety and preliminary preliminary 
efficacy of alectinib plus bevacizumab in ALK-positive patients. With protocol version 8.2.2017, the 
sample size of this cohort will decrease to 20 participants. The combination of alectinib/bevacizumab will 
be deemed unsafe if 2 or more patients are observed to have grade ≥2 CNS hemorrhagic events. Twenty 
patients are needed to guarantee that the discontinuation rate is not higher than 28% based upon the upper 
bound of the 95% exact binomial confidence interval. 
ALK rearrangements are identified in approximately 4-6% of patients with NSCLC. At MGH alone, 
approximately 500 patients with NSCLC undergo genotyping annually. Additionally, MGH is a 
referral center for patients with ALK-positive NSCLC. Recently, data from the phase III global 
ALEX study has established the superiority of alectinib over crizotinib, establishing alectinib as a 
new standard of care. With this new data, we expect to enroll 1-2 patients per month. 
12.3
Interim Monitoring Plan
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. Patients with cerebral hemorrhages and particular adverse events:  
gastrointestinal perforation, complication of wound healing, bleeding/hemorrhage, hypertension, 
proteinuria, thromboembolic accident (venous and arterial) will be followed until their resolution.
Each case of intracerebral hemorrhage will be reviewed by the DSMC in order to define whether it is 
clinically significant. The scoring of the intracerebral hemorrhage grade by the investigators, whatever the 
grade, will be confirmed or re-evaluated by the DSMC, based on clinical and radiological criteria sent the 
DSMC. The score assigned by the DSMC will be the only one taken into account for evaluation of the 
end of the study.


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The study will stop early if out of the first 15 patients, 3 experience intracerebral hemorrhages. If the 
intracerebral hemorrhage rate is as low as 5%, the chance of observing 3 or more events is less than 0.05. 
If the intracerebral hemorrhage rate is as high as 25%, the probability of observing 3 or more events is 
more than 0.75. This rule has 95% confidence that the upper bound of the true intracerebral hemorrhage 
rate is less than 0.43. 
12.4
Analysis of Primary Endpoints
See section 12.1. 
12.5
Analysis of Secondary Endpoints
Secondary endpoints will be analyzed for exploratory purposes only. 
Safety - Toxicity will be assessed using CTCAE v4.0 criteria. All participants who receive any study 
drug will be evaluable for toxicity. Summary tables of adverse events and serious adverse events will be 
created. 
CNS objective response rate – CNS response rate will be evaluated using a modified RECIST criteria 
(Long et al, 2012). It will consist of complete responses and partial responses. 
CNS DCR – CNS DCR will be evaluated using a modified RECIST criteria (Long et al, 2012). It will 
consist of complete responses, partial responses and stable disease. 
CNS PFS – CNS PFS will be defined as the time from the start of study drug treatment to the date of first 
document progression in the CNS or death due to CNS disease. 
Overall objective response rate – Overall ORR will be assessed by RECIST version 1.1. and will 
consist of intra- and extra-cranial complete responses and partial responses. 
Overall DCR – Overall DCR is defined as either complete response, partial response or stable disease 
(SD) as assessed by RECIST v1.1. 
Progression-free survival (PFS) - PFS will be defined as the time from the start date of study drug 
treatment to the date of first documented progression or death due to any cause.
Select Tumor Genotyping (optional) - Exploratory, hypothesis-generating analyses will be performed to 
correlate any findings from the various potential biomarker studies listed in Section 9 with the study 
endpoints above.
Patient Reported Outcomes – PROs of HRQoL, brain-metastasis-related symptoms, and health status 
will be measured using the EORTC QLQ-C30 and EORT QLQ-BN20. 
Summary statistics (mean, standard deviation, median, and range) of linear transformed scores will be 
reported for all the items and subscales of the EORTC QLQ-C30 questionnaire, and the QLQ-BN2- 
according to the EORTC scoring manual guidelines. Completion and compliance rates will be 
summarized at each time-point with reasons for missing data. Only patients with a baseline assessment 
and at least one post-treatment assessment will be included in the analyses.
13. PUBLICATION PLAN


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It is anticipated that the results of this study will first be reported in abstract form, followed by 
presentation in a peer-reviewed manuscript. 


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REFERENCES
1.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell 
lung cancer. N Engl J Med 2010;363:1693-703.
2.
Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of 
blocking the resistant gatekeeper mutant. Cancer Cell 2011;19:679-90.
3.
Ou S, Gadgeel S, Chiappori A, et al. Safety and efficacy analysis of RO5424802/CH5424802 in 
anaplastic lymphoma kinase (ALK)-postive non-small cell lung cancer (NSCLC) patients who have failed 
crizotinib in a dose-finding phase I study (AF-002JG, NCT01588028). Eur Cancer Congr 2013; LBA 44.
4.
Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as 
first-line treatment for advanced EGFR mutation-positive, nonsquamous non-small cell lung cancer 
(NSCLC): An open-label randomized trial. J Clin Oncol 32:5s, 2014 (suppl; abstr 8005).
5.
Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys 
BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. 
Lancet Oncol 2012;13:1087-95.
6.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-80.
7.
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene 
in non-small-cell lung cancer. Nature 2007;448:561-6.
8.
Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms of the EML4-ALK 
transforming gene in non-small cell lung cancer. Cancer Res 2008;68:4971-6.
9.
Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an 
immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 
2009;15:3143-9.
10.
Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 
2013;31:1105-11.
11.
Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc 
Natl Acad Sci U S A 2008;105:19893-7.
12.
Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with 
non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-53.
13.
Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-
positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-9.
14.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-
positive lung cancer. N Engl J Med 2013;368:2385-94.
15.
Mok T, Kim D, Wu Y, et al. First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-
carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer 
(NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol 32:5s, 2014 (suppl; abstr 8002).
16.
Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with 
advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. 
Lancet Oncol 2011;12:1004-12.
17.
Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-
rearranged lung Cancers. Sci Transl Med 2012;4:120ra17.
18.
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with 
ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18:1472-82.
19.
Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer 
resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9.
20.
Gainor JF, Varghese AM, Ou SH, et al. ALK Rearrangements Are Mutually Exclusive with 
Mutations in EGFR or KRAS: An Analysis of 1,683 Patients with Non-Small Cell Lung Cancer. Clin 
Cancer Res 2013;19:4273-81.
21.
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 
1997;18:4-25.
22.
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing 


Protocol #:15-055
Version Date:  October 7, 2020 
70
bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated 
locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-91.
23.
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-
small-cell lung cancer. N Engl J Med 2006;355:2542-50.
24.
Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either 
placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin 
Oncol 2009;27:1227-34.
25.
Camidge DR. Taking aim at ALK across the blood-brain barrier. J Thorac Oncol 2013;8:389-90.
26.
Sørensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of 
the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988;6:1474-80.
27.
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase 
inhibitor crizotinib. J Clin Oncol 2011;29:e443-5.
28.
Ou S, Gadgeel S, Chiappori A, et al. Consistent Therapeutic Efficacy of CH5424802/RO5424802 
in Brain Metastases Among Crizotinib-Refractory ALK-Positive Non-Small Cell Lung Cancer (NSCLC) 
Patients in an Ongoing Phase I/II Study (AF-002JG/NP28761). J Thorac Oncol 2013;8(S2): Abstract 
O16.07.
29.
Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged 
advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet 
Oncol 2013;14:590-8.
30.
Inoue A, Nishio M, Kiura K, et al. One-year Follow-up of a Phase I/II Study of a Highly 
Selective ALK Inhibitor CH5424802/RO5424802 in ALK-Rearranged Advanced Non-Small Cell Lung 
Cancer (NSCLC). J Thorac Oncol 2013;8(S2): Abstract P3.11-034.
31.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan 
in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.
32.
Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in 
patients with central nervous system metastases. Clin Cancer Res 2010;16:269-78.
33.
De Braganca KC, Janjigian YY, Azzoli CG, et al. Efficacy and safety of bevacizumab in active 
brain metastases from non-small cell lung cancer. J Neurooncol 2010;100:443-7.
34.
Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell 
lung cancer and brain metastases. J Clin Oncol 2009;27:5255-61.
35.
Besse B, Le Moulec S, Senellart H, et al. Final overall survival (OS) results of a noncomparative 
phase II study of bevacizumab (B) plus first-line chemotherapy or second-line erlotinib (E) in 
nonsquamous NSCLC (ns-NSCLC) patients with asymptomatic untreated brain metastases (BM) 
(BRAIN). J Clin Oncol 31, 2013 (suppl; abstr 8059).
36.
Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as 
first-line treatment for advanced EGFR-mutation positive nonsquamous non-small cell lung cancer 
(NSCLC): An open-label randomized trial. J Clin Oncol 32;5s, 2014 (suppl; abstr 8005).
37.
Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in 
metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91:173-80.
38.
Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-
VEGF therapy? Neuro Oncol 2008;10:624-30.
39.
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354:980-2; discussion -2.
40.
Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed and 
refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-
arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 2004;10:3577-85.
41.
Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in 
patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006;24:769-77.
42.
D'Adamo DR, Anderson SE, Albritton K, et al. Phase II study of doxorubicin and bevacizumab 
for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005;23:7135-42.


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


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Appendix B 
List of Substrates, Inhibitors, and Inducers of Drug-Metabolizing
Enzymes and Transporters
This representative list is not intended to be an exhaustive list. Each patient’s concomitant medications 
should be carefully considered by the investigator with regard to the risk-benefit for the particular patient 
and appropriate monitoring, including any concomitant medication, dose adjustment, or therapeutic 
alternatives, which should be determined by the investigator caring for the patient.
PgP Substrates
aliskiren, ambrisentan,
colchicine, dabigatran,
digoxin, everolimus,
fexofenadine, imatinib,
lapatinib, maraviroc, nilotinib,
posaconazole, pravastatin,
ranolazine, saxagliptin,
sirolimus, sitagliptin, talinolol,
tolvaptan, topotecan
This information in this appendix is adapted from Levien and Baker 20031, Zhang 20102, and FDA 
Guidance on Drug-Drug Interactions.
Also see:
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm080499.htm
1 Levien TL, and Baker DE Cytochrome P450 Drug Interactions. Therapeutic Research Center
Pharmacist’s Letter/Prescriber’s Letter [resource on the Internet]. 2003. Available from:
www.pharmacistsletter.com and www.prescribersletter.com.
2 Zhang L. Transporter Mediated Drug‐Drug Interactions. FDA. Clinical Pharmacology Advisory
Committee Meeting Topic 4: Transporter‐Mediated Drug‐Drug Interactions Atlanta, GA, March 17,
2010.
Appendix C: Adverse Event Fax Cover Sheet


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AE / SAE FAX No: (650) 238-6067
Genentech Study Number
Principal Investigator
Site Name
Reporter name
Reporter Telephone #
Reporter Fax #
Initial Report Date
[DD] / [MON] / [YY]
Follow-up Report Date
[DD] / [MON] / [YY]
Subject Initials
(Enter a dash if patient has no middle 
name)
[ ] - [ ] - [ ]
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET
Appendix D
Modification of Diet in Renal Disease (MDRD) Formula
The estimating glomerular filtration rate (eGFR) will be calculated on the basis of the
following formula (Miller 2009):
eGFR = 175 x SCRT -1.154 x AGE -0.203 [x 0.742 if female] [x 1.212 if


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African American] (conventional units)

ICF_001.pdf: 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es  
O H R S 1 0. 0 3. 1 4
P a ge 1  of 2 0  
D F CI Pr ot oc ol N u m ber:  
1 5 -0 5 5
A p pr o ve d Date ( D F CI I R B A p pr o val):  
 0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
Pr ot o c ol Titl e:   A P h a s e I/II Tri al t o E v al u at e t h e S af et y a n d T ol er a bilit y of Al e cti ni b 
a n d B e v a ci z u m a b i n P ati e nt s wit h A d v a n c e d, A L K -P o siti v e, N o n -s m all C ell L u n g 
C a n c er  
D F/ H C C Pri n ci p al R e s e ar c h D o ct or / I n stit uti o n:   
J u sti n G ai n or, M D / M a s s a c h u s ett s  G e n er al H o s pit al  
D F/ H C C Sit e -R e s p o n si bl e R e s e ar c h D o ct or( s) / I n stit uti o n( s):   
D a ni el C o st a, M D P h D / B et h I sr a el D e a c o n e s s M e di c al C e nt er  
P h a s e I C o n s e nt  
A.
IN T R O D U C TI O N
Y o u ar e i n vit e d t o t a k e p art i n a cli ni c al tri al, a t y p e of r e s e ar c h st u d y, b e c a u s e 
y o u h a v e a d v a n c e d n o n -s m all c ell l u n g c a n c er ( N S C L C). F or p ur p o s e s of t hi s 
r e s e ar c h, y o u will b e r ef err e d t o a s a “ p arti ci p a nt.” T hi s r e s e ar c h st u d y i s 
e v al u ati n g t w o dr u g s, al e cti ni b a n d b e v a ci z u m a b, a s p o s si bl e tr e at m e nt s f or 
N S C L C.  
It i s e x p e ct e d t h at b et w e e n 3 a n d 1 2  p e o pl e will t a k e p art i n t h e P h a s e I p orti o n 
of t hi s r e s e ar c h st u d y.  
G e n e nt e c h/ F. H off m a n n - L a R o c h e, Lt d. , a p h ar m a c e uti c al c o m p a n y, i s 
s u p p orti n g t hi s r e s e ar c h st u d y b y pr o vi di n g f u n di n g f or t h e r e s e ar c h st u d y a s w ell 
a s t h e st u d y dr u g s.    
T hi s r e s e ar c h c o n s e nt f or m e x pl ai n s w h y t hi s r e s e ar c h st u d y i s b ei n g d o n e, w h at 
i s i n v ol v e d i n p arti ci p ati n g i n t h e r e s e ar c h st u d y, t h e p o s si bl e ri s k s a n d b e n efit s 
of p arti ci p ati o n , alt er n ati v e s t o p arti ci p ati o n, a n d y o ur ri g ht s a s a r e s e ar c h 
p arti ci p a nt .  T h e d e ci si o n t o p arti ci p at e i s y o ur s.  If y o u d e ci d e t o p arti ci p at e, 
pl e a s e si g n a n d d at e at t h e e n d of t hi s f or m. W e will gi v e y o u a c o p y s o t h at y o u 
c a n r ef er t o it w hil e y o u ar e i n v ol v e d i n t hi s r e s e ar c h st u d y.  If y o u c h o o s e n ot t o 
p arti ci p at e i n t hi s r e s e ar c h st u d y, th e r e s e ar c h d o ct or s will di s c u s s ot h er 
tr e at m e nt o pti o n s wit h y o u a n d/ or r ef er y o u b a c k t o y o ur pri m ar y d o ct or.  
W e e n c o ur a g e y o u t o t a k e s o m e ti m e t o t hi n k t hi s o v er , t o di s c u s s it wit h ot h er 
p e o pl e a n d y o ur pri m ar y d o ct or , a n d t o a s k q u e sti o n s n o w a n d at a n y ti m e i n t h e 
f ut ur e. 
N C T 0 2 5 2 1 0 5 1
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f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 2  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
B.  W H Y I S T HI S R E S E A R C H S T U D Y B EI N G D O N E ?   
 
T hi s i s a P h a s e I/II cli ni c al tri al.   Y o u ar e b ei n g a s k e d t o p arti ci p at e i n t h e P h a s e I  
p orti o n of t h e st u d y.  A  P h a s e I cli ni c al tri al t e st s t h e s af et y of a n i n v e sti g ati o n al 
i nt er v e nti o n a n d al s o tri e s t o d efi n e t h e a p pr o pri at e d o s e ( s) of t h e i n v e sti g ati o n al 
i nt er v e nti o n t o u s e f or f urt h er st u di e s.  “I n v e sti g ati o n al” m e a n s t h at t h e 
i nt er v e nti o n i s b ei n g st u di e d.  
 
I n t hi s r e s e ar c h st u d y, w e ar e i n v e sti g ati n g t h e c o m bi n ati o n of t w o st u d y dr u g s: 
al e cti ni b a n d b e v a ci z u m a b. T h e F D A (t h e U. S. F o o d a n d Dr u g A d mi ni str ati o n) 
h a s n ot a p pr o v e d  al e cti ni b a s a tr e at m e nt f or a n y di s e a s e.  
 
It h a s b e e n f o u n d t h at s o m e p e o pl e wit h N S C L C h a v e a c h a n g e ( m ut ati o n) i n a 
c ert ai n g e n e c a ll e d t h e a n a pl a sti c l y m p h o m a r e c e pt or t yr o si n e ki n a s e  (A L K ) 
g e n e. T hi s m ut at e d g e n e h el p s c a n c er c ell s gr o w. Al e cti ni b b el o n g s t o a cl a s s of 
dr u g s d e si g n e d t o i n hi bit A L K. T hi s dr u g h a s b e e n u s e d i n ot h er r e s e ar c h 
st u di e s. I nf or m ati o n fr o m t h o s e ot h er r e s e ar c h st u di e s s u g g e st s  t h at al e cti ni b 
m a y b e eff e cti v e i n ki lli n g c a n c er c ell s t h at h a v e c h a n g e s  i n A L K. O nl y 
p arti ci p a nt s wit h c h a n g e s i n t h e A L K g e n e will b e all o w e d t o p arti ci p at e i n t hi s 
st u d y.   
 
I n t hi s r e s e ar c h st u d y, al e cti ni b will b e c o m bi n e d  wit h b e v a ci z u m a b.  
B e v a ci z u m a b ( al s o c all e d A v a sti n) w or k s b y sl o wi n g or st o p pi n g t h e gr o wt h of  
c ell s i n c a n c er t u m or s b y d e cr e a si n g t h e bl o o d s u p pl y of t h e t u m or s. If bl o o d  
s u p pl y i s d e cr e a s e d, o x y g e n a n d n utri e nt s t h at ar e n e e d e d f or t u m or gr o wt h ar e  
d e cr e a s e d . T h e F D A h a s a p pr o v e d b e v a ci z u m a b a s a tr e at m e nt o pti o n f or y o ur 
di s e a s e  
 
T h e p ur p o s e of t hi s st u d y i s t o t e st t h e s af et y of al e cti ni b a n d b e v a ci z u m a b. W e 
will al s o d et er mi n e h o w eff e cti v e t hi s c o m bi n ati o n i s i n p arti ci p a nt s wit h 
a d v a n c e d, A L K -p o siti v e N S C L C  wit h a f o c u s o n p arti ci p a nt s wit h br ai n 
m et a st a s e s.  
 
C.  W H A T O T H E R O P TI O N S A R E T H E R E ?  
 
T a ki n g p art i n t hi s r e s e ar c h st u d y i s v ol u nt ar y. I n st e a d of b ei n g i n t hi s r e s e ar c h 
st u d y, y o u h a v e ot h er o pti o n s w hi c h m a y i n cl u d e t h e f oll o wi n g :  
 
•  R e c ei v e  s t a n d ar d tre at m e nt i n cl u di n g cri z oti ni b ( X A L K O RI) or  c eriti ni b 
(Z y k a di a).  
•  R e c ei v e st a n d ar d c h e m ot h er a p y  
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Rese arc h C o nse nt F o r m  
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Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 3  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  R e c ei v e r a di ati o n t h er a p y t o br ai n m et a st a s e s.  
•  T a k e p art i n a n ot h er r e s e ar c h st u d y.  
•  R e c ei v e  n o t h er a p y s p e cifi c t o y o ur c a n c er.  
•  C o mf ort c ar e, al s o c all e d p alli a ti v e c ar e.  T hi s t y p e of c ar e m a y h el p t o 
r e d u c e p ai n, tir e d n e s s, a p p etit e pr o bl e m s a n d ot h er pr o bl e m s c a u s e d 
b y t h e c a n c er.  It d o e s n ot tr e at t h e c a n c er dir e ctl y, b ut i n st e a d tri e s t o 
tr e at t h e s y m pt o m s.   
 
Pl e a s e t al k t o t h e r e s e ar c h d o ct or a b o ut y o ur o pti o n s b ef or e y o u d e ci d e w h et h er 
y o u will t a k e p art i n t hi s r e s e ar c h st u d y.  
 
D.  W H A T I S I N V O L V E D I N T H E R E S E A R C H S T U D Y ?  
 
Si n c e w e ar e l o o ki n g f or t h e hi g h e st d o s e of t h e st u d y dr u g t h at c a n b e 
a d mi ni st er e d s af el y wit h o ut s e v er e or u n m a n a g e a bl e si d e eff e ct s i n  p arti ci p a nt s 
t h at h a v e A L K -p o siti v e l u n g c a n c er , n ot e v er y o n e w h o p arti ci p at e s i n t hi s 
r e s e ar c h st u d y will r e c ei v e t h e s a m e d o s e of t h e st u d y dr u g.  T h e d o s e y o u g et 
will d e p e n d o n t h e n u m b er of p arti ci p a nt s w h o h a v e b e e n e nr oll e d i n t h e st u d y 
b ef or e y o u a n d h o w w ell t h e y h a v e t ol er at e d t h eir d o s e s.  
 
S o m eti m e s it i s h ar d t o k e e p tr a c k of all of t h e d et ail s a n d pr o c e d ur e s t h at ar e 
p art of a r e s e ar c h st u d y.  W e will d e s cri b e t h e m i n t hi s c o n s e nt f or m a n d y o u c a n 
r ef er t o t hi s at a n y ti m e d uri n g t h e r e s e ar c h st u d y.  
 
If y o u t a k e p art i n t hi s r e s e ar c h st u d y y o u will b e gi v e n a dr u g di ar y.  Y o u will b e 
a s k e d t o d o c u m e nt i nf or m ati o n i n t h e dr u g di ar y a b o ut t h e st u d y tr e at m e nt y o u 
ar e b ei n g a s k e d t o t a k e.  
 
B ef or e t h e r e s e ar c h st art s ( s cr e e ni n g) :   
Aft er si g ni n g t h i s c o n s e nt f or m, y o u will b e a s k e d t o u n d er g o s o m e s cr e e ni n g 
t e st s or pr o c e d ur e s t o fi n d o ut if y o u c a n b e i n t h e r e s e ar c h st u d y.  M a n y of t h e s e 
t e st s a n d pr o c e d ur e s ar e li k el y t o b e p art of r e g ul ar c a n c er c ar e a n d m a y b e 
d o n e e v e n if it t ur n s o ut t h at y o u  d o n ot t a k e p art i n t h e r e s e ar c h st u d y.  If y o u 
h a v e h a d s o m e of t h e s e t e st s or pr o c e d ur e s r e c e ntl y, t h e y m a y or m a y n ot h a v e 
t o b e r e p e at e d.   
 
•  A m e di c al hi st or y , w hi c h i n cl u d e s q u e sti o n s a b o ut y o ur h e alt h, c urr e nt 
m e di c ati o n s, a n d a n y all er gi e s.  
•  P erf or m a n c e st at u s , w hi c h e v al u at e s h o w y o u ar e a bl e t o c arr y o n wit h 
y o ur u s u al a cti viti e s.  
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 4  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  P h y si c al e x a m, i n cl u di n g m e a s ur e m e nt of h ei g ht, w ei g ht a n d vit al si g n s 
(t e m p er at ur e, br e at hi n g r at e, bl o o d pr e s s ur e a n d p ul s e). 
•  A n a s s e s s m e nt of y o ur t u m or b y o n e or m or e of t h e f oll o wi n g st a n d ar d 
a s s e s s m e nt t o ol s: C T  ( C o m p ut eri z e d T o m o gr a p h y) s c a n a n d  M RI 
( M a g n eti c R e s o n a n c e I m a gi n g)  
•  Bl o o d t e st s, f or st a n d ar d l a b or at or y t e st s ( a b o ut 2 t a bl e s p o o n s), a 
pr e g n a n c y t e st (if y o u c a n b e c o m e pr e g n a nt), a n d t e st s  t o c h e c k h o w 
q ui c kl y y o ur bl o o d cl ot s.  
•  Uri n e t e st . 
•  E K G, a t e st t h at m e a s ur e s t h e el e ctri c al a cti vit y a n d r h yt h m of t h e h e art.  
•  P ati e nt q u e sti o n n air e s , w hi c h i n cl u d e q u e sti o n s a b o ut y o ur h e alt h  
 
If t h e s e t e st s s h o w t h at y o u ar e eli gi bl e t o p arti ci p at e i n t h e r e s e ar c h st ud y, y o u 
will b e gi n t h e st u d y tr e at m e nt.  If y o u d o n ot m e et t h e eli gi bilit y crit eri a, y o u will 
n ot b e a bl e t o p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
Aft er t h e s cr e e ni n g pr o c e d ur e s c o nfir m t h at y o u ar e eli gi bl e t o p arti ci p at e 
i n t h e r e s e ar c h st u d y: 
E a c h tr e at m e nt c y cl e l a st 2 1 d a y s ( 3 w e e k s).  
 
Al e cti ni b  i s a c a p s ul e t h at y o u t a k e b y m o ut h. Y o u will b e gi v e n a dr u g di ar y t o 
r e c or d t h e d o s e of al e cti ni b  y o u t a k e e a c h d a y.  T h e di ar y will al s o i n cl u d e s p e ci al 
i n str u cti o n s f or t a ki n g al e cti ni b.  
 
Y o u will b e gi v e n  B e v a ci z u m a b vi a I V, w hi c h i s c all e d a n i nf u si o n.  
 
Y o u will r e c ei v e a n i nf u si o n of  b e v a ci z u m a b o n t h e fir st d a y of e a c h tr e at m e nt 
c y cl e ( o n c e e v er y 2 1 d a y s).  
 
St u d y Tr e at m e nt P eri o d  
A s c h e d ul e of cli ni c vi sit s f or t h e st u d y i s s u m m ari z e d b el o w. At e v er y v i sit, y o u 
s h o ul d t ell t h e st u d y st aff h o w y o u ar e f e eli n g a n d w h et h er y o ur h e alt h h a s 
c h a n g e d. Y o u m a y h a v e ot h er l a b t e st s d o n e a s p art of y o ur c a n c er c ar e i n 
a d diti o n t o t h o s e li st e d b el o w.  
 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 5  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
C y cl e 1 D a y 1:  
•  P erf or m a n c e st at u s .  
•  P h y si c al e x a m . 
•  R o uti n e bl o o d t e st s  ( a b o ut 2 t a bl e s p o o n s of bl o o d).  
•  Uri n e t e st.  
•  E K G . 
•  P ati e nt q u e sti o n n air e s . 
 
C y cl e 1 D a y 1 5:  
•  P erf or m a n c e st at u s .  
•  P h y si c al e x a m . 
•  R o uti n e bl o o d t e st s  ( a b o ut 2 t a bl e s p o o n s of bl o o d). 
 
C y cl e s 2 -1 0  
D a y 1  of E a c h C y cl e  
•  P erf or m a n c e st at u s .  
•  P h y si c al e x a m . 
•  R o uti n e bl o o d t e st s ( a b o ut 2 t a bl e s p o o n s of bl o o d).  
•  Uri n e t e st.  
•  E K G  o nl y b e p erf or m e d o n D a y 1 of C y cl e 2 a n d C y cl e 8.  
•  P ati e nt q u e sti o n n air e s . 
•  A n a s s e s s m e nt of y o ur t u m or . Y o u will o nl y h a v e br ai n M RI s p erf or m e d 
if a b n or m aliti e s w er e d et e ct e d o n t h e i niti al s cr e e ni n g M RI .   
 
C y cl e s 1 1 a n d B e y o n d  
D a y 1 of E a c h C y cl e  
•  P erf or m a n c e st at u s .  
•  P h y si c al e x a m . 
•  R o uti n e bl o o d t e st s ( a b o ut 2 t a bl e s p o o n s of bl o o d).  
•  Uri n e t e st.  
•  E K G  o nl y b e p erf or m e d o n D a y 1 of C y cl e 1 8.   
•  P ati e nt q u e sti o n n air e s . 
•  A n a s s e s s m e nt of y o ur t u m or .  
 
E n d of St u d y Tr e at m e nt Vi sit  
W h e n y o u st o p al e cti ni b a n d b e v a ci z u m a b p er m a n e ntl y, y o u will r et ur n t o t h e 
st u d y cli ni c. T h e f oll o wi n g pr o c e d ur e s will b e d o n e at t hi s vi sit:  
•  P erf or m a n c e st at u s .  
•  P h y si c al e x a m . 
•  R o uti n e bl o o d t e st s ( a b o ut 2 t a bl e sp o o n s of bl o o d).  
3/ 7/ 2 0 2 3 6: 5 3 p m
3/7/2023 6:53 pm


 
 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 6  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  Uri n e t e st.  
•  E K G .  
•  P ati e nt q u e sti o n n air e s . 
•  A n a s s e s s m e nt of y o ur t u m or .  
 
3 0 D a y F oll o w -u p Vi sit  
Y o u will al s o vi sit t h e cli ni c 3 0 d a y s aft er y o u st o p t a ki n g st u d y dr u g s. T h e 
f oll o wi n g t e st s a n d pr o c e d ur e s will b e d o n e:  
•  R e vi e w of m e di c al hi st or y a n d m e di c ati o n s  
•  P ati e nt q u e sti o n n air e s  
 
E.  H O W L O N G WI L L I B E I N T HI S R E S E A R C H  S T U D Y ?  
 
Y o u will b e i n t hi s r e s e ar c h st u d y f or u p t o a y e ar.   
 
T h e r e s e ar c h d o ct or m a y d e ci d e t o t a k e y o u off t h e r e s e ar c h st u d y f or m a n y 
r e a s o n s i n cl u di n g if: 
•  It i s c o n si der e d t o b e i n y o ur b e st i nt er e st  
•  T h e st u d y tr e at m e nt or pr o c e d ur e s ar e f o u n d t o b e u n s af e or i n eff e cti v e  
•  T h er e i s a n y pr o bl e m wit h f oll o wi n g st u d y tr e at m e nt s a n d pr o c e d ur e s  
•  Y o ur c o n diti o n w or s e n s  
•  A d e ci si o n i s m a d e t o cl o s e t h e st u d y  
•  Or f or ot h er u nf or e s e e n r e a s o n s t h at m a k e it n e c e s s ar y t o st o p y o ur 
p arti ci p ati o n i n t h e r e s e ar c h st u d y  
 
If y o u ar e r e m o v e d fr o m t h e r e s e ar c h st u d y, t h e r e s e ar c h d o ct or will e x pl ai n t o 
y o u w h y y o u w er e r e m o v e d.   
 
I n a d diti o n, y o u c a n st o p p arti ci p ati n g i n t h e r e s e ar c h st u d y at a n y ti m e . 
H o w e v er, t h e F D A r e q uir e s t h at a n y i nf or m ati o n c oll e ct e d u p t o t h e p oi nt of y o ur 
wit h dr a w al c a n n ot b e r e m o v e d fr o m t h e st u d y.  If y o u d e ci d e t o st o p p arti ci p ati n g 
i n t hi s r e s e ar c h st u d y, w e e n c o ur a g e y o u t o t al k t o t h e r e s e ar c h d o ct or a n d y o ur 
p ri m ar y d o ct or fir st.  
 
3/ 7/ 2 0 2 3 6: 5 3 p m
3/7/2023 6:53 pm


 
 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 7  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
F.  W H A T A R E T H E RI S K S O R  DI S C O M F O R T S O F T H E R E S E A R C H S T U D Y ?  
 
T h er e ar e ri s k s t o t a ki n g p art i n a n y r e s e ar c h st u d y. O n e ri s k i s t h at y o u m a y g et 
a st u d y dr u g or st u d y d o s e of a dr u g t h at d o e s n ot h el p tr e at y o ur di s e a s e or t h at 
m a k e s y o u r c o n diti o n or di s e a s e w or s e.  A n ot h er ri s k i s t h at t h er e m a y b e si d e 
eff e ct s.   
 
All c a n c er tr e at m e nt s c a n h a v e si d e eff e ct s, w hi c h c a n r a n g e fr o m mil d a n d 
r e v er si bl e t o s e v er e, l o n g l a sti n g a n d p o s si bl y lif e-t hr e at e ni n g.  T h er e i s a gr e at 
d e al of v ari a bi lit y a m o n g si d e eff e ct s of diff er e nt c a n c er tr e at m e nt s  a n d b et w e e n 
i n di vi d u al s.  I n a r e s e ar c h st u d y, all of t h e ri s k s  or si d e eff e ct s m a y n ot b e k n o w n 
b ef or e y o u st art t h e st u d y.  Y o u n e e d t o t ell y o ur d o ct or or a m e m b er of t h e 
st u d y t e a m i m m e di at el y if y o u e x p eri e n c e a n y si d e eff e ct s.  
 
E v er y o n e i n t h e r e s e ar c h st u d y will b e w at c h e d c ar ef ull y f or si d e eff e ct s.  Y o u will 
b e m o nit or e d d uri n g t h e a d mi ni str ati o n of st u d y dr u g s  t o k e e p tr a c k of y o ur bl o o d 
c o u nt s a n d or g a n f u n cti o n, p arti c ul arl y y o ur ki d n e y a n d li v er f u n cti o n.  If y o u 
e x p eri e n c e si d e eff e ct s, t h e y m a y g o a w a y aft er y o u st o p t a ki n g t h e st u d y dr u g.  
S o m e si d e eff e ct s c a n b e mil d; b ut ot h er s c a n b e l o n g l a sti n g a n d m a y n e v er g o 
a w a y.  S o m e m a y b e lif e -t hr e at e ni n g or f at al.  
 
Si n c e t h e eff e ct of t h e st u d y dr u g( s) t a k e n wit h ot h er m e di c ati o n s m a y n ot b e 
k n o w n, it i s i m p ort a nt t h at y o u t ell t h e r e s e ar c h d o ct or a b o ut all pr e s cri pti o n a n d 
n o n -pr e s cri pti o n dr u g s, h er b al pr e p ar ati o n s a n d n utriti o n al s u p pl e m e nt s t h at y o u 
ar e t a ki n g or pl a n ni n g t o t a k e.  T h er e  m a y al s o b e s o m e f o o d s t h at y o u s h o ul d 
a v oi d w hil e o n t hi s r e s e ar c h st u d y a n d y o ur r e s e ar c h d o ct or will r e vi e w t hi s 
i nf or m ati o n wit h y o u. 
 
D uri n g t h e r e s e ar c h st u d y, y o u will b e n otifi e d of n e wl y di s c o v er e d si d e eff e ct s or 
si g nifi c a nt fi n di n g s, w hi c h m a y aff e ct y o ur h e alt h or willi n g n e s s t o p arti ci p at e.  
Y o u m a y b e a s k e d t o si g n a n e w c o n s e nt f or m t h at s h o w s t h at y o u h a v e b e e n 
i nf or m e d of n e w i nf or m ati o n r el ati n g t o t hi s r e s e ar c h st u d y. 
 
Ri s k s A s s o ci at e d wit h  Al e cti ni b:  
C o m m o n ( o c c ur s i n gr e at er t h a n 1 0 % o f p ati e nt s) 
•  L o s s of t a st e  
•  A b n or m all y hi g h l e v el s of bilir u bi n i n t h e bl o o d. ( Bilir u bi n i s a bil e pi g m e nt 
pr o d u c e d b y t h e li v er w hi c h i s n or m all y a n d c o nti n u all y e x cr et e d fr o m t h e 
b o d y) . T hi s m a y i n di c at e t h at t o o m a n y r e d bl o o d c ell s ar e b ei n g 
d e str o y e d, o r t h at t h e li v er or g all bl a d d er i s n ot f u n cti o ni n g pr o p erl y. 
•  C o n sti p ati o n  
3/ 7/ 2 0 2 3 6: 5 3 p m
3/7/2023 6:53 pm


 
 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 8  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  In cr e a s e i n li v er e n z y m e, i n di c ati n g p o s si bl e li v er  d a m a g e  ( A S T/ A L T 
i n cr e a s e) 
•  N o s e a n d t hr o at i nfl a m m ati o n  ( n a s o p h ar y n giti s) 
•  R a s h  
•  A b n or m al ki d n e y t e st w hi c h m a y i n di c at e p o s si bl e ki d n e y  d a m a g e  (bl o o d 
cr e ati ni n e i n cr e a s e ) 
•  L o w w hit e bl o o d c ell c o u nt w hi c h m a y i n cr e a s e y o ur ri s k f or i nf e cti o n, s u c h 
a s p n e u m o ni a a n d/ or s e v er e bl o o d i nf e cti o n ( n e utr o p hil c o u nt d e cr e a s e)  
•  I n cr e a s e d bl o o d l e v el of e n z y m e fr o m m u s cl e w hi c h m a y i n di c at e p o s si ble 
m u s cl e d a m a g e ( Bl o o d C P K i n cr e a s e)  
•  M u s cl e p ai n  ( m y al gi a) 
•  W hit e bl o o d c ell d e cr e a s e ( w hi c h m a y i n cr e a s e y o ur ri s k of i nf e cti o n)  
•  Bl o o d al k ali n e p h o s p h at a s e i n cr e a s e ( w hi c h m a y i n di c at e p o s si bl e li v er  
d a m a g e)  
•  Or al i nfl a m m ati o n ( s t o m atiti s) 
•  N a u s e a  
•  W ei g ht i n cr e a s e  
•  Di arr h e a  
•  F e eli n g  of b o dil y di s c o mf ort  ( m al ai s e) 
 
Al e cti ni b al s o c o nt ai n s a s u b st a n c e c all e d s o di u m l a ur yl s ulf at e t h at i s k n o w n t o  
s o m eti m e s c a u s e g a str oi nt e sti n al pr o bl e m s, s u c h a s n a u s e a, v o miti n g a n d 
di arr h e a.  
 
R ar e b ut s eri o u s:  
•  Int er stiti al l u n g di s e a s e (I L D; l u n g s c arri n g ) w hi c h c o ul d c a u s e br e at hi n g 
diffi c ult y, c o u g h, a n d f e v er. I L D c a n b e lif e t hr e at e ni n g. 
•  L o w bl o o d pr e s s ur e a n d sl o w er bl o o d cl otti n g.  
•  E y e di s or d er s, s u c h a s bl urr e d vi si o n . 
 
Ri s k s A s s o ci at e d wit h B e v a ci z u m a b:  
Fr e q u e nt ( C h a n c e  of 1 0 -5 0 % t h at t hi s will h a p p e n):  
•  N a u s e a a n d v o miti n g  
•  H e a d a c h e s  
•  Hi g h bl o o d pr e s s ur e, wit h i n cr e a s e d ri s k of h e art pr o bl e m s, h e a d a c h e, a n d 
str o k e.  
•  P ai n  
•  A b d o mi n al p ai n  
•  S h ort n e s s of br e at h  
•  M o ut h s or e s  
3/ 7/ 2 0 2 3 6: 5 3 p m
3/7/2023 6:53 pm


 
 
Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 9  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  W e a k n e s s  
•  U p p er r e s pir at or y i nf e cti o n  
•  C hill s  
•  L o s s of a p p et it e 
•  Bl e e di n g (i n cl u di n g i n st o m a c h or i nt e sti n e s)  
•  R u n n y n o s e or i n cr e a s e i n t e ar s i n y o ur e y e s  
•  Ki d n e y d a m a g e, f o u n d b y t e sti n g y o ur uri n e  
•  L o s s of f u n cti o n of t h e o v ari e s, w hi c h c a n l e a d t o m e n o p a u s e  
 
O c c a si o n al ( C h a n c e of 5 -1 0 % t h at t hi s will h a p p e n):  
•  H o ar s e n e s s  
•  N o s e bl e e d s  
•  L o w l e v el s of p ot a s si u m i n t h e bl o o d w hi c h c a n c a u s e a n irr e g ul ar h e art 
b e at  
•  H air l o s s  
•  Dr y s ki n  
•  H ol e i n y o ur i nt e sti n e  m a y o c c ur w hi c h m a y r e q uir e  h o s pit ali z ati o n a n d/ or 
s ur g er y  w hi c h c o ul d b e s eri o u s or lif e t hr e at e ni n g.   
•  B l o o d cl ot s i n y o ur v ei n s a n d art eri e s. T h e s e c a n c a u s e c h e st p ai n, h e art  
att a c k, or str o k e. A bl o o d cl ot i n y o ur e y e mi g ht c a u s e vi si o n l o s s. Cl ot s  
c a n b e s eri o u s a n d lif e t hr e at e ni n g.  
•  All er gi c r e a cti o n w h e n t h e i nf u si o n i s gi v e n. A s eri o u s all er gi c r e a cti o n  
m a y r e s ult  i n d e at h. 
•  Sl o w e d gr o wt h a n d d e v el o p m e nt ( b a s e d o n l a b or at or y st u di e s)  
 
R ar e ( L e s s t h a n 5 % c h a n c e t hi s will h a p p e n):  
•  I n a bilit y of h e art t o p u m p bl o o d pr o p erl y, w hi c h c a n c a u s e w e a k n e s s a n d 
tir e d n e s s, fl ui d r et e nti o n, a n d fl ui d b uil d-u p i n t h e l u n g s, w hi c h c a n c a u s e 
s h ort n e s s of br e at h ( c o n g e sti v e h e art f ail ur e)  
•  D e cr e a s e d a bilit y  of y o ur w o u n d s t o h e al. T hi s c a n l e a d  t o i nf e cti o n s, 
h o s pit ali z ati o n, or c o ul d p o s si bl y b e f at al.  
•  A v er y r ar e pr o bl e m i n y o ur br ai n t h at m a y c a u s e c o nf u si o n, bli n d n e s s,  
a n d c o m a. T h i s i s a s s o ci at e d wit h v er y hi g h bl o o d pr e s s ur e a n d i s n ot 
t h o u g ht t o b e a p er m a n e nt c o n diti o n. 
•  C o nf u si o n  
•  A b d o mi n al a b s c e s s or i nf e cti o n i n y o ur a b d o m e n  
•  Fi st ul a or h ol e i n y o ur b o w el. T hi s i s a n a b n or m al c o n n e cti o n b et w e e n t w o  
diff er e nt or g a n s a n d m a y l e a d t o lif e t hr e at e ni n g c o m pli c ati o n s i n cl u di n g 
s eri o u s i nf e cti o n s, bl e e di n g, or d y sf u n cti o n of t h e or g a n s  
•  D e h y dr ati o n  
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 0  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
•  A b n or m al bl e e di n g fr o m i n y o ur b o d y or fr o m t h e t u m or w hi c h c o ul d b e 
s eri o u s of lif e t hr e at e ni n g  
 
C a n c er r e s e ar c h oft e n i n cl u d e s bi o p si e s, s c a n s, x -r a y s t h at ar e al s o pr o vi d e d a s 
r o uti n e c ar e.  T h e f oll o wi n g d e s cri b e s t h e si d e eff e ct s of pr o c e d ur e s d o n e o nl y 
f or t h e p ur p o s e s of r e s e ar c h.  
 
R a di ati o n Ri s k s A s s o ci at e d wit h S c a n s a n d X -R a y s :  
W hil e y o u ar e i n t hi s r e s e ar c h st u d y, C T s c a n s  m a y b e u s e d t o e v al u at e y o ur 
di s e a s e.  T h e fr e q u e n c y of t h e s e e x a m s i s sli g htl y gr e at er t h a n w h at y o u w o ul d 
r e c ei v e a s st a n d ar d c ar e. I n t h e l o n g t er m, o v er m a n y y e ar s, t h er e i s a v er y l o w 
ri s k of d e v el o pi n g a n e w c a n c er a s a r e s ult of t h e r a di ol o gi c al e v al u ati o n an d 
tr e at m e nt f or y o ur c a n c er.   
 
Ri s k s A s s o ci at e d wit h M RI S c a n s :  
W h e n h a vi n g a n M RI ( M a g n eti c R e s o n a n c e I m a gi n g) s c a n, y o u will li e still o n a 
t a bl e t h at sli d e s i nt o a t u n n el sli g htl y wi d er t h a n y o ur b o d y. P e o pl e w h o f e el 
u n c o mf ort a bl e i n c o nfi n e d s p a c e s  ( cl a u str o p h o bi a) m a y f e el u n c o mf ort a bl e i n t h e 
n arr o w c yli n d er. If y o u f e el u n c o mf ort a bl e i n c o nfi n e d s p a c e s, pl e a s e t ell y o ur 
r e s e ar c h d o ct or. Y o ur d o ct or m a y gi v e y o u a m e di c ati o n t o m a k e y o u f e el m or e 
c o mf ort a bl e. A s i m a g e s ar e t a k e n, a l o u d b a n gi n g n o i s e will b e pr o d u c e d.  
E ar pl u g s or h e a d p h o n e s will b e a v ail a bl e if n e e d e d . T h e M RI c a n b e st o p p e d at 
a n y ti m e at y o ur r e q u e st, b ut t h e s c a n m a y n ot b e c o m pl et e.  
 
Ri s k s A s s o ci at e d wit h C o ntr a st A g e nt s U s e d D uri n g S c a n s:  
T h er e i s a s m all ri s k wit h u si n g a c o ntr a st a g e nt t h at i s  i nj e ct e d i nt o a v ei n d uri n g 
C T s c a n s a n d M RI s. T h e c o ntr a st a g e nt i s a s p e ci al d y e t h at hi g hli g ht s or g a n s, 
bl o o d v e s s el s or ti s s u e t o m a k e t h e m m or e vi si bl e.  D e p e n di n g o n t h e t y p e of 
c o ntr a st a g e nt t h at i s u s e d, i t m a y c a u s e d e cr e a s e d  ki d n e y f u n cti o n or w or s e n 
ki d n e y f u n cti o n i n p e o pl e w h o alr e a d y h a v e d e cr e a s e d ki d n e y f u n cti o n.  
T h er ef or e, w e will m o nit or y o ur ki d n e y f u n cti o n cl o s el y w hil e y o u p arti ci p at e i n 
t hi s st u d y.  If t h er e i s a n y c h a n g e i n y o ur ki d n e y f u n cti o n, w e m a y h a v e t o 
re m o v e y o u fr o m t h e st u d y.  
 
U n c o m m o nl y , s o m e p e o pl e h a v e all er gi c r e a cti o n s ( s u c h a s hi v e s a n d it c hi n g) t o 
t h e c o ntr a st a g e nt.  S eri o u s r e a cti o n s (f or e x a m pl e, dr o p i n bl o o d pr e s s ur e, 
diffi c ult y br e at hi n g  or s e v er e all er gi c r e a cti o n a n d d e at h) ar e r ar e.   
 
R e pr o d u cti v e Ri s k s :  
T h e dr u g s u s e d i n t hi s r e s e ar c h st u d y m a y aff e ct a f et u s.  W hil e p arti ci p ati n g i n 
t hi s r e s e ar c h st u d y, y o u s h o ul d n ot b e c o m e pr e g n a nt or f at h er a b a b y, a n d 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 1  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
s h o ul d n ot n ur s e a b a b y.  W e c a n pr o vi d e c o u n s eli n g a b o ut pr e v e nti n g 
pr e g n a n c y f or eit h er m al e or f e m al e st u d y p arti ci p a nt s. L et y o ur d o ct or k n o w 
i m m e di at el y if y o u b e c o m e pr e g n a nt or fi n d o ut t h at y o u ar e g oi n g t o b e t h e 
f at h er of a c hil d. 
 
If a f e m al e b e c o m e s pr e g n a nt w hil e o n t hi s st u d y or wit hi n 9 0 d a y s aft er t h e l a st 
d o s e of t h e  st u d y dr u g, a r e p ort s h o ul d b e c o m pl et e d a n d pr o vi d e d t o t h e 
s p o n s or. W e w o ul d al s o li k e t o f oll o w -u p wit h y o u t o o bt ai n t h e o ut c o m e of t h e 
pr e g n a n c y if t hi s o c c ur s.  
 
 
N o n -P h y si c al Ri s k s :  
B e c a u s e of si d e eff e ct s or t h e ti m e r e q uir e d f or t e st s a n d cli ni c  vi sit s w hil e y o u 
ar e o n t hi s r e s e ar c h st u d y, y o u m a y b e u n a bl e t o k e e p u p wit h y o ur n or m al d ail y 
a cti viti e s.   
 
T h e q u e sti o n n air e s u s e d i n t hi s st u d y m a y b e u p s etti n g. If y o u fi n d t h e 
q u e sti o n n air e s u p s etti n g, y o u m a y s p e a k wit h t h e r e s e ar c h d o ct or or a s k t o b e 
r ef err e d f or a d diti o n al e m oti o n al s u p p ort. 
 
G.  W H A T A R E T H E B E N E FI T S  O F T H E R E S E A R C H S T U D Y ?  
 
T hi s st u d y m a y or m a y n ot  h el p y o u.  T a ki n g p art i n t hi s r e s e ar c h st u d y m a y h el p 
u s l e ar n m or e a b o ut al e cti ni b a n d b e v a ci z u m a b a s  tr e at m e nts  f or A L K -p o siti v e 
l u ng c a n c er  t h at m a y h el p p e o pl e i n t h e f ut ur e. 
 
H.  C A N I S T O P B EI N G I N T H E R E S E A R C H S T U D Y A N D W H A T A R E M Y RI G H T S ?  
 
Y o u h a v e t h e ri g ht t o c h o o s e n ot t o si g n t hi s f or m.  If y o u d e ci d e n ot t o si g n t hi s 
f or m, y o u c a n n ot p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
Y o u c a n  st o p b ei n g i n t h e r e s e ar c h st u d y at a n y ti m e.  T ell t h e r e s e ar c h d o ct or if 
y o u ar e t hi n ki n g a b o ut st o p pi n g or d e ci d e t o st o p.  H e or s h e will t ell y o u h o w t o 
st o p.  L e a vi n g t h e r e s e ar c h st u d y will n ot aff e ct y o ur m e di c al c ar e  o ut si d e of t h e 
r e s e ar c h st u d y.   
 
If y o u c h o o s e n ot t o p arti ci p at e, ar e n ot eli gi bl e t o p arti ci p at e, or wit h dr a w fr o m 
t hi s r e s e ar c h st u d y, t hi s will n ot aff e ct y o ur pr e s e nt or f ut ur e c ar e a n d will n ot 
c a u s e a n y p e n alt y or l o s s of b e n efit s t o w hi c h y o u ar e ot h er wi s e e ntitl e d.  
It i s i mp ort a nt t o t ell t h e r e s e ar c h d o ct or if y o u ar e t hi n ki n g a b o ut st o p pi n g s o  
y o ur r e s e ar c h d o ct or c a n e v al u at e t h e  ri s k s fr o m st o p pi n g t h e st u d y dr u g s. 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 2  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
A n ot h er r e a s o n t o t ell y o ur r e s e ar c h d o ct or t h at y o u ar e t hi n ki n g a b o ut st o p pi n g 
i s t o di s c u s s w h at f oll o w-u p c ar e a n d t e sti n g c o ul d b e m o st h el pf ul f or y o u.  
 
I. W I L L I B E P AI D T O T A K E P A R T I N T HI S R E S E A R C H S T U D Y ?  
 
Y o u will n ot b e p ai d f or p arti ci p ati o n i n t hi s st u d y.  
 
W e m a y u s e y o ur s a m pl e s a n d i nf or m ati o n t o d e v el o p a n e w pr o d u ct or m e di c al 
t e st t o b e s ol d.  T h e h o s pit al, G e n e nt e c h/ F. H off m a n n - L a R o c h e, Lt d., a n d 
r e s e ar c h er s m a y b e n efit if t hi s h a p p e n s. T h er e ar e n o pl a n s t o p a y y o u if y o ur 
s a m pl e s ar e u s e d f or t hi s p ur p o s e.  
 
J.  W H A T A R E T H E C O S T S ?  
 
T a ki n g p art i n t hi s r e s e ar c h st u d y mi g ht  l e a d t o a d d e d c o st s t o y o u or y o ur 
i n s ur a n c e c o m p a n y. 
 
Y o u will n ot b e c h ar g e d f or al e cti ni b a n d b e v a ci z u m a b.  
 
Y o u or y o ur i n s ur a n c e c o m p a n y will b e c h ar g e d f or p orti o n s of y o ur c ar e d uri n g 
t hi s r e s e ar c h st u d y t h at ar e c o n si d er e d st a n d ar d c ar e. Y o u m a y b e r e s p o n si bl e 
f or c o-p a y m e nt s a n d d e d u cti bl e s t h at  ar e t y pi c al f or y o ur i n s ur a n c e c o v er a g e.  
 
If y o u h a v e q u e sti o n s a b o ut y o ur i n s ur a n c e c o v er a g e, or t h e it e m s y o u mi g ht b e 
r e q uir e d t o p a y f or, pl e a s e c all fi n a n ci al s er vi c e s f or i nf or m ati o n.  T h e c o nt a ct 
i nf or m ati o n f or fi n a n ci al s er vi c e s  ar e :   
 
•  B et h I sr a el D e a c o n e s s M e di c al C e nt er: ( 6 1 7) 6 6 7 -5 6 6 1  
•  M a s s a c h u s ett s G e n er al H o s pit al: ( 6 1 7) 7 2 6 -2 1 9 1  
 
T h e N ati o n al C a n c er I n stit ut e pr o vi d e s a n  o nli n e r e s o ur c e t o h el p p e o pl e 
p arti ci p ati n g i n c a n c er cli ni c al tri al s u n d er st a n d w hi c h s er vi c e s  t h eir i n s ur a n c e 
c o m p a n y i s r e q uir e d b y l a w t o p a y.  T hi s c a n b e f o u n d at t h e w e b sit e b el o w or 
c a n b e pr o vi d e d b y t h e st u d y t e a m:  
 
w w w. c a n c er. g o v or 1 -8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7)  
 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 3  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
K.  W H A T H A P P E N S I F I A M I N J U R E D O R SI C K B E C A U S E I T O O K P A R T I N T HI S 
R E S E A R C H S T U D Y ?  
 
If y o u t hi n k y o u h a v e b e e n i nj ur e d a s a r e s ult of t a ki n g p art i n t hi s r e s e ar c h st u d y, 
t ell t h e p er s o n i n c h ar g e of t hi s r e s e ar c h st u d y a s s o o n a s p o s si bl e.  T h e 
r e s e ar c h d o ct or’ s n a m e a n d p h o n e n u m b er ar e li st e d i n t hi s c o n s e nt f or m. 
 
T h e tr e ati n g h o s pit al  will off er y o u t h e c ar e n e e d e d t o tr e at i nj uri e s dir e ctl y 
r e s ulti n g fr o m t a ki n g p art i n t hi s r e s e ar c h.  T h e tr e ati n g h o s pit al  m a y bill  y o ur 
i n s ur a n c e c o m p a n y or ot h er t hir d p arti e s, if a p pr o pri at e, f or t h e c o st s of t h e c ar e 
y o u g et f or t h e i nj ur y,  b ut y o u m a y al s o b e r e s p o n si bl e f or s o m e of t h e m.  
T h er e ar e n o pl a n s f or D a n a -F ar b er/ P art n er s C a n c er C ar e ( D F/ P C C) o n b e h alf of 
t h e D a n a-F ar b er/ H ar v ar d C a n c er C e nt er ( D F/ H C C)  t o p a y y o u or gi v e y o u ot h er 
c o m p e n s ati o n f or t h e i nj ur y. Y o u d o n ot gi v e u p y o ur  l e g al ri g ht s b y si g ni n g t hi s 
f or m. 
 
L.  W H A T A B O U T C O N FI D E N TI A LI T Y ?  
 
W e will t a k e m e a s ur e s t o pr ot e ct t h e pri v a c y a n d s e c urit y of all y o ur p er s o n al 
i nf or m ati o n, b ut w e c a n n ot g u ar a nt e e c o m pl et e c o nfi d e nti alit y of st u d y d at a.  
 
M e di c al i nf or m ati o n cr e at e d b y t hi s r e s e ar c h st u d y m a y b e c o m e p art of y o ur 
h o s pit al m e di c al r e c or d  a n d m a y b e f or w ar d e d t o y o ur pri m ar y d o ct or . 
I nf or m ati o n t h at d o e s n ot b e c o m e p art of y o ur m e di c al r e c or d will b e st or e d i n 
y o ur st u d y fil e . It m a y al s o b e c o m e p art of a D F/ H C C r e s e ar c h d ata b a s e.   
 
T h e r e s ult s of t hi s r e s e ar c h st u d y m a y b e p u bli s h e d. Y o u will n ot b e i d e ntifi e d i n 
p u bli c ati o n s wit h o ut y o ur p er mi s si o n.  
 
A d e s cri pti o n of t hi s cli ni c al tri al will b e a v ail a bl e o n htt p:// w w w. Cli ni c al T ri al s. g o v, 
a s r e q uir e d b y U. S. L a w.  T hi s W e b sit e will n ot i n cl u d e i nf or m ati o n t h at c a n 
i d e ntif y y o u.  At m o st, t h e W e b sit e will i n cl u d e a s u m m ar y of t h e r e s ult s.  Y o u 
c a n s e ar c h t hi s W e b sit e at a n y ti m e.  
 
M.  W H O M D O I C O N T A C T I F I H A V E Q U E S TI O N S A B O U T T H E R E S E A R C H S T U D Y ?  
 
If y o u h a v e q u e sti o n s a b o ut t h e st u d y, pl e a s e c o nt a ct t h e r e s e ar c h d o ct or or 
st u d y st aff a s li st e d b el o w:  
 
M a s s a c h u s ett s G e n er al H o s pit al ( M G H)  
J u sti n G ai n or, M D: 6 1 7 -7 2 4 -4 0 0 0  
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 4  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
 
B et h I sr a el D e a c o n e s s M e di c al C e nt er ( BI D M C)  
D a ni el C o st a, M D P h D: ( 6 1 7) 6 6 7-9 2 3 6  
 
2 4 h o ur C o nt a ct : C all Dr. G ai n or at 6 1 7-7 2 4 -4 0 0 0 a n d a s k t h e d o ct or t o b e 
p a g e d.  
 
F or q u e sti o n s a b o ut y o ur ri g ht s a s a r e s e ar c h p arti ci p a nt, pl e a s e c o nt a ct a 
r e pr e s e nt ati v e of t h e Offi c e f or H u m a n R e s e ar c h St u di e s at D F CI ( 6 1 7) 6 3 2 -
3 0 2 9. T hi s c a n i n cl u d e q u e sti o n s a b o ut y o ur p arti ci p ati o n i n t h e st u d y, c o n c er n s 
a b o ut t h e st u d y, a r e s e ar c h r el at e d i nj ur y, or if y o u f e el/f elt u n d er pr e s s ur e t o 
e nr oll i n t hi s r e s e ar c h st u d y or t o c o nti n u e t o p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 
N.  P RI V A C Y  O F P R O T E C T E D H E A L T H  I N F O R M A TI O N 
 
F e d er al l a w r e q uir e s D a n a -F ar b er/ H ar v ar d C a n c er C e nt er ( D F/ H C C) a n d it s 
affili at e d r e s e ar c h d o ct or s, h e alt h c ar e pr o vi d er s, a n d p h y si ci a n n et w or k t o 
pr ot e ct t h e pri v a c y of i nf or m ati o n t h at i d e ntifi e s y o u a n d r el at e s t o y o u r p a st, 
pr e s e nt, a n d f ut ur e p h y si c al a n d m e nt al h e alt h c o n diti o n s (“ pr ot e ct e d h e alt h 
i nf or m ati o n”).  If y o u e nr oll i n t hi s r e s e ar c h st u d y, y o ur “ pr ot e ct e d h e alt h 
i nf or m ati o n” will b e u s e d a n d s h ar e d wit h ot h er s a s e x pl ai n e d b el o w. 
 
1.  W h at pr ot e ct e d h e alt h i n f or m ati o n a b o ut m e will b e u s e d or s h ar e d wit h 
ot h er s d uri n g t hi s r e s e ar c h ?  
 
•  E xi sti n g m e di c al r e c or d s , i n cl u di n g m e nt al h e alt h r e c or d s. 
•  N e w h e alt h i nf or m ati o n cr e at e d fr o m st u d y -r el at e d t e st s, pr o c e d ur e s, 
vi sit s, a n d/ or q u e sti o n n air e s  
 
 
2.  W h y will pr ot e ct e d i nf or m ati o n a b o ut m e b e u s e d or s h ar e d wit h ot h er s ? 
 
T h e m ai n r e a s o n s i n cl u d e t h e f oll o wi n g:  
 
•  T o c o n d u ct a n d o v er s e e t h e r e s e ar c h d e s cri b e d e arli er i n t hi s f or m;  
•  T o e n s ur e t h e r e s e ar c h m e et s l e g al, i n stit uti o n al, a n d a c cr e dit ati o n 
r e q uir e m e nt s;  
•  T o c o n d u ct  p u bli c h e alt h a cti viti e s (i n cl u di n g r e p orti n g of a d v er s e e v e nt s 
or sit u ati o n s w h er e y o u or ot h er s m a y b e at ri s k of h ar m); a n d  
•  T o pr o vi d e t h e st u d y s p o n s or wit h i nf or m ati o n ari si n g fr o m a n a d v er s e 
e v e nt or ot h er e v e nt t h at r el at e s t o t h e s af et y or t o xi cit y of t h e dr u g f or t h e 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 5  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
p ur p o s e of t hi s or ot h er r e s e ar c h r el ati n g t h e st u d y dr u g a n d it s u s e i n 
c a n c er; a n d,  
•  Ot h er r e a s o n s m a y i n cl u d e f or tr e at m e nt, p a y m e nt, or h e alt h c ar e 
o p er ati o n s.  F or e x a m pl e, s o m e m e di c al i nf or m ati o n pr o d u c e d b y t hi s 
r e s e ar c h st u d y m a y b e c o m e p art of y o ur h o s pit al m e di c al r e c or d b e c a u s e 
t h e i nf or m ati o n m a y b e n e c e s s ar y f or y o ur m e di c al c ar e. ( Y o u will al s o b e 
gi v e n a n oti c e f or u s e a n d s h ari n g of pr ot e ct e d h e alt h i nf or m ati o n.)  
 
3.  W h o will u s e or s h ar e pr ot e ct e d h e alt h i nf or m ati o n a b o ut  m e ?  
 
•  D F/ H C C a n d it s affili at e d r e s e ar c h d o ct or s a n d e ntiti e s p arti ci p ati n g i n t h e 
r e s e ar c h will u s e a n d s h ar e y o ur pr ot e ct e d h e alt h i nf or m ati o n.  I n a d diti o n, 
ot h er D F/ H C C offi c e s t h at d e al wit h r e s e ar c h o v er si g ht, billi n g or q u alit y 
a s s ur a n c e will b e a bl e t o u s e a n d s h ar e y o ur pr ot e ct e d h e alt h i nf or m ati o n.  
 
4.  Wit h w h o m o ut si d e of D F/ H C C  m a y m y pr ot e ct e d h e alt h i nf or m ati o n b e 
s h ar e d ?  
 
W hil e all r e a s o n a bl e eff ort s will b e m a d e t o pr ot e ct t h e c o nfi d e nti alit y of y o ur 
pr ot e ct e d h e alt h i nf or m ati o n, it m a y al s o b e  s h ar e d wit h t h e f oll o wi n g e ntiti e s:  
 
•  O ut si d e i n di vi d u al s or e ntiti e s t h at h a v e a n e e d t o a c c e s s t hi s i nf or m ati o n 
t o p erf or m f u n cti o n s r el ati n g t o t h e c o n d u ct of t hi s r e s e ar c h s u c h a s 
a n al y si s b y o ut si d e l a b or at ori e s o n b e h alf of D F/ H C C a n d it s affili at e s (f or 
e x a m pl e, d at a st or a g e c o m p a ni e s, i n s ur er s, or l e g al a d vi s or s).  
•  T h e s u p p ort er s  of t h e st u d y, it s s u b c o ntr a ct or s, a n d it s a g e nt( s): 
G e n e nt e c h/ F. H off m a n n - L a R o c h e, Lt d.  
•  Ot h er r e s e ar c h d o ct or s a n d m e di c al c e nt er s p arti ci p ati n g i n t hi s r e s e ar c h, 
if a p plic a bl e  
•  F e d er al a n d st at e a g e n ci e s (f or e x a m pl e, t h e D e p art m e nt of H e alt h a n d 
H u m a n S er vi c e s, t h e F o o d a n d Dr u g A d mi ni str ati o n, t h e N ati o n al 
I n stit ut e s of H e alt h, a n d/ or t h e Offi c e f or H u m a n R e s e ar c h Pr ot e cti o n s), or 
ot h er d o m e sti c or f or ei g n g o v er n m e nt b o di e s if r e q uir e d b y l a w a n d/ or 
n e c e s s ar y f or o v er si g ht p ur p o s e s. A q u alifi e d r e pr e s e nt ati v e of t h e F D A 
a n d t h e N ati o n al C a n c er I n stit ut e m a y r e vi e w y o ur m e di c al r e c or d s.  
•  H o s pit al a c cr e diti n g a g e n ci e s  
•  A d at a s af et y m o nit ori n g b o ar d or g a ni z e d t o o v er s e e t hi s r e s e ar c h, if 
a p pli c a bl e  
 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 6  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
S o m e w h o m a y r e c ei v e y o ur pr ot e ct e d h e alt h i nf or m ati o n m a y n ot h a v e t o 
s ati sf y t h e pri v a c y r ul e s a n d r e q uir e m e nt s.  T h e y, i n f a ct, m a y s h ar e y o ur 
i nf or m ati o n wit h ot h er s wit h o ut y o ur p er mi s si o n.  
 
5.  F or h o w l o n g will pr ot e ct e d h e alt h i nf or m ati o n a b o ut m e b e u s e d or 
s h ar e d wit h ot h er s ?  
 
•  T h er e i s n o s c h e d ul e d d at e at w hi c h y o ur pr ot e ct e d h e alt h i nf or m ati o n t h at 
i s b ei n g u s e d or s h ar e d f or t hi s r e s e ar c h will b e d e str o y e d, b e c a u s e 
r e s e ar c h i s a n o n g oi n g pr o c e s s.   
 
6.  St at e m e nt of pri v a c y ri g ht s:  
 
•  Y o u h a v e t h e ri g ht t o wit h dr a w y o ur p er mi s si o n f or t h e r e s e ar c h d o ct or s 
a n d p arti ci p ati n g D F/ H C C e ntiti e s t o u s e or s h ar e y o ur pr ot e ct e d h e alt h 
i nf or m ati o n.  W e will n ot b e a bl e t o wit h dr a w all t h e i nf or m ati o n t h at 
alr e a d y h a s b e e n u s e d or s h ar e d wit h ot h er s t o c arr y o ut r el at e d a cti viti e s 
s u c h a s o v er si g ht, or t h at i s n e e d e d t o e n s ur e q u alit y of t h e st u d y. T o 
wit h dr a w y o ur p er mi s si o n, y o u m u st d o s o i n writi n g b y c o nt a cti n g t h e 
r e s e ar c h er li st e d a b o v e i n t h e s e cti o n: “ W h o m d o I c o nt a ct if I h a v e 
q u e s ti o n s a b o ut t h e r e s e ar c h st u d y ?” 
•  Y o u h a v e t h e ri g ht t o r e q u e st a c c e s s t o y o ur pr ot e ct e d h e alt h i nf or m ati o n 
t h at i s u s e d or s h ar e d d uri n g t hi s r e s e ar c h a n d t h at i s r el at e d t o y o ur 
tr e at m e nt or p a y m e nt f or y o ur tr e at m e nt, b ut y o u m a y a c c e s s t hi s 
i nf or m ati o n o nl y aft er t h e st u d y i s c o m pl et e d.  T o r e q u e st t hi s i nf or m ati o n, 
pl e a s e c o nt a ct t h e r e s e ar c h er li st e d a b o v e i n t h e s e cti o n: “ W h o m d o I 
c o nt a ct if I h a v e q u e sti o n s a b o ut t h e r e s e ar c h st u d y ?”  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 7  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
O.  O P TI O N A L R E S E A R C H S T U DI E S :  
 
O n e g o al of t hi s st u d y i s t o l e ar n m o r e a b o ut w h o m a y b e st r e s p o n d t o t h e st u d y 
dr u g s al e cti ni b a n d b e v a ci z u m a b . D uri n g t hi s st u d y, if f e a si bl e a n d if y o u 
c o n s e nt, fr e s h t u m or bi o p si e s will b e p erf or m e d d uri n g s cr e e ni n g a n d/ or aft er y o u 
st o p r e c ei vi n g t h e st u d y dr u g s . T h e s e s a m pl e s, al o n g with st or e d ti s s u e s a m pl e s, 
will b e u s e d t o l e ar n h o w c a n c er c ell s r e s p o n d t o al e cti ni b a n d b e v a ci z u m a b . T h e 
s a m pl e s will al s o b e u s e d t o s e q u e n c e t h e A L K g e n e a n d ot h er g e n e s t h o u g ht t o 
b e i m p ort a nt i n c a n c er. T hi s i nf or m ati o n m a y h el p u s u n d er st a n d w hi c h p a ti e nt s 
will r e s p o n d b e st t o al e cti ni b a n d b e v a ci z u m a b , a n d w h y ot h er A L K i n hi bit or s 
st o p w or ki n g. T h e r e s e ar c h t e st s p erf or m e d o n y o ur ti s s u e will n ot b e n efit y o u 
dir e ctl y, b ut c o ul d h el p ot h er p ati e nt s i n t h e f ut ur e.  
 
If y o u a gr e e, fr e s h t u m or bi o p si e s will b e d o n e at t h e s cr e e ni n g vi sit a n d/ or at t h e 
ti m e of di s e a s e pr o gr e s si o n, if y o ur st u d y d o ct or t hi n k s t h e bi o p si e s will b e 
f e a si bl e a n d s af e. T e st s d o n e o n t h e ti s s u e c oll e ct e d at t h e s e bi o p si e s will b e 
d o n e t o h el p u s l e ar n m or e a b o ut w h o m a y or m a y n ot r e s p o n d t o t h e st u d y 
dr u g s al e cti ni b a n d b e v a ci z u m a b . Y o u will h a v e a c h a n c e t o a gr e e or n ot a gr e e 
t o h a v e fr e s h bi o p si e s c oll e ct e d b el o w.  
 
Ri s k s a s s o ci at e d wit h bi o p si e s : 
Bi o p si e s ar e n or m all y p erf or m e d u n d er t h e g ui d a n c e of a n i m a gi n g t e c h ni q u e. 
E a c h  pr o c e d ur e r e q uir e s a s e p ar at e c o n s e nt pri or t o t h e bi o p s y. T h e ri s k s m a y 
i n cl u d e:  
•  P ai n a n d di s c o mf ort. T h e a m o u nt of p ai n a n d di s c o mf ort will v ar y, 
d e p e n di n g o n t h e l o c ati o n of t h e bi o p s y sit e. T h e s e ri s k s c a n b e di s c u s s e d 
wit h t h e st u d y d o ct or.  
•  Mi n or bl e e di n g at t h e bi o p s y sit e.  
•  T e n d er n e s s at t h e bi o p s y sit e.  
•  S c arri n g at t h e bi o p s y sit e.  
•  R ar el y, a n i nf e cti o n at t h e bi o p s y sit e.  
 
A d diti o n al ri s k s of a l u n g bi o p s y m a y i n cl u d e:  
•  C oll a p s e of y o ur l u n g d uri n g or f oll o wi n g t h e bi o p s y.  
•  S e v er e bl e e di n g.  
•  I nf e cti o n s u c h a s p n e u m o ni a. U s u all y t hi s t y p e of i nf e cti o n c a n b e tr e at e d 
wit h a nti bi oti c s.  
•  S p a s m s of t h e br e at hi n g ( br o n c hi al) t u b e s, w hi c h c a n c a u s e br e at hi n g 
diffi c ulti e s ri g ht aft er t h e bi o p s y.  
•  Irr e g ul ar h e art b e at (r h yt h m). 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 8  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
U n c o m m o nl y, c o m pli c ati o n s fr o m bi o p si e s c a n b e lif e -t hr e at e ni n g. A s wit h a n y 
i nt er v e nti o n al pr o c e d ur e, ot h er p ot e nti all y s eri o u s c o m pli c ati o n s fr o m bl e e di n g or 
or g a n d a m a g e m a y o c c ur. T h e s e mi g ht r e q uir e a d diti o n al s ur gi c al i nt er v e nti o n.  
 
P er mi s si o n f or bi o p s y t o c oll e ct fr e s h t u m or ti s s u e d uri n g t hi s st u d y  
Pl e a s e i n di c at e w h et h er or n ot y o ur wi s h t o u n d er g o a bi o p s y or bi o p si e s t o 
pr o vi d e a d diti o n al t u m or ti s s u e f or r e s e ar c h t e st s b y c h o o si n g o n e of t h e o pti o n s 
b el o w a n d writi n g y o ur i niti al s i n t h e s p a c e pr o vi d e d.  
 
 Y e s       
 
 
 
 
 I niti als                       D at e  
 N o        
 
 
 
 
 I niti al s                       D at e  
 
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 1 9  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
P.  D O C U M E N T A TI O N O F C O N S E N T  
 
M y si g n at ur e b el o w i n di c at e s : 
•  I h a v e h a d e n o u g h ti m e t o r e a d t h e c o n s e nt a n d t hi n k a b o ut 
p arti ci p ati n g i n t hi s st u d y;  
•  I h a v e h a d all of m y q u e sti on s a n s w er e d t o m y s ati sf a cti o n;  
•  I a m willi n g t o p arti ci p at e i n t hi s st u d y; 
•  I h a v e b e e n t ol d t h at my p arti ci p ati o n i s v ol u nt ar y a n d I c a n wit h dr a w at 
a n y ti m e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g n at ur e of P arti ci p a nt  
 
 
 
D at e  
or L e g all y A ut h ori z e d R e pr e s e nt ati v e   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R el ati o n s hi p of L e g all y A ut h ori z e d R e pr e s e nt ati v e t o P arti ci p a nt   
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Rese arc h C o nse nt F o r m  
f or Bi o me dic al Rese a rc h 
Da na -Far ber/ Har var d Ca ncer Ce nter  
BI D M C/ B C H/ B W H/ D F CI/ M G H/ P art ners Net w or k Affiliat es   
O H R S 1 0. 0 3. 1 4  
 
P a ge 2 0  of 2 0  
 
D F CI Pr ot oc ol N u m ber:  
       1 5 -0 5 5  
A p pr o ve d Date ( D F CI I R B A p pr o val):                  0 3/ 2 6/ 2 0 1 9  
Date P oste d f or Use:  
0 3/ 2 8/ 2 0 1 9  
  
 
A d ult P arti ci p a nt s  
 
T o b e c o m pl et e d b y p er s o n o bt ai ni n g c o n s e nt:  
 
T h e c o n s e nt di s c u s si o n w a s i niti at e d o n   
 ( d at e). 
 
Si g n at ur e of i n di vi d u al o bt ai ni n g c o n s e nt:  
 
 
Pri nt e d n a m e of a b o v e :   
 
 
D at e:  
 
 
 A c o p y of t hi s si g n e d c o n s e nt f or m will b e gi v e n t o t h e p arti ci p a nt  or l e g all y a ut h ori z e d 
r e pr e s e nt ati v e, or, w h er e t h e p arti ci p a nt  i s a mi n or, t h e p arti ci p a nt ’ s p ar e nt or l e g al g u ar di a n. 
F or A d ult P arti ci p a nt s  
 1)  T h e p arti ci p a nt i s a n a d ult a n d pr o vi d e d c o n s e nt t o p arti ci p at e.  
 
 1 a)  P arti ci p a nt ( or l e g all y a ut h ori z e d r e pr e s e nt ati v e) i s a n o n -E n gli s h s p e a k er a n d  
 
si g n e d t h e tr a n sl at e d S h ort F or m i n li e u of E n gli s h c o n s e nt d o c u m e nt:  
 
A s s o m e o n e w h o u n d er st a n d s b ot h E n gli s h a n d t h e l a n g u a g e s p o k e n b y t h e p arti ci p a nt, I 
i nt er pr et e d a n d/ or wit n e s s e d, i n t h e p arti ci p a nt’ s l a n g u a g e, t h e r e s e ar c h er’ s pr e s e nt ati o n 
of t h e E n gli s h c o n s e nt f or m.  T h e p arti ci p a nt w a s gi v e n t h e o p p ort u nit y t o a s k q u e st i o n s.  
Si g n at ur e of I nt er pr et er / Wit n e s s:  
 
Pri nt e d N a m e of I nt er pr et er / Wit n e s s:  
 
D at e:  
 
 
 1 b)  P arti ci p a nt i s illit er at e  
 
T h e c o n s e nt f or m w a s r e a d t o t h e p arti ci p a nt w h o w a s gi v e n t h e  o p p ort u nit y  
 
t o a s k q u e sti o n s.  
Si g n at ur e of Wit n e s s:  
 
Pri nt e d N a m e of Wit n e s s:  
 
D at e:  
 
 2)  T h e p arti ci p a nt  i s a n a d ult w h o l a c k s c a p a cit y t o pr o vi d e c o n s e nt a n d hi s/ h er l e g all y 
a ut h ori z e d r e pr e s e nt ati v e:  
 2 a) g a v e p er mi s si o n f or t h e a d ult p arti ci p a nt  t o p arti ci p at e  
 2 b) di d n ot gi v e p er mi s si o n f or t h e a d ult p arti ci p a nt  t o p arti ci p at e  
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